scaRNA20 promotes pseudouridylatory modification of small nuclear snRNA U12 and improves cardiomyogenesis.

Non-coding RNAs, particularly small Cajal-body associated RNAs (scaRNAs), play a significant role in spliceosomal RNA modifications. While their involvement in ischemic myocardium regeneration is known, their role in cardiac development is unexplored. We investigated scaRNA20's role in iPSC differentiation into cardiomyocytes (iCMCs) via overexpression and knockdown assays. We measured scaRNA20-OE-iCMCs and scaRNA20-KD-iCMCs contractility using Particle Image Velocimetry (PIV), comparing them to control iCMCs. We explored scaRNA20's impact on alternative splicing via pseudouridylation (Ψ) of snRNA U12, analyzing its functional consequences in cardiac differentiation. scaRNA20-OE-iPSC differentiation increased beating colonies, upregulated cardiac-specific genes, activated TP53 and STAT3, and preserved contractility under hypoxia. Conversely, scaRNA20-KD-iCMCs exhibited poor differentiation and contractility. STAT3 inhibition in scaRNA20-OE-iPSCs hindered cardiac differentiation. RNA immunoprecipitation revealed increased Ψ at the 28th uridine of U12 RNA in scaRNA20-OE iCMCs. U12-KD iCMCs had reduced cardiac differentiation, which improved upon U12 RNA introduction. In summary, scaRNA20-OE in iPSCs enhances cardiomyogenesis, preserves iCMC function under hypoxia, and may have implications for ischemic myocardium regeneration.

Hutchinson-Gilford progeria patient-derived cardiomyocyte model of carrying LMNA gene variant c.1824 C > T.

Cardiovascular diseases, atherosclerosis, and strokes are the most common causes of death in patients with Hutchinson-Gilford progeria syndrome (HGPS). The LMNA variant c.1824C > T accounts for ~ 90% of HGPS cases. The detailed molecular mechanisms of Lamin A in the heart remain elusive due to the lack of appropriate in vitro models. We hypothesize that HGPS patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMCs) will provide a model platform to study the cardio-pathologic mechanisms associated with HGPS. To elucidate the effects of progerin in cardiomyocytes, we first obtained skin fibroblasts (SFs) from a de-identified HGPS patient (hPGP1, proband) and both parents from the Progeria Research Foundation. Through Sanger sequencing and restriction fragment length polymorphism, with the enzyme EciI, targeting Lamin A, we characterized hPGP1-SFs as heterozygous mutants for the LMNA variant c.1824 C > T. Additionally, we performed LMNA exon 11 bisulfite sequencing to analyze the methylation status of the progeria cells. Furthermore, we reprogrammed the three SFs into iPSCs and differentiated them into iCMCs, which gained a beating on day 7. Through particle image velocimetry analysis, we found that hPGP1-iCMCs had an irregular contractile function and decreased cardiac-specific gene and protein expressions by qRT-PCR and Western blot. Our progeria-patient-derived iCMCs were found to be functionally and structurally defective when compared to normal iCMCs. This in vitro model will help in elucidating the role of Lamin A in cardiac diseases and the cardio-pathologic mechanisms associated with progeria. It provides a new platform for researchers to study novel treatment approaches for progeria-associated cardiac diseases.

RNA binding proteins in cancer chemotherapeutic drug resistance.

Drug resistance has been a major obstacle in the quest for a cancer cure. Many chemotherapeutic treatments fail to overcome chemoresistance, resulting in tumor remission. The exact process that leads to drug resistance in many cancers has not been fully explored or understood. However, the discovery of RNA binding proteins (RBPs) has provided insight into various pathways and post-transcriptional gene modifications involved in drug tolerance. RBPs are evolutionarily conserved proteins, and their abnormal gene expression has been associated with cancer progression. Additionally, RBPs are aberrantly expressed in numerous neoplasms. RBPs have also been implicated in maintaining cancer stemness, epithelial-to-mesenchymal transition, and other processes. In this review, we aim to provide an overview of RBP-mediated mechanisms of drug resistance and their implications in cancer malignancy. We discuss in detail the role of major RBPs and their correlation with noncoding RNAs (ncRNAs) that are associated with the inhibition of chemosensitivity. Understanding and exploring the pathways of RBP-mediated chemoresistance will contribute to the development of improved cancer diagnosis and treatment strategies.

Pathological implications of cellular stress in cardiovascular diseases.

Cellular stress has been a key factor in the development of cardiovascular diseases. Major types of cellular stress such as mitochondrial stress, endoplasmic reticulum stress, hypoxia, and replicative stress have been implicated in clinical complications of cardiac patients. The heart is the central regulator of the body by supplying oxygenated blood throughout the system. Impairment of cellular function could lead to heart failure, myocardial infarction, ischemia, and even stroke. Understanding the effect of these distinct types of cellular stress on cardiac function is crucial for the scientific community to understand and develop novel therapeutic approaches. This review will comprehensively explain the different mechanisms of cellular stress and the most recent findings related to stress-induced cardiac dysfunction.

Modern approaches on stem cells and scaffolding technology for osteogenic differentiation and regeneration.

The process of bone repair has always been a natural mystery. Although bones do repair themselves, supplemental treatment is required for the initiation of the self-regeneration process. Predominantly, surgical procedures are employed for bone regeneration. Recently, cell-based therapy for bone regeneration has proven to be more effective than traditional methods, as it eliminates the immune risk and painful surgeries. In clinical trials, various stem cells, especially mesenchymal stem cells, have shown to be more efficient for the treatment of several bone-related diseases, such as non-union fracture, osteogenesis imperfecta, osteosarcoma, and osteoporosis. Furthermore, the stem cells grown in a suitable three-dimensional scaffold support were found to be more efficient for osteogenesis. It has been shown that the three-dimensional bioscaffolds support and simulate an in vivo environment, which helps in differentiation of stem cells into bone cells. Bone regeneration in patients with bone disorders can be improved through modification of stem cells with several osteogenic factors or using stem cells as carriers for osteogenic factors. In this review, we focused on the various types of stem cells and scaffolds that are being used for bone regeneration. In addition, the molecular mechanisms of various transcription factors, signaling pathways that support bone regeneration and the senescence of the stem cells, which limits bone regeneration, have been discussed.