Objectives Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema. Methods We compared whole-tissues, ADSCs, and adipocytes from body mass index–matched lipedema (n = 14) and unaffected (n = 10) patients using comprehensive global lipidomic and metabolomic analyses, transcriptional profiling, and functional assays. Results Transcriptional profiling revealed >4400 significant differences in lipedema tissue, with altered levels of mRNAs involved in critical signaling and cell function-regulating pathways (e.g., lipid metabolism and cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation and differentiation in lipedema. Profiling lipedema adipocytes revealed >900 changes in lipid composition and >600 differentially altered metabolites. Transcriptional profiling of lipedema ADSCs and non-lipedema ADSCs revealed significant differential expression of >3400 genes including some involved in extracellular matrix and cell-cycle/proliferation signaling pathways. One upregulated gene in lipedema ADSCs, Bub1, encodes a cell-cycle regulator, central to the kinetochore complex, which regulates several histone proteins involved in cell proliferation. Downstream signaling analysis of lipedema ADSCs demonstrated enhanced activation of histone H2A, a key cell proliferation driver and Bub1 target. Critically, hyperproliferation exhibited by lipedema ADSCs was inhibited by the small molecule Bub1 inhibitor 2OH-BNPP1 and by CRISPR/Cas9-mediated Bub1 gene depletion. Conclusion We found significant differences in gene expression, and lipid and metabolite profiles, in tissue, ADSCs, and adipocytes from lipedema patients compared to non-affected controls. Functional assays demonstrated that dysregulated Bub1 signaling drives increased proliferation of lipedema ADSCs, suggesting a potential mechanism for enhanced adipogenesis in lipedema. Importantly, our characterization of signaling networks driving lipedema identifies potential molecular targets, including Bub1, for novel lipedema therapeutics.
Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a significant nosocomial pathogen, causing serious threats concerning community-wide outbreaks globally, as well as in Pakistan. Antimicrobial resistance in A. baumannii is increasing day by day. Objectives: The study aimed to find out the antibiotic resistance (AMR) patterns and evaluate the AMR genes in clinical isolates from patients admitted to the surgical Intensive Care units (ICUs) at different hospitals in Lahore, Pakistan. Methods: A total of 593 clinical specimens were collected from patients admitted to the surgical ICUs of three different local hospitals in Lahore, Pakistan. From these samples, a total of 90 A. baumannii isolates were identified and further investigated to observe phenotypic resistance patterns and detect carbapenemases resistance genes. Results: The results showed that phenotypic resistance against amikacin was 27.2%, ceftriaxone 100%, ceftazidime 27.2%, cefepime 63.3%, ciprofloxacin and co-trimoxazole 100%, gentamicin 40%, imipenem 22.2%, meropenem 21.1%, piperacillin-tazobactam 27.2%, tigecycline 27.2%, and tetracycline 63.3%. All A. baumannii isolates were found to be sensitive to colistin (CT), polymixin-B (PB), and tobramycin (TOB). The PCR amplification of carbapenemases genes revealed the prevalence of blaOXA-23, blaOXA-51, and blaOXA-40 in 73, 90, and 64.4% of the isolates, respectively, along with blaNDM1 (92.2%), blaVIM (40%), blaIMP (90%), ISAba1 (85.5%), sul1 (16.6%), sul2 (20%), armA (32.2%), and PER-1 (12%) while the blaOXA-24 and blaOXA-58 genes were not detected in the isolates. The sequence analysis of the blaOXA-23 and blaOXA-51 genes showed 98% and 95% similarity with previously reported sequences in the GenBank database. Conclusions: The present study indicated that the emergence of high carbapenem resistance in CRAB isolates has increased, which may pose serious limitations in the choice of drugs for nosocomial infections.
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