Biology subjects

Zhi, Y.

Publications and source records attributed to Zhi, Y..

5 recordsLinked to original sources

bioRxiv2026

Circadian clock gates retinal regeneration by orchestrating Cxcl12-dependent immune coordination

The circadian clock orchestrates tissue homeostasis and repair, yet its role in central nervous system (CNS) regeneration remains largely unexplored. Here, we identify the circadian clock as an essential regulator of adult zebrafish retinal regeneration, a CNS model. Retinal injuries induced at distinct circadian times elicit differential Muller glia (MG) reprogramming and progenitor proliferation, both of which exhibit robust diurnal fluctuations. Disrupting circadian rhythms--via constant darkness (DD) or day-night reversal (DL)--suppresses MG reprogramming, MG-derived progenitor cell (MGPC) formation and neuronal regeneration, concomitant with dampened retinal immune responses. Notably, intravitreal immune stimulation restores MGPC numbers in the retina under DD conditions, linking immune activation to circadian-regulated regeneration. Single-cell RNA-seq reveals that DD disrupts MG reprogramming trajectories while inducing unfolded protein response (UPR) and suppressing ATP/protein synthesis. Moreover, clock disruption alters microglia heterogeneity, and cell-cell communication analysis identifies the Cxcl12-Cxcr4 signaling as a key chemotactic axis between MG/endothelial cell and immune populations. Mechanistically, Bmal1b directly binds E-box motifs in the cxcl12a/12b promoters, driving their rhythmic transcription to orchestrate the immune response after injury. Importantly, exogenous Cxcl12a partially restores both immune and regenerative responses in clock-disrupted retinas, establishing the Cxcl12-Cxcr4 axis as a circadian-immune checkpoint for retinal repair. Collectively, our findings reveal a novel paradigm in which the circadian clock gates CNS regeneration through Cxcl12-mediated immune coordination, offering potential therapeutic insights for CNS repair in mammals.

neuroscience↗

bioRxiv2025

Pharmacological Induction of Irreversible Senescence in Drug-Tolerant Persister Cells Prevents Tumor Relapse

Despite substantial advances in targeted therapies, most patients with advanced cancers ultimately relapse. This relapse is frequently seeded by drug-tolerant persister cells (DTPs), which persist as minimal residual disease (MRD) by adopting a reversible quiescent state and later reacquire proliferative capacity under ongoing treatment. To address this, we sought to convert quiescent DTPs into an irreversible, non-proliferative state by pharmacologically inducing senescence. Through large-scale chemical screening and combination optimization, we identified SAHA plus tilorone dihydrochloride (SIC) as a regimen that robustly induces senescence in melanoma DTPs and abolishes their proliferative potential in vitro. Mechanistically, SAHA relieves HDAC1-mediated repression of HMGA2, a key senescence driver, while tilorone synergistically inhibits autophagy to promote a fully senescent state. In a melanoma xenograft mouse model receiving MAPK-targeted therapy, SIC treatment significantly suppressed MRD progression. Importantly, SIC also induced robust senescence across diverse DTP models irrespective of tumor origin, mutational background, or prior treatment. Collectively, these findings provide proof-of-concept that converting DTPs from reversible quiescence to permanent senescence represents an effective strategy to prevent relapse under targeted therapy and position SIC as a broadly applicable pharmacological approach for durable control of residual disease in advanced cancers.

cancer biology↗

bioRxiv2024

Protein S-glutathionylation confers cell resistance to ferroptosis

Ferroptosis is a type of cell death that is strongly associated with the cellular redox state. Glutathione is the key to buffering lipid peroxidation in ferroptosis and can also modify proteins by S-glutathionylation under oxidative stress. Here, we showed that the strong associations among glutathione pools, protein S-glutathionylation, and susceptibility to ferroptosis existed broadly in ferroptosis induced by erastin or acetaminophen. Deficiency of CHAC1, a glutathione-degrading enzyme, led to decreased glutathione pools and reduced protein S-glutathionylation, improved liver function and attenuated hepatocyte ferroptosis upon acetaminophen challenge, which could be retarded by CHAC1 overexpression. We conducted quantitative redox proteomics in primary mouse hepatocytes to identify glutathione pool-sensitive S-glutathionylated proteins and found that S-glutathionylation is required to maintain the function of ADP-ribosylation factor 6 (ARF6). Our data suggest that aberrant ARF6 S-glutathionylation increases the labile iron pool by delaying the recycling of transferrin receptors, thereby promoting ferroptosis. Our study reveals the importance of protein S-glutathionylation in conferring cell resistance to ferroptosis. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/592374v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@82dbaeorg.highwire.dtl.DTLVardef@1247cc5org.highwire.dtl.DTLVardef@7b7147org.highwire.dtl.DTLVardef@49ff07_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHighly upregulated CHAC1 decreases glutathione pools and protein S-glutathionylation. C_LIO_LIReduced protein S-glutathionylation associated with decreased glutathione pools promotes ferroptosis. C_LIO_LIS-glutathionylation of ARF6 at Cys90 promotes ARF6 activation. C_LIO_LIReduced S-glutathionylation of ARF6 provides a labile iron pool to drive ferroptosis. C_LI

cell biology↗

bioRxiv2022

Outer Membrane Vesicle Mediated Multidrug Resistance Gene Transfer in Avibacterium Paragallinarum

Infectious coryza is an acute upper respiratory tract infectious disease caused by Avibacterium paragallinarum, which can cause growth retardation and egg production decline of bred chickens, and bring great economic losses to poultry industry. A. Paragallinarum is a Gram-negative bacterium and can release outer membrane vesicles (OMVs). In this study, a comparative genomic analysis of A. Paragallinarum isolate P4chr1 and its OMVs were carried out, and the ability to transfer antibiotic resistance genes via the OMVs was studied. The sequencing and data analysis showed that genome size of A. paragallinarum P4chr1 is about 2.77 Mb and it has a 25 kb tolerance island covering 6 types of antibiotics and 11 resistance genes. The genome size of its OMVs is about 2.69 Mb, covering 97% genome length and almost all gene sequences of P4chr1. When purified and DNase treated A. paragallinarum P4chr1 OMVs were co-cultured with antibiotic sensitive A. paragallinarum Modesto strain on an antibiotic containing plate, the colonies grown on the plate were detected corresponding antibiotic resistance gene (ARG). However, antimicrobial susceptibility test exposed that drug resistance genes delivered by OMVs were not persistent, they only existed temporarily on the antibiotic plates. The antibiotic resistance and ARGs disappeared at second bacterial passage. Overall, this study is the first report to compare genomic characteristics of OMVs with its parent A. paragallinarum strain, and to study A. paragallinarum ARG transfer via OMVs. This work has provided useful data for further study on the issue of non-plasmid ARG transfer mediated by A. paragallinarum OMVs.

molecular biology↗

bioRxiv2020

Molecular mechanism of SARS-Cov-2 components caused ARDS in murine model

COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1, anti-IL-6, anti-TNF, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNF, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.

pathology↗