MicroRNAs Targeting Critical Molecular Pathways in Diabetic Cardiomyopathy Emerging Valuable for Therapy.

MicroRNAs have emerged as an important regulator of post-transcriptional gene expression studied extensively in many cancers, fetal development, and cardiovascular diseases. Their endogenous nature and easy manipulation have made them potential diagnostic and therapeutic molecules. Diseases with complex pathophysiology such as Diabetic Cardiomyopathy display symptoms at a late stage when the risk of heart failure has become very high. Therefore, the utilization of microRNAs as a tool to study pathophysiology and device-sustainable treatments for DCM could be considered. The present review focuses on the mechanistic insights of diabetic cardiomyopathy and the potential role of microRNAs.

Identification and expression analysis of conserved microRNAs during short and prolonged chromium stress in rice (Oryza sativa).

MicroRNAs (miRNAs) are one of the most critical epigenetic regulators of gene expression which modulate a spectrum of development and defence response processes in plants. Chromium (Cr) contamination in rice imposes a serious concern to human health as rice is used as staple food throughout the world. Although several studies have established the differential response of miRNAs in rice during heavy metal (arsenic, cadmium) and heat or cold stress, no report is available about the response of miRNAs during Cr stress. In the present study, we identified 512 and 568 known miRNAs from Cr treated and untreated samples, respectively. Expression analysis revealed that 13 conserved miRNAs (miR156, miR159, miR160, miR166, miR169, miR171, miR396, miR397, miR408, miR444, miR1883, miR2877, miR5072) depicted preferential up- or down-regulation (> 4-fold change; P value < 0.05). Target gene prediction of differentially expressed miRNAs and their functional annotation suggested the important role of miRNAs in defence and detoxification of Cr though ATP-binding cassette transporters (ABC transporters), transcription factors, heat shock proteins, auxin response, and metal ion transport. Real-time PCR analysis validated the differential expression of selected miRNAs and their putative target genes. In conclusion, our study identifies and predicts miRNA-mediated regulation of signalling pathway in rice during Cr stress.

Differential expression of novel MicroRNAs from developing fetal heart of Gallus gallus domesticus implies a role in cardiac development.

Heart development is a complex process regulated by multi-layered genetic as well epigenetic regulators many of which are still unknown. Besides their critical role during cardiac development, these molecular regulators emerge as key modulators of cardiovascular pathologies, where fetal cardiac genes' re-expression is witnessed. MicroRNAs have recently emerged as a crucial part of signalling cascade in both development and diseases. We aimed to identify, validate, and perform functional annotation of putative novel miRNAs using chicken as a cardiac development model system. Novel miRNAs were obtained through deep sequencing of small RNAs extracted from chicken embryonic cardiac tissue of different developmental stages. After filtering out real pre-miRNAs, their expression analysis, potential target gene's prediction and functional annotations were performed. Expression analysis revealed that miRNAs were differentially expressed during different developmental stages of chicken heart. The expression of selected putative novel miRNAs was further validated by real-time PCR. Our analysis indicated the presence of novel cardiac miRNAs that might be regulating critical cardiac development events such as cardiac cell growth, differentiation, cardiac action potential generation and signal transduction.

Functional annotation of differentially expressed fetal cardiac microRNA targets: implication for microRNA-based cardiovascular therapeutics.

Gene expression pattern of a failing heart depicts remarkable similarity with developing fetal heart. Elucidating genetic as well as epigenetic mechanisms regulating the gene expression during cardiac development will improve our understanding of cardiovascular diseases. In the present study, we aimed to validate and characterize differentially expressed known microRNAs (miRNA) obtained from next generation sequencing data of two fetal cardiac developmental stages (days 4th and 14th) from chicken (G. gallus domesticus) using bioinformatic approaches. Potential mRNA targets of individual miRNA were identified and classified according to their biological, cellular, and molecular functions. Functional annotation of putative target genes was performed to predict their association with cardiovascular diseases. We identified a total of 19 differentially expressed miRNAs between 4th and 14th day sample from the data sets obtained by next generation sequencing. A total of nearly 1522 potential targets ranging from 15 to 270 for each miRNA were predicted out of which 1221 were unique, while 301 were overlapping. Gene ontology and KEGG analysis revealed that majority of these target genes regulate critical cellular and molecular processes including transcriptional regulation, protein transport, signal transduction, matrix remodeling, Ras signaling, MAPK signaling, and TGF-beta signaling pathways indicating the complex nature of microRNA-mediated gene regulation during cardiogenesis. We found a significant association between potential target genes and cardiovascular diseases validating a link between fetal cardiac miRNAs and regulation of cardiovascular disease-related genes. These important findings may lay a foundation for further understanding the regulatory mechanisms operative in gene re-programming in the failing heart.

MicroRNA-mediated MMP Regulation: Current Diagnostic and Therapeutic Strategies for Metabolic Syndrome.

INTRODUCTION: Metabolic Syndrome (MS) is a global socioeconomic problem rapidly progressing in accordance with increasing Body Mass Index (BMI) and age. It is a consortium of risk factors, such as dyslipidaemia, insulin resistance, leptin resistance, reduced adiponectin, glucose intolerance, hyperglycemia, and hypertension. Collectively, these factors accelerate the onset of type 2 diabetes mellitus, cardiovascular disease, stroke, and certain cancers such as breast, liver pancreatic, and colon cancer. Extracellular Matrix (ECM) and basement membrane remodeling play a central role during pathogenesis of MS as they regulate diverse cell functions including proliferation, differentiation, and migration. Therefore, regulation of proteins that remodel the ECM offers promising therapeutic opportunities for most of the MS. Matrix Metalloproteinases (MMPs), a family of zinc dependent endopeptidases, are the main enzymes involved in ECM remodeling. Emerging studies have reported altered levels of MMPs and the Tissue Inhibitors of Metalloproteinases (TIMPs) during MS. A number of pharmaceutical MMP inhibitors are being developed, but they have yet to be recognized for clinical applications. CONCLUSION: Recently, microRNAs (~21-23-nucleotide, small non-coding, endogenous, single-stranded RNAs) have emerged as a class of promising entities for therapeutic intervention due to their ability to manipulate gene expression. The combined strategy of targeting ECM remodeling through regulation of MMPs by small non-coding RNA has produced encouraging results in pre-clinical studies for cancer and cardiovascular diseases. This review serves to provide insight into the role of microRNAs as modulators of MS and their potential as therapeutics tool through direct and indirect interactions with the MMPs.

Synthesis and Characterization of Sygyzium cumini Nanoparticles for Its Protective Potential in High Glucose-Induced Cardiac Stress: a Green Approach.

There exists a complex and multifactorial relationship between diabetes and cardiovascular disease. Hyperglycemia is an important factor imposing damage (glucose toxicity) on cardiac cell leading to diabetic cardiomyopathy. There are substantial clinical evidences on the adverse effects of conventional therapies in the prevention/treatment of diabetic cardiovascular complications. Currently, green-synthesized nanoparticles have emerged as a safe, efficient, and inexpensive alternative for therapeutic uses. The present study discloses the silver nanoparticle biosynthesizing capability and cardioprotective potential of Syzygium cumini seeds already reported to have antidiabetic properties. Newly generated silver nanoparticles S. cumini MSE silver nanoparticles (SmSNPs) were characterized by UV-visible spectroscopy, scanning electron microscopy (SEM), zeta sizer, X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. Using methanolic extract of S. cumini seeds, an average size of 40-100-nm nanoparticles with 43.02 nm and -19.6 mV zeta potential were synthesized. The crystalline nature of SmSNPs was identified by using XRD. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays revealed the antioxidative potential to be 66.87 (±0.7) % and 86.07 (±0.92) % compared to 60.29 (±0.02) % and 85.67 (±1.27) % for S. cumini MSE. In vitro study on glucose-stressed H9C2 cardiac cells showed restoration in cell size, nuclear morphology, and lipid peroxide formation upon treatment of SmSNPs. Our findings concluded that S. cumini MSE SmSNPs significantly suppress the glucose-induced cardiac stress in vitro by maintaining the cellular integrity and reducing the oxidative damages therefore establishing its therapeutic potential in diabetic cardiomyopathy.