Biology subjects

Rabi, S. A.

Publications and source records attributed to Rabi, S. A..

3 recordsLinked to original sources

bioRxiv2025

Improving Cardiac Resilience to Ischemia/Reperfusion: The Role of Butyrate in Mitochondrial and Metabolic Recovery

BackgroundCardiac transplantation is limited by a persistent shortage of donor organs. While hearts donated after circulatory death (DCD) could expand donors pool, their use is hindered by high rates of primary graft dysfunction (PGD) due to ischemia/reperfusion (I/R)-induced metabolic injury. Here, we investigate the therapeutic potential of the short-chain fatty acid butyrate (BT) to restore metabolic function in cardiomyocytes following I/R. MethodAdult human ventricular cardiomyocytes were used for in vitro cell perfusion (IVCP). Following a period of warm ischemia, butyrate (BT) was introduced into a prechilled UW solution to mimic the standard in situ cold flush performed during heart explant. Cells were then reperfused with cultural media for 1h at 37{degrees}C, after which both cells and perfusate were harvested for spectrometric metabolite profiling and molecular analyses using standard methods. ResultsBT reprograms cardiac substrate use from glucose to BT, enhancing mitochondrial oxidative phosphorylation and ATP production, as evidenced by increased lactate clearance and upregulated mitochondrial BT-oxidation enzymes. This metabolic shift restores redox balance by elevating NAD+/NADPH pool and reducing ADP/ATP ratio, while suppressing histone deacetylation and promoting gene expression linked to mitochondrial biogenesis, damage repair, recycling, and turnover via enhanced mitofusion and PINK1/Parkin-mediated mitophagy. BT subsequently reduces mitochondrial ROS, enhances electron transport chain activity, and preserves oxidative phosphorylation, thereby lowering caspase-3/7 activity, preventing apoptosis, and promoting cardiomyocyte metabolic recovery. ConclusionBT restores mitochondrial and metabolic function, preserves ATP synthesis after I/R injury, and mitigates metabolic maladaptation, offering strong potential to improve cardiac viability, graft function, and transplantation outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/661163v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@82ab11org.highwire.dtl.DTLVardef@acffeborg.highwire.dtl.DTLVardef@1d5b958org.highwire.dtl.DTLVardef@7b4ca1_HPS_FORMAT_FIGEXP M_FIG Improving Cardiac Resilience to Ischemia/Reperfusion: The Role of Butyrate in Mitochondrial and Metabolic Recovery C_FIG

cell biology↗

bioRxiv2025

Advancing Cardiac Graft Assessment Methods During Normothermic Machine Perfusion to Achieve Improved Transplantation Outcomes

Heart failure, a leading global health challenge, affects over 23 million people worldwide, with heart transplantation being the gold standard for end-stage disease. However, the scarcity of viable donor hearts presents a significant barrier, with only one-third of available grafts used due to stringent selection criteria. Machine perfusion technologies, particularly normothermic machine perfusion (NMP), offer promise in improving graft preservation and assessment, yet their full potential for predicting transplantability remains underexplored. This study investigates three assessment methods to enhance human heart evaluation during NMP, focusing on mitochondrial function, left ventricular (LV) performance, and inflammatory markers. First, resonance Raman spectroscopy (RRS) is employed to assess mitochondrial redox state as a proxy for metabolic competency, offering a non-invasive and dynamic evaluation of mitochondrial function during ex vivo preservation. Second, LV function is quantified using intraventricular balloons, providing critical insights into graft viability and performance. Third, inflammatory markers and endothelial activation are assessed from perfusate to predict post-transplant outcomes. These methods were tested on human donor hearts declined for transplantation, preserved via static cold storage (SCS) and subsequently assessed with NMP in Langendorff mode. The results demonstrate that these parameters can be easily integrated into existing clinical perfusion workflows and hold potential for improving heart transplantation outcomes by enhancing graft selection and optimizing donor heart use. Future studies will further validate these biomarkers across different preservation techniques and evaluate their clinical applicability.

bioengineering↗

bioRxiv2020

The SARS-CoV-2 Spike mutation D614G increases entry fitness across a range of ACE2 levels, directly outcompetes the wild type, and is preferentially incorporated into trimers

Early in the current pandemic, the D614G mutation arose in the Spike protein of SARS-CoV-2 and quickly became the dominant variant globally. Mounting evidence suggests D614G enhances viral entry. Here we use a direct competition assay with single-cycle viruses to show that D614G outcompetes the wildtype. We developed a cell line with inducible ACE2 expression to confirm that D614G more efficiently enters cells with ACE2 levels spanning the different primary cells targeted by SARS-CoV-2. Using a new assay for crosslinking and directly extracting Spike trimers from the pseudovirus surface, we found an increase in trimerization efficiency and viral incorporation of D614G protomers. Our findings suggest that D614G increases infection of cells expressing a wide range of ACE2, and informs the mechanism underlying enhanced entry. The tools developed here can be broadly applied to study other Spike variants and SARS-CoV-2 entry, to inform functional studies of viral evolution and vaccine development.

microbiology↗