Identification of PPREs and PPRE associated genes in the human genome: insights into related kinases and disease implications.

Introduction: "Peroxisome Proliferator-Activated Receptors" (PPARs) belong to the class of transcription factors (TF) identified as Nuclear Receptors (NR). Upon activation by peroxisome proliferators (PPs), PPARs modulate a diverse range of genes, consequently regulating intra-cellular lipid metabolism, glucose uptake, apoptosis, and cell proliferation. Subsequent to the heterodimerization of Retinoid X Receptors (RXR) with PPARs induced by the binding of activators to PPARs, facilitates the binding of the resulting complex to Peroxisome Proliferator-Activated Receptors Response Elements (PPRE), with a consensus sequence 5'AGGTCANAGGTCA-3', and regulate the transcription of the targeted genes. Methods: A comprehensive screening of PPRE within the whole human genome was performed using the Genome Workbench and UCSC Genome Browser to find the associated genes. Subsequently, the kinase subset was isolated from the extracted list of PPRE-related genes. Functional enrichment of the kinases was performed using FunRich, ToppGene, and ShinyGO. Network analysis and enrichment studies were then further performed using NDEx to elucidate these identified kinases' connections and significance. Additionally, the disease association of the PPRE kinases was analyzed using DisGeNET data in R studio and the COSMIC dataset. Results: A comprehensive analysis of 1002 PPRE sequences within the human genome (T2T), yielded the identification of 660 associated genes, including 29 kinases. The engagement of these kinases in various biological pathways, such as apoptosis, platelet activation, and cytokine pathways, revealed from the functional enrichment analysis, illuminates the multifaceted role of PPAR in the regulation of cellular homeostasis and biological processes. Network analysis reveals the kinases interact with approximately 5.56% of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) network. Disease association analysis using DisGeNET and COSMIC datasets revealed the significant roles of these kinases in cellular processes and disease modulation. Discussion: This study elucidates the regulatory role of PPAR-associated genes and their association with numerous biological pathways. The involvement of the kinases with disease-related pathways highlights new potential for the development of therapeutic strategies designed for disease management and intervention.

Hexacoordinated tin complexes catalyse imine hydrogenation with H2.

Frustrated Lewis pair (FLP) hydrogenation catalysts predominantly use alkyl- and aryl-substituted Lewis acids (LA) that offer a limited number of combinations of substituents, limiting our ability to tune their properties and, ultimately, their reactivity. Nevertheless, main-group complexes have numerous ligands available for such purposes, which could enable us to broaden the range of FLP catalysis. Supporting this hypothesis, we demonstrate here that hexacoordinated tin complexes with Schiff base ligands catalyse imine hydrogenation via activation of H2(g). As shown by hydrogen-deuterium scrambling, [Sn(tBu2Salen)(OTf)2] activated H2(g) at 25 °C and 10 bar of H2. After tuning the ligands, we found that [Sn(Salen)Cl2] was the most efficient imine hydrogenation catalyst despite having the lowest activity in H2(g) activation. Moreover, various imines were hydrogenated in yields up to 98% thereby opening up opportunities for developing novel FLP hydrogenation catalysts based on hexacoordinated LA of main-group elements.

Idiopathic pulmonary fibrosis (IPF): disease pathophysiology, targets, and potential therapeutic interventions.

Idiopathic pulmonary fibrosis (IPF) is a progressive, degenerative pulmonary condition. Transforming growth factor (TGF)-ß, platelet-derived growth factor (PDGF), and tumor necrosis factor-α (TNF-α) are the major modulators of IPF that mediate myofibroblast differentiation and promote fibrotic remodeling of the lung. Cigarette smoke, asbestos fiber, drugs, and radiation are known to favor fibrotic remodeling of the lungs. Oxidative stress in the endoplasmic reticulum (ER) also leads to protein misfolding and promotes ER stress, which is predominant in IPF. This phenomenon further results in excess reactive oxygen species (ROS) aggregation, increasing oxidative stress. During protein folding in the ER, thiol groups on the cysteine residue are oxidized and disulfide bonds are formed, which leads to the production of hydrogen peroxide (H2O2) as a by-product. With the accumulation of misfolded proteins in the ER, multiple signaling cascades are initiated by the cell, collectively termed as the unfolded protein response (UPR). UPR also induces ROS production within the ER and mitochondria and promotes both pro-apoptotic and pro-survival pathways. The prevalence of post-COVID-19 pulmonary fibrosis (PCPF) is 44.9%, along with an alarming increase in "Coronavirus Disease 2019" (COVID-19) comorbidities. Fibrotic airway remodeling and declined lung function are the common endpoints of SARS-CoV-2 infection and IPF. Flavonoids are available in our dietary supplements and exhibit medicinal properties. Apigenin is a flavonoid found in plants, including chamomile, thyme, parsley, garlic, guava, and broccoli, and regulates several cellular functions, such as oxidative stress, ER stress, and fibrotic responses. In this study, we focus on the IPF and COVID-19 pathogenesis and the potential role of Apigenin in addressing disease progression.

Genome-wide screening and identification of potential kinases involved in endoplasmic reticulum stress responses.

AIM: This study aims to identify endoplasmic reticulum stress response elements (ERSE) in the human genome to explore potentially regulated genes, including kinases and transcription factors, involved in the endoplasmic reticulum (ER) stress and its related diseases. MATERIALS AND METHODS: Python-based whole genome screening of ERSE was performed using the Amazon Web Services elastic computing system. The Kinome database was used to filter out the kinases from the extracted list of ERSE-related genes. Additionally, network analysis and genome enrichment were achieved using NDEx, the Network and Data Exchange software, and web-based computational tools. To validate the gene expression, quantitative RT-PCR was performed for selected kinases from the list by exposing the HeLa cells to tunicamycin and brefeldin, ER stress inducers, for various time points. KEY FINDINGS: The overall number of ERSE-associated genes follows a similar pattern in humans, mice, and rats, demonstrating the ERSE's conservation in mammals. A total of 2705 ERSE sequences were discovered in the human genome (GRCh38.p14), from which we identified 36 kinases encoding genes. Gene expression analysis has shown a significant change in the expression of selected genes under ER stress conditions in HeLa cells, supporting our finding. SIGNIFICANCE: In this study, we have introduced a rapid method using Amazon cloud-based services for genome-wide screening of ERSE sequences from both positive and negative strands, which covers the entire genome reference sequences. Approximately 10 % of human protein-protein interactomes were found to be associated with ERSE-related genes. Our study also provides a rich resource of human ER stress-response-based protein networks and transcription factor interactions and a reference point for future research aiming at targeted therapeutics.

Plant PUF RNA-binding proteins: A wealth of diversity for post-transcriptional gene regulation.

PUF proteins are a conserved group of sequence-specific RNA-binding proteins that typically function to negatively regulate mRNA stability and translation. PUFs are well characterized at the molecular, structural and functional levels in Drosophila, Caenorhabditis elegans, budding yeast and human systems. Although usually encoded by small gene families, PUFs are over-represented in the plant genome, with up to 36 genes identified in a single species. PUF gene expansion in plants has resulted in extensive variability in gene expression patterns, diversity in predicted RNA-binding domain structure, and novel combinations of key amino acids involved in modular nucleotide binding. Reports on the characterization of plant PUF structure and function continue to expand, and include RNA target identification, subcellular distribution, crystal structure, and molecular mechanisms. Arabidopsis PUF mutant analysis has provided insight into biological function, and has identified roles related to development and environmental stress tolerance. The diversity of plant PUFs implies an extensive role for this family of proteins in post-transcriptional gene regulation. This diversity also holds the potential for providing novel RNA-binding domains that could be engineered to produce designer PUFs to alter the metabolism of target RNAs in the cell.