Analysis of differentially expressed genes and molecular pathways in familial hypercholesterolemia involved in atherosclerosis: A systematic and bioinformatics approach

Background and Aims: Familial hypercholesterolemia (FH) is one of the major risk factor for the progression of atherosclerosis and coronary artery disease. This study focused on identifying the dysregulated molecular pathways and core genes that are differentially regulated in FH and to identify the possible genetic factors and potential underlying mechanisms that increase the risk to atherosclerosis in patients with FH. Methods: The Affymetrix microarray dataset (GSE13985) from the GEO database and the GEO2R statistical tool were used to identify the differentially expressed genes (DEGs) from the white blood cells (WBCs) of five heterozygous FH patients and five healthy controls. The interaction between the DEGs was identified by applying the STRING tool and visualized using Cytoscape software. MCODE was used to determine the gene cluster in the interactive networks. The identified DEGs were subjected to the DAVID v6.8 webserver and ClueGo/CluePedia for functional annotation, such as gene ontology (GO) and enriched molecular pathway analysis of DEGs. Results: We investigated the top 250 significant DEGs (p-value < 0.05; fold two change ≥ 1 or ≤ −1). The GO analysis of DEGs with significant differences revealed that they are involved in critical biological processes and molecular pathways, such as myeloid cell differentiation, peptidyl-lysine modification, signaling pathway of MyD88-dependent Toll-like receptor, and cell-cell adhesion. The analysis of enriched KEGG pathways revealed the association of the DEGs in ubiquitin-mediated proteolysis and cardiac muscle contraction. The genes involved in the molecular pathways were shown to be differentially regulated by either activating or inhibiting the genes that are essential for the canonical signaling pathways. Our study identified seven core genes (UQCR11, UBE2N, ADD1, TLN1, IRAK3, LY96, and MAP3K1) that are strongly linked to FH and lead to a higher risk of atherosclerosis. Conclusion: We identified seven core genes that represent potential molecular biomarkers for the diagnosis of atherosclerosis and might serve as a platform for developing therapeutics against both FH and atherosclerosis. However, functional studies are further needed to validate their role in the pathogenesis of FH and atherosclerosis

Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.This publication was supported by Qatar University Internal Grant No QUST-2-CHS-2020-12. Udhaya Kumar. S, one of the authors, gratefully acknowledges the Indian Council of Medical Research (ICMR), India, for providing him a Senior Research Fellowship [ISRM/11(93)/2019]. The authors would like to thank the Vellore Institute of Technology, India, and Qatar University, Qatar, for providing the necessary research facilities and encouragement to carry out this work

Deciphering the crosstalk between inflammation and biofilm in chronic wound healing: Phytocompounds loaded bionanomaterials as therapeutics

In terms of the economics and public health, chronic wounds exert a significant detrimental impact on the health care system. Bacterial infections, which cause the formation of highly resistant biofilms that elude standard antibiotics, are the main cause of chronic, non-healing wounds. Numerous studies have shown that phytochemicals are effective in treating a variety of diseases, and traditional medicinal plants often include important chemical groups such alkaloids, phenolics, tannins, terpenes, steroids, flavonoids, glycosides, and fatty acids. These substances are essential for scavenging free radicals which helps in reducing inflammation, fending off infections, and hastening the healing of wounds. Bacterial species can survive in chronic wound conditions because biofilms employ quorum sensing as a communication technique which regulates the expression of virulence components. Fortunately, several phytochemicals have anti-QS characteristics that efficiently block QS pathways, prevent drug-resistant strains, and reduce biofilm development in chronic wounds. This review emphasizes the potential of phytocompounds as crucial agents for alleviating bacterial infections and promoting wound healing by reducing the inflammation in chronic wounds, exhibiting potential avenues for future therapeutic approaches to mitigate the healthcare burden provided by these challenging conditions

Molecular dynamics, residue network analysis, and cross-correlation matrix to characterize the deleterious missense mutations in GALE causing galactosemia III.

Epimerase-deficiency galactosemia (EDG) is caused by mutations in the UDP-galactose 4'-epimerase enzyme, encoded by gene GALE. Catalyzing the last reaction in the Leloir pathway, UDP-galactose-4-epimerase catalyzes the interconversion of UDP-galactose and UDP-glucose. This study aimed to use in-depth computational strategies to prioritize the pathogenic missense mutations in GALE protein and investigate the systemic behavior, conformational spaces, atomic motions, and cross-correlation matrix of the GALE protein. We searched four databases (dbSNP, ClinVar, UniProt, and HGMD) and major biological literature databases (PubMed, Science Direct, and Google Scholar), for missense mutations that are associated with EDG patients, our search yielded 190 missense mutations. We applied a systematic computational prediction pipeline, including pathogenicity, stability, biochemical, conservational, protein residue contacts, and structural analysis, to predict the pathogenicity of these mutations. We found three mutations (p.K161N, p.R239W, and p.G302D) with a severe phenotype in patients with EDG that correlated with our computational prediction analysis; thus, they were selected for further structural and simulation analyses to compute the flexibility and stability of the mutant GALE proteins. The three mutants were subjected to molecular dynamics simulation (MDS) with native protein for 200 ns using GROMACS. The MDS demonstrated that these mutations affected the beta-sheets and helical region that are responsible for the catalytic activity; subsequently, affects the stability and flexibility of the mutant proteins along with a decrease and more deviations in compactness when compared to that of a native. Also, three mutations created major variations in the combined atomic motions of the catalytic and C-terminal regions. The network analysis of the residues in the native and three mutant protein structures showed disturbed residue contacts occurred owing to the missense mutations. Our findings help to understand the structural behavior of a protein owing to mutation and are intended to serve as a platform for prioritizing mutations, which could be potential targets for drug discovery and development of targeted therapeutics

COVID-19 Outcomes in Patients Hospitalised with Acute Myocardial Infarction (AMI): A Protocol for Systematic Review and Meta-Analysis

Background: Patients with cardiovascular disease and risk factors for cardiovascular illness are more likely to acquire severe 2019 novel coronavirus (2019-nCoV) infection (COVID-19). COVID-19 infection is more common in patients with cardiovascular illness, and they are more likely to develop severe symptoms. Nevertheless, whether COVID-19 patients are more likely to develop cardiovascular disorders such as acute myocardial infarction (AMI) is still up for debate. Methods: We will follow the preferred reporting items for systematic review and meta-analysis (PRISMA) to report our final study, including a systematic search of the bibliographic database using the appropriate combination of search terms or keywords. The choice of search terms is discussed in more detail later in this paper. The obtained results will be screened, and the data extracted from the studies selected for systematic review will be based on the predefined inclusion and exclusion criteria. Using the obtained data, we will then perform the associated Meta-analysis to generate the forest plot (pooled estimated effect size Hazard Ratio (HR) and 95% Confidence Intervals (CI) values) using the random-effects model. Any publication bias will be assessed using the funnel plot symmetry, Orwin and Classic Fail-Safe N Test and Begg and Mazumdar Rank Correlation Test and Egger&rsquo;s Test of the intercept. In cases where insufficient data occur, we will also perform a qualitative review. Discussion: This systematic review will explore COVID-19 clinical outcomes, especially survival in patients hospitalised with Acute Myocardial Infarction, by utilising a collection of previously published data on hospitalised COVID-19 patients and Myocardial Infarction. Highlighting these prognostic survival analyses of COVID-19 patients with AMI will have significant clinical implications by allowing for better overall treatment strategies and patient survival estimates by offering clinicians a method of quantitatively analysing the pattern of COVID-19 cardiac complications

A Clinical Investigation on the Theragnostic Effect of MicroRNA Biomarkers for Survival Outcome in Cervical Cancer: A PRISMA-P Compliant Protocol for Systematic Review and Comprehensive Meta-Analysis

Background: The most often diagnosed malignancy in women worldwide is cancer of the cervix. It is also the most prevalent kind of gynecological cancer in women. This cancer originates in the opening of the cervix and spreads through sexual contact. Even though human papillomavirus (HPV) may not cause cancer immediately, it does develop over time as a result of the virus&rsquo;s lengthy persistence to cause dysplastic changes overtime, particularly in high-risk kinds. The primary objective of this research is to see if miRNAs are dysregulated as a result of treatment resistance in cervical cancer (CC). The aim is to see if these microRNAs may be utilized as biomarkers for detecting chemoresistance in CC, particularly for clinical applications. Methods: The recommended protocol for comprehensive study and meta-analysis (PRISMA-P) standards will be utilized for the analysis and data interpretation. The bibliographic databases will be methodically searched using a combination of search keywords. Based on established inclusion and exclusion criteria, the acquired findings will be reviewed, and data retrieved from the selected scientific papers for systematic review. We will then construct a forest from the pooled Hazard ratio (HR) and 95% C.I. values, data obtained using the random-effects model. Discussion: The focus of this study is to identify the function of miRNAs as a chemoresistance regulator and determine if they have the potential scope to be considered as biomarkers for cervical cancer. Through this systematic review and meta-analysis, the goal is to collect, compare, and analyze the data pertaining to the role of miRNAs in cervical cancer, thereby, enabling us to understand the role they play in chemosensitivity