👤 Umair Abrar Baig

This umbrella review aims to synthesize evidence from previously conducted meta-analyses and review articles to assess the effects of bempedoic acid on lipid profile and cardiovascular events. While adhering to the Preferred Reporting Items for Overviews of Reviews guidelines, PubMed, Google Scholar, Web of Science, and Scopus were searched from the database inception to June 2024 to identify relevant articles. The outcomes were total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol, triglyceride (TAG), apolipoprotein B (APOB), high-sensitivity CRP (hs-CRP), major cardiovascular events (MACE), cardiovascular mortality, and myocardial infarction (MI). A corrected covered area (CCA) assessment was performed to determine overlap among reviews. Each included review was assessed for its quality and rigor via the AMSTAR-2 tool. From 18,297 articles identified during the literature search, 18 meta-analyses were included. A significant overlap was noted across studies with a corrected cover area of 44.4%. Bempedoic acid's effects on cardiovascular outcomes and lipid levels have been extensively studied. For cardiovascular mortality, the evidence is mixed: Goyal et al. Our findings show that bempedoic acid significantly reduces the risk of MACE, nonfatal MI, coronary and noncoronary revascularization, and hospitalizations for unstable angina. While results on cardiovascular mortality are mixed, suggesting a need for further study, bempedoic acid proves to be an effective treatment for improving lipid profiles and reducing cardiovascular events, especially in patients who cannot tolerate statins. It presents a valuable option for cardiovascular risk management, potentially enhancing patient outcomes and quality of life. Further research is needed to assess its long-term benefits and broader applicability. Show less

High-density lipoprotein cholesterol (HDL-C) has long been inversely associated with atherosclerotic cardiovascular disease risk, but pharmacologic efforts to raise HDL-C have consistently failed to reduce cardiovascular events. This has shifted focus from HDL quantity to quality, emphasizing functional properties such as cholesterol efflux, antioxidative capacity, and anti-inflammatory activity. Dysfunctional HDL, often modified by oxidative and inflammatory processes mediated by myeloperoxidase, loses its ability to promote reverse cholesterol transport, support endothelial function, and suppress vascular inflammation. Advanced proteomic and lipidomic studies have revealed compositional remodeling that underlies HDL's functional heterogeneity and disease-specific signatures. Functional measures like cholesterol efflux capacity and cell-free HDL assays correlate more strongly with cardiovascular outcomes than static HDL-C levels, providing a more accurate index of vascular protection. Despite the promising therapies such as cholesterol ester transfer protein (CETP) inhibitors, niacin, and apolipoprotein A-I infusions (reconstituted high-density lipoprotein (CSL112)), none have yet demonstrated definitive event reduction. Future directions include standardizing HDL functional assays, prioritizing quality over concentration, and integrating HDL-targeted and metabolic therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transport 2 (SGLT2) inhibitors, to restore HDL's protective phenotype and redefine preventive cardiology. Show less

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer with poor prognosis and limited response to conventional therapies. The fibroblast growth factor receptor 1 (FGFR1) has emerged as a pivotal molecular target among the oncogenic drivers of OSCC because of its critical role in tumor cell proliferation, migration, and chemoresistance. This research employed a comprehensive multi-tiered computational drug-discovery approach, integrating multi-class QSAR modeling, virtual screening, and molecular dynamics simulations, to identify novel small-molecule FGFR1 inhibitors with therapeutic potential for OSCC. The ChEMBL database was utilized to create a dataset of 3,222 distinct inhibitors, subsequently categorized into four bioactivity classes. Exploratory data analysis revealed that more potent compounds had a higher average molecular weight, an increased number of hydrogen bond acceptors, a higher count of rotatable bonds, and a higher. The ROS technique was employed on the training set to address the issue of dataset imbalance. We employed 10 distinct machine learning techniques to develop and assess multi-class QSAR models. These models explain how the chemical structures of substances connect to their biological functions mathematically. The Extra Trees (ET) classifier had the best performance, achieving a test set accuracy of 0.926 and MCC of 0.902. This made it the optimal model for our upcoming virtual screening. We employed the validated ET model to examine a repository of FDA-approved drugs and identified high-priority potential drugs. Molecular docking studies in the FGFR1 active site (PDB ID: 6MZW) followed by 200 ns molecular dynamics simulations demonstrated the stability of the top candidates. The study identified two significant lead compounds, CHEMBL155526361 and CHEMBL155529723, exhibiting robust binding affinities and strong interactions. This study provides a robust computational framework and remarkable molecular scaffolds for further preclinical investigation. This will expedite the search for innovative therapeutics for OSCC. The online version contains supplementary material available at 10.1186/s12885-025-15471-4. Show less

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics. Show less

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype. Show less