Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease development and regression. Targeting epigenetic key enzymes, especially the DNA methyltransferases, histone methyltransferases, histone acetylases, histone deacetylases and their regulated target genes, could represent an attractive new route for the diagnosis and treatment of cardiovascular diseases. Herein, we summarize the knowledge on epigenetic history and essential regulatory mechanisms in cardiovascular diseases. Furthermore, we discuss the preclinical studies and drugs that are targeted these epigenetic key enzymes for cardiovascular diseases therapy. Finally, we conclude the clinical trials that are going to target some of these processes. 

/pdf/epigenetic-regulation-in-cardiovascular-disease-mechanisms-18lq0r10.pdf

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient‐derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation‐dependent manner. Mechanistic studies identify that AML cell‐derived exosomes play a vital role during the AML cell‐mediated MSCs education/reprogramming process. Pre‐administration of mice BM microenvironment with AML‐derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML‐derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome‐based AML cells‐MSCs communication. Collectively, the data show that AML‐educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202105811

Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities

Gastric cancer is one of the most common malignant tumours worldwide. Genetic and epigenetic alterations are key factors in gastric carcinogenesis and drug resistance to chemotherapy. Competing endogenous RNA (ceRNA) regulation models have defined circRNA/lncRNA as miRNA sponges that indirectly regulate miRNA downstream target genes. The ceRNA regulatory network is related to the malignant biological behaviour of gastric cancer. The circRNA/lncRNA-miRNA-mRNA axis may be a marker for the early diagnosis and prognosis of gastric cancer and a potential therapeutic target for gastric cancer. Exosomal ncRNAs play an important role in gastric cancer and are expected to be ideal biomarkers for the diagnosis, prognosis, and treatment of gastric cancer. This review summarizes the specific ceRNA regulatory network (circRNA/lncRNA-miRNA-mRNA) discovered in gastric cancer in recent years, which may provide new ideas or strategies for early clinical diagnosis, further development, and application. 

Research progress on the circRNA/lncRNA-miRNA-mRNA axis in gastric cancer.

Human diseases have been a critical threat from the beginning of human history. Knowing the origin, course of action and treatment of any disease state is essential. A microscopic approach to the molecular field is a more coherent and accurate way to explore the mechanism, progression, and therapy with the introduction and evolution of technology than a macroscopic approach. Non-coding RNAs (ncRNAs) play increasingly important roles in detecting, developing, and treating all abnormalities related to physiology, pathology, genetics, epigenetics, cancer, and developmental diseases. Noncoding RNAs are becoming increasingly crucial as powerful, multipurpose regulators of all biological processes. Parallel to this, a rising amount of scientific information has revealed links between abnormal noncoding RNA expression and human disorders. Numerous non-coding transcripts with unknown functions have been found in addition to advancements in RNA-sequencing methods. Non-coding linear RNAs come in a variety of forms, including circular RNAs with a continuous closed loop (circRNA), long non-coding RNAs (lncRNA), and microRNAs (miRNA). This comprises specific information on their biogenesis, mode of action, physiological function, and significance concerning disease (such as cancer or cardiovascular diseases and others). This study review focuses on non-coding RNA as specific biomarkers and novel therapeutic targets. 

/pdf/non-coding-rnas-in-human-health-and-disease-potential-h4w0c7n4.pdf

Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets

Electrochemical nano biosensors for the detection of extracellular vesicles exosomes: From the benchtop to everywhere?

Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases.

Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA-ES3 is associated with the high glucose-induced calcification/senescence of human aortic vascular smooth muscle cells (HA-VSMCs). However, the mechanism of lncRNA-ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix-loop-helix family member e40 (Bhlhe40) was decreased significantly in HA-VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA-VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence-associated β-galactosidase-positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA-ES3 in HA-VSMCs by binding to the promoter region of the lncRNA-ES3 gene (LINC00458). Upregulation or inhibition of lncRNA-ES3 expression significantly promoted or reduced calcification/senescence of HA-VSMCs, respectively. Additionally, we identified that lncRNA-ES3 functions in this process by suppressing the expression of miR-95-5p, miR-6776-5p, miR-3620-5p, and miR-4747-5p. The results demonstrate that lncRNA-ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA-ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.

LncRNA‐ES3 inhibition by Bhlhe40 is involved in high glucose–induced calcification/senescence of vascular smooth muscle cells

Vascular calcification/aging is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular diseases. The calcification/senescence of vascular smooth muscle cells (VSMCs) induced by hyperglycemia can cause diabetic vascular calcification/aging. However, the mechanism of VSMCs calcification/senescence involved in diabetic vascular calcification/aging remains unknown. The purpose of this study was to determine how the high glucose (HG) information in circulating blood is transmitted from vascular endothelial cells (ECs) to VSMCs, which are not contacted with blood directly. Exosomes have attracted much attention for their vital roles in regulating cell-to-cell communication. In this study, we found that milk fat globule epidermal growth factor 8 (MFGE8) was enriched in high glucose induced human umbilical vein endothelial cell exosomes (HG-HUVEC-Exo) and regulate VSMCs calcification/senescence, characterized by up-regulated expressions of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as the increased mineralized nodules and senescence-associated {beta}-galactosidase (SA-{beta}-gal) positive cells. Upstream mechanism studies showed that sirtuin1 (SIRT1) was involved in VSMCs calcification/senescence by affecting the expression of MFGE8. We also found that inflammatory response mediated by IL-1{beta}, IL-6, and IL-8 was closely associated with MFGE8 and played a key role in regulating HG-HUVEC-Exo-induced VSMCs calcification/senescence. These findings provide a new insight into the mechanism of exosomal MFGE8 as a potential preventive and therapeutic target for the intervention of diabetic vascular calcification/aging.

/pdf/exosomal-mfge8-from-high-glucose-induced-endothelial-cells-4jn6kcpauw.pdf

Qun-Yan Xiang

Papers

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases.

LncRNA‐ES3 inhibition by Bhlhe40 is involved in high glucose–induced calcification/senescence of vascular smooth muscle cells

Exosomal MFGE8 from high glucose induced endothelial cells is involved in calcification/senescence of vascular smooth muscle cells