Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-β/SMADs and Wnt/β-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts. 

https://www.nature.com/articles/s41392-022-00925-z.pdf

Signaling pathways and targeted therapy for myocardial infarction

MicroRNAs (miRNAs) are a novel class of small, non-coding, single-stranded RNAs that negatively regulate gene expression via translational inhibition or mRNA degradation followed by protein synthesis repression Many miRNAs are expressed in a tissue- and/or cell-specific manner and their expression patterns are reflective of underlying patho-physiologic processes miRNAs can be detected in serum or in plasma in a remarkably stable form, making them attractive biomarkers for human diseases This review describes the progress of identifying circulating miRNAs as novel biomarkers for diverse cardiovascular diseases, including acute myocardial infarction, heart failure, coronary artery disease, diabetes, stroke, essential hypertension, and acute pulmonary embolism In addition, the origin and function and the different strategies to identify circulating miRNAs as novel biomarkers for cardiovascular diseases are also discussed Rarely has an opportunity arisen to advance such new biology for the diagnosis of cardiac diseases

Circulating microRNAs: novel biomarkers for cardiovascular diseases

Reactive oxygen species (ROS) are important molecules in the living organisms as a part of many signaling pathways. However, if overproduced, they also play a significant role in the development of cardiovascular diseases, such as arrhythmia, cardiomyopathy, ischemia/reperfusion injury (e.g., myocardial infarction and heart transplantation), and heart failure. As a result of oxidative stress action, apoptosis, hypertrophy, and fibrosis may occur. MicroRNAs (miRNAs) represent important endogenous nucleotides that regulate many biological processes, including those involved in heart damage caused by oxidative stress. Oxidative stress can alter the expression level of many miRNAs. These changes in miRNA expression occur mainly via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, calcineurin/nuclear factor of activated T cell (NFAT), or nuclear factor kappa B (NF-κB) pathways. Up until now, several circulating miRNAs have been reported to be potential biomarkers of ROS-related cardiac diseases, including myocardial infarction, hypertrophy, ischemia/reperfusion, and heart failure, such as miRNA-499, miRNA-199, miRNA-21, miRNA-144, miRNA-208a, miRNA-34a, etc. On the other hand, a lot of studies are aimed at using miRNAs for therapeutic purposes. This review points to the need for studying the role of redox-sensitive miRNAs, to identify more effective biomarkers and develop better therapeutic targets for oxidative-stress-related heart diseases.

https://www.mdpi.com/1422-0067/21/1/358/pdf

Oxidative Stress-Responsive MicroRNAs in Heart Injury.

Small non-coding microRNAs (miRNAs) are implicated in gene regulation, including those involved in coronary artery disease (CAD). Our aim was to identify whether specific serum miRNAs present in the circulating lipoproteins (Lp) are associated with stable or vulnerable CAD patients. A cardiovascular disease-focused screening array was used to assess miRNAs distribution in sera collected from 95 CAD patients: 30 with stable angina (SA), 39 with unstable angina (UA), 26 at one month after myocardial infarction (MI) and 16 healthy control subjects. We found that miR-486, miR-92a and miR-122 presented the highest expression in CAD sera. These miRNA together with miR-125a, miR-146a and miR-33a were further individually analyzed by TaqMan assays. The results were consistent with PCR-array screening data that all of these miRNAs were significantly increased in CAD patients compared to controls. Using a binary logistic regression model, we established that miR-486 and miR-92a in association with some high-density lipoprotein (HDL) components can designate vulnerable CAD patients. Further, all classes of Lp were isolated from sera by density gradient ultracentrifugation. Analysis of the selected miRNAs in each Lp class showed that they were associated mainly with HDL, miR-486 and miR-92a having the highest levels. In UA and MI patients, miR-486 prevailed in HDL2, while miR-92a prevailed in HDL3, and their levels discriminate between stable and vulnerable CAD patients. We identified two circulating miRNAs that in association with some lipid metabolism biomarkers can be used as an additional tool to designate vulnerable CAD patients.

/pdf/mir-486-and-mir-92a-identified-in-circulating-hdl-3jk8say2ym.pdf

MiR-486 and miR-92a Identified in Circulating HDL Discriminate between Stable and Vulnerable Coronary Artery Disease Patients

Abstract Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments. 

/pdf/signaling-pathways-and-therapeutic-interventions-in-gastric-1780pl43.pdf

Signaling pathways and therapeutic interventions in gastric cancer

The upregulation of Th1 cells has been suggested to have an essential function in the development of atherosclerosis (AS) Recent studies indicate that miR-146a is a microRNA specifically and highly expressed in Th1-driven autoimmune disease The aim of the study was to investigate the possible mechanisms of the miR-146a in the onset of acute coronary syndrome (ACS) The results showed that the expression of miR-146a in peripheral blood mononuclear cells (PBMCs) was significantly increased in patients with ACS We showed that overexpression of miR-146a in PBMCs could significantly upregulate the function of Th1 cells Furthermore, we showed that miR-146a treatment could modulate the Th1 differentiation through posttranscriptional enhancing the T-bet pathway in PBMCs In addition, this study also provided evidence that miR-146a treatment in vitro could induce the protein expression of TNF-alpha, MCP-1, NF-kappaB p65, which are key pro-inflammatory cytokines and critical transcription factor in AS In contrast, miR-146a inhibitor could attenuate these phenomena significantly The results support the concept that miR-146a may be a novel regulatory factor in Th1 differentiation and a new therapeutic target for AS and ACS

miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome.

Background
The crucial role of T helper (Th) cells and chronic inflammation in atherosclerosis and coronary artery disease is no longer controversial. Evidence has revealed that Th cell type 1 (Th1) is closely associated with the pathogenesis of acute coronary syndrome (ACS). But the mechanisms involved in the generation of Th1 cells have not been fully elucidated. IFN regulatory factor (IRF)-1 is a pleiotropic transcription factor involved in innate immunity and chronic inflammation disease. The study was undertaken to investigate the potential effect of IRF-1 on the Th1 cell function in patients with ACS in vitro.

Inhibition of IFN Regulatory Factor-1 Down-Regulate Th1 Cell Function in Patients with Acute Coronary Syndrome

Regulatory mechanisms for acute inflammatory responses post myocardial infarction (MI) have yet to be fully understood. In particular, the mechanisms by which cardiac macrophages modulate MI-induced myocardial inflammation remains unclear. In this study, using a mouse MI model, we showed that β-catenin-mediated signaling was activated in cardiac macrophages post-MI, especially in Ly-6C-positive proinflammatory macrophages. Using a RAW264.7-based β-catenin reporter cell line, we confirmed the presence of active β-catenin and its downstream signaling in cardiac macrophages after MI. Moreover, lentivirus-mediated inducible expression of constitutively active β-catenin revealed that β-catenin plays a role in promoting the inflammatory response by RAW264.7 cells. Depletion of endogenous macrophages and adoptive transfer of active β-catenin-expressing RAW264.7 cells resulted in enhancement of acute myocardial inflammation in recipient mice after MI, as demonstrated by elevated levels of lymphocyte infiltrates and increased expression of proinflammatory cytokines. However, infarct volume, myocardial tissue repair, and left ventricle function were not influenced by the expression of active β-catenin in the adoptive transfer assay. Our research has demonstrated that β-catenin-mediated signaling is important for cardiac macrophages to modulate post-MI inflammatory responses. These findings may be valuable for developing novel therapeutic strategies for MI.

Beta-catenin promotes macrophage-mediated acute inflammatory response after myocardial infarction.

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miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome.

Inhibition of IFN Regulatory Factor-1 Down-Regulate Th1 Cell Function in Patients with Acute Coronary Syndrome

Beta-catenin promotes macrophage-mediated acute inflammatory response after myocardial infarction.