Biology subjects

Abbate, G.

Publications and source records attributed to Abbate, G..

2 recordsLinked to original sources

bioRxiv2023

UCHL1-dependent control of Hypoxia-Inducible Factor Transcriptional Activity in Liver Disease.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver diseases. Fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast like phenotype that is contractile, proliferative and profibrogenic. Hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. HIF activation during HSC activation can by either due to localised decreases in oxygen levels, or through oxygen-independent mechanisms that are not completely understood. Here we describe a role for the deubiquitinase UCHL1 in regulating HIF levels and activity during HSC activation and liver fibrosis. Increased HIF1 expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1 levels. UCHL1 specifically cleaves the degradative ubiquitin chains from HIF1 leading to increased HIF1 levels, even in sufficiently oxygenated cells. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. These results demonstrate how small molecule inhibitors of DUBs can modulate the activity of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity via modulation of the ubiquitin-proteasomal degradation pathway may represent a therapeutic opportunity with other HIF-related pathologies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/523142v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d82ee9org.highwire.dtl.DTLVardef@1eff21aorg.highwire.dtl.DTLVardef@1ffb0eforg.highwire.dtl.DTLVardef@1b93dc9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Design, development, and preliminary assessment of a novel peripheral intravenous catheter aimed at reducing early failure rates

BackgroundPeripheral intravenous catheters (PIVCs) are the most commonly used invasive medical device, yet despite best efforts by end-users, PIVCs experience unacceptably high early failure rates. We aimed to design a new PIVC that reduces the early failure rate of in-dwelling PIVCs and we conducted preliminary tests to assess its efficacy and safety in a large animal model of intravenous access. MethodsWe used computer-aided design and simulation to create a PIVC with a ramped tip geometry, which directs the infused fluid away from the vein wall; we called the design the FloRamp. We created FloRamp prototypes (test device) and tested them against a market-leading device (BD Insyte; control device) in a highly-controlled setting with five insertion sites per device in four pigs. We measured resistance to infusion and visual infusion phlebitis (VIP) every six hours and terminated the experiment at 48 hours. Veins were harvested for histology and seven pathological markers were assessed. ResultsComputer simulations showed that the optimum FloRamp tip reduced maximum endothelial shear stress by 60%, from 12.7Pa to 5.1Pa, compared to a typical PIVC tip, and improved the infusion dynamics of saline in the blood stream. In the animal study, we found that 2/5 of the control devices were occluded after 24 hours, whereas all test devices remained patent and functional. The FloRamp created less resistance to infusion (0.73{+/-}0.81 vs 0.47{+/-}0.50, p=0.06) and lower VIP scores (0.60{+/-}0.93 vs 0.31{+/-}0.70, p=0.09) that the control device, although neither findings were significantly different. Histopathology revealed that 5/7 of the assessed markers were lower in veins with the FloRamp. ConclusionsAs PIVCs are used in almost every hospitalized patient, there is an urgent need to reduce failure rates. Herein we report preliminary assessment of a novel PIVC design, which could be advantageous in clinical settings through decreased device occlusion.

bioengineering↗