Biology subjects

Zu, Y.

Publications and source records attributed to Zu, Y..

5 recordsLinked to original sources

bioRxiv2025

Targeting Endothelial PERK Accelerates Lymphoid Regeneration by Enhancing DLL4-NOTCH3 Signaling at the Pre-B Niche

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome, yet strategies to enhance lymphocyte regeneration are limited. We studied the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We revealed that PERK activation is a prominent feature of BM endothelium in leukemia patients and is a hallmark response in mouse BM following ionizing irradiation. Ablating endothelial Perk boosted Notch ligand DLL4 expression and promoted DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis shows that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment and niche cytokine production. NOTCH3 is critical for the upregulation of IL7 following irradiation and for supporting the expansion of lymphoid progenitors in mesenchymal sphere cultures. These findings not only unveil a previously unrecognized ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising therapeutic strategy to improve immune recovery after myeloablative transplantation. SummaryZou et al unravel that the adaptive ER stress response in bone marrow blood vessels restricts the post-transplant regeneration of immune progenitor cells by attenuating the expression of Notch ligand DLL4. Targeting ER stress sensor PERK can accelerate immune recovery after transplantation by enhancing DLL4-NOTCH3 signaling and IL7 cytokine production.

cell biology↗

bioRxiv2025

Inhibiting RhoA Activation via GDP-state Stabilization to Relieve Heart Failure

High rates of heart failure (HF) morbidity and mortality have made targeting myocardial remodeling--particularly hypertrophy and fibrosis--a key therapeutic focus. RhoA, which regulates cytoskeletal reorganization and cell migration, plays a role in this process. However, RhoA has long been considered "undruggable", due to its strong binding to its endogenous substrates, GDP/GTP, and the lack of well-defined pockets for drug targeting. Here, we discovered a cryptic pocket proximate to GDP within RhoA and identified a natural product, AH001, binds here and interacts with GDP, stabilizing RhoAs interaction with its endogenous inhibitor, RhoGDI. AH001 reduced the downstream MRTFA nuclear translocation and downregulated fibrosis/hypertrophy proteins. Consequently, AH001 mitigated myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. Our findings highlight the therapeutic potential of inhibiting RhoA activation in myocardial remodeling, ultimately targeting HF, and offer a promising avenue for developing reversible inhibitors against undruggable GTPases.

pharmacology and toxicology↗

bioRxiv2025

Embryonic Durotaxis: A Mechanical Framework for Understanding Cesarean Scar Pregnancy

Cesarean scar pregnancy (CSP) is an increasingly common complication associated with the rise in cesarean section rates, yet its underlying mechanisms remain poorly understood. In this study, we identified a stiffness gradient between healthy and scarred uterine tissues in both human cesarean samples and mouse uterine scar models. By employing gradient stiffness hydrogels, we demonstrated that mouse embryos and human trophoblast spheroids exhibit durotaxis, migrating preferentially toward stiffer areas. This migration occurs through three-dimensional complex behaviors--translation, swinging, and rolling--characterized by periodic patterns that align with cavity oscillations. Embryonic durotaxis is initiated from asymmetric adhesion forces and is driven by embryonic protrusive forces, generated from Marangoni-like tissue flows. The intrinsic cavity oscillations further amplify and sustain embryonic durotaxis. Finally, pharmacological inhibition of embryonic durotaxis significantly reduced CSP incidence in the mouse model. Our findings establish the concept of embryonic durotaxis, which may provide novel therapeutic avenues for CSP prevention.

developmental biology↗

bioRxiv2023

The Parkinson's drug entacapone disrupts gut microbiome homeostasis via iron sequestration

Increasing evidence shows that many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single cell chemical imaging to investigate the impact of two widely prescribed nervous system targeted drugs on the gut microbiome. Ex vivo supplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. Importantly, we demonstrate that the impact of these drugs on microbial metabolism is much more pronounced than their impact on abundances, with low concentrations of drugs reducing the activity, but not the abundance of key microbiome members like Bacteroides, Ruminococcus or Clostridium species. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Remarkably, entacapone-induced iron starvation selected for iron-scavenging organisms carrying antimicrobial resistance and virulence genes. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and identifies metal sequestration as a mechanism of drug-induced microbiome disturbance.

microbiology↗

bioRxiv2021

Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China

Persistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 358 viral genomes of four major HPV types, including HPV 16 (n=82), 18 (n=35), 52 (n=121) and 58 (n=100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 strains associated with potentially high oncogenicity. These findings expanded our knowledge on the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.

genomics↗