Biology subjects

Prince, A.

Publications and source records attributed to Prince, A..

6 recordsLinked to original sources

bioRxiv2026

FDA-approved drug library screen identifies antidepressants, antimicrobials, anti-COPD, and anti-CVD agents as blockers of NLRP3 inflammasome and sepsis in a sex-dependent manner.

The NLRP3 inflammasome pathway is central to host defense, but dysregulated activation of inflammasomes promotes diseases associated with metabolic syndrome (diabetes, obesity, CVD, MASLD), neurodegenerative diseases (Alzheimers, Parkinsons), autoinflammatory conditions (CAPS, gout), and respiratory illnesses (asthma/COPD, COVID-19). Therapeutic modulation of NLRP3 is challenging as it requires selective blockade of detrimental inflammasome activation without broadly suppressing innate immunity. Here, we used a phenotypic screen in THP1-ASC-GFP monocytes to identify FDA-approved drugs that can block LPS-induced priming of the NLRP3 inflammasome or inhibit NLRP3 assembly without disrupting upstream priming. Various classes of drugs, such as antidepressants (Fluoxetine, Duloxetine), antihypertensives (Irbesartan, Amlodipine, Nebivolol), antidiabetics (Rosiglitazone), {beta}-adrenergic agonists (Salmeterol), antimalarials (Mefloquine), antifungals (Azoles, Ciclopirox), and antivirals (Saquinavir, Remdesivir), were identified as potent blockers of either priming or assembly of the NLRP3 inflammasome. Secondary validation demonstrated that several compounds suppressed NF-{kappa}B activation, reduced LPS binding to immune cells, decreased pro-inflammatory cytokine production, enhanced efferocytic capacity of macrophages, and enhanced autophagy in vitro and in vivo. Mechanistic analyses further revealed drug-specific effects on lysosomal biogenesis, mitochondrial morphology, and mitochondrial reactive oxygen species. In murine models of acute inflammation and endotoxemia, selected compounds attenuated NLRP3 inflammasome activation, reduced systemic and local inflammatory cytokines, limited tissue injury, and improved survival following LPS-induced sepsis, with efficacy varying by sex. Further studies in primary human cells and in vivo disease models are needed to assess the repurposing and therapeutic relevance of identified drugs.

cell biology↗

bioRxiv2025

CFTR function in alveolar type 1 cells drives lung liquid secretion and host defense

Loss of the liquid layer that lines the lungs air-facing surface underpins mechanisms of major lung diseases, but the development of therapies that restore liquid secretion is hampered by an incomplete understanding of the cell types that drive it. Here, we show CFTR function in alveolar type 1 (AT1) cells - a cell type that comprises 95% of the lung surface but is presumed to be unimportant in CFTR-related diseases - is critical to lung liquid secretion and the secretion-mediated clearance of particles and S. aureus from lung alveoli. Our findings reveal essential roles for AT1 cells in lung homeostasis and defense, and they call for a reevaluation of the role of AT1 cells in CFTR-related diseases. We suggest AT1 cells be considered key targets of secretion-restoring therapies.

cell biology↗

bioRxiv2024

Microvascular preservation and cardiomyocyte hyperplasia underlie adaptive right ventricular development in congenital heart disease-associated pulmonary arterial hypertension

AbstractO_ST_ABSBackgroundC_ST_ABSRight ventricular (RV) failure is the primary cause of death among patients with pulmonary arterial hypertension (PAH). Patients with congenital heart disease- associated PAH (CHD-PAH) demonstrate improved outcomes compared to patients with other forms of PAH, which is related to the maintenance of an adaptively hypertrophied RV. In an ovine model of CHD-PAH, we aimed to elucidate the cellular, microvascular, and transcriptional adaptations to congenital pressure overload that support RV function in CHD-PAH. MethodsFetal surgery was performed on late gestation lambs to insert a large aortopulmonary graft, leading to a persistent congenital left-right shunt and RV pressure load. At 3 days and 4-6 weeks of life, shunt RV microvasculature, cardiomyocyte structure, and myocardial growth mechanisms were compared to age-matched controls and unoperated fetal RV. RNA sequencing was performed to assess differences in the RV transcriptomes. ResultsAt 4-6 weeks of age, shunt lambs demonstrate significant RV enlargement (shunt 37.1 {+/-} 2.9g vs control 15.9 {+/-} 1.0g, p<0.001) but maintain stable microvascular density (fetal 3.0 {+/-} 0.6 vs shunt 2.9 {+/-} 0.3 vs control 3.1 {+/-} 0.6 capillaries per 1000 {micro}m3, p>0.05). Shunt RV cardiomyocytes are significantly smaller by cross-sectional area and more numerous than age-matched controls (shunt 73.3 {+/-} 5.5 {micro}m2 vs control 99.2 {+/-} 4.9 {micro}m2, p=0.013). At 3 days, shunt RV cardiomyocytes show evidence of increased proliferative capacity and ongoing hyperplasia compared to controls. RNA sequencing analyses reveal a distinct gene expression profile in shunt RV consistent with a delay in terminal differentiation and metabolic adaptations to support adaptive function. ConclusionsThis study provides novel insights into the development of adaptive RV hypertrophy in CHD-PAH, demonstrating roles for preserved microvascular density and increased postnatal cardiomyocyte hyperplasia in supporting RV performance. Future investigations into the mechanisms underlying these changes could have significant implications for the development of novel therapeutic strategies for supporting RV function.

physiology↗

bioRxiv2024

Cellular heterogeneity in hypertrophic burn scars in response to carbon dioxide laser therapy

Fractional carbon dioxide (AFCO2) laser therapy is used for treating pathological scarring, but the clinical outcomes are variable and the mechanisms of scar reduction poorly understood. We investigated the mechanisms underpinning efficacy of AFCO2 laser therapy, performing single-cell RNA sequencing in skin biopsies from patients with hypertrophic scars after AFCO2 laser therapy. Patients with younger scars (Good Responder, GR, <6 years from healing) had better scar reduction than patients with older scars (Poor Responder, PR, >6 years from healing) by various measures of scarring. scRNAseq analysis revealed that genes enriched in GR were associated with extracellular matrix and structure organisation (COL14A1, POSTN, SPARC); whereas genes enriched in PR were related to enhanced immune responses (IL-12, MSTN, HLA-DQA). The groups had distinct intercellular communication networks and differentiation trajectories after AFCO2, with regenerative Mesenchymal fibroblasts associated with a good response and inflammatory Secretory Papillary and Inflammatory Fibroblasts with a poor response.

cell biology↗

bioRxiv2023

Disulfiram reduces atherosclerosis and enhances efferocytosis, autophagy, and atheroprotective gut microbiota in hyperlipidemic mice.

Pyroptosis executor Gasdermin (GsdmD) promotes atherosclerosis in mice and humans. Disulfiram (DSF) was recently shown to potently inhibit GsdmD, but the in-vivo efficacy and mechanism of DSFs anti-atherosclerotic activity is yet to be explored. We used human/mouse macrophages and a hyperlipidemic mouse model of atherosclerosis to determine DSF anti-atherosclerotic efficacy and mechanism. DSF-fed hyperlipidemic apoE-/- mice showed significantly reduced IL-1{beta} release upon in-vivo Nlrp3 inflammasome assembly and showed smaller atherosclerotic lesions ([~]27% and 29% reduction in males and females, respectively). The necrotic core area was also smaller ([~]50% and 46% reduction in DSF-fed males and females, respectively). DSF induced autophagy in macrophages, hepatocytes/liver, and in atherosclerotic plaques. DSF modulated other atheroprotective pathways such as efferocytosis, phagocytosis, and gut microbiota. DSF-treated macrophages showed enhanced phagocytosis/efferocytosis, with a mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic-force microscopy analysis revealed altered biophysical membrane properties of DSF treated macrophages, showing increased ordered-state of the plasma membrane and increased adhesion strength. Furthermore, the 16sRNA sequencing of DSF-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species. Taken together, our data shows that DSF can simultaneously modulate multiple atheroprotective pathways, and thus may serve as novel adjuvant therapeutic to treat atherosclerosis.

cell biology↗

bioRxiv2019

Interplay of bacterial membrane vesicle and host lipid physicochemical parameters during host-bacterial membrane vesicle interaction

Bacterial membrane vesicles (MVs) facilitate long-distance delivery of virulence factors crucial for pathogenicity. The entry and trafficking mechanisms of virulence factors inside host cells are recently emerging, however, if bacterial MVs can fuse and modulate the physicochemical properties of the host lipid membrane and membrane lipid parameter for fusion remains unknown. Here we reconstitute the interaction of bacterial MV with host cell lipid membranes and quantitatively show that bacterial MV interaction increases the fluidity, dipole potential, and Compressibility of a biologically relevant multi-component host membrane upon fusion. The presence of cylindrical lipids such as phosphatidylcholine and a moderate acyl chain length of C16 helps the MV interaction. While significant binding of bacterial MVs to the raft-like lipid membranes with phase-separated regions of the membrane was observed, however, MVs prefer binding to the liquid-disordered regions of the membrane. Further, the elevated levels of cholesterol tend to hinder the interaction of bacterial MVs as evident from the favorable excess Gibbs free energy of mixing of bacterial MVs with host lipid membranes. The findings provide new insights that might have implications for the regulation of host machinery by bacterial pathogens through the manipulation of host membrane properties.

biochemistry↗