Biology subjects

Zhai, P.

Publications and source records attributed to Zhai, P..

5 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-derived Wnt5a drives doxorubicin-induced cardiomyopathy by amplifying cellular senescence

Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent, but its use is limited by cardiotoxicity that can progress to cardiomyopathy and heart failure. Cellular senescence contributes to DOX-induced cardiac injury, yet the upstream signals that initiate and propagate senescence in the injured heart remain unclear. Here, we identify Wnt5a, a non-canonical Wnt ligand, as a mediator of anthracycline cardiomyopathy. WNT5A was increased in serum from cancer patients receiving anthracycline therapy and in a pathologic human cardiomyocyte population in the context of DOX-induced cardiomyopathy. In mouse hearts, DOX induced early cardiomyocyte-enriched Wnt5a expression before overt cardiac dysfunction. Cardiomyocyte-specific Wnt5a deletion attenuated DOX-induced cardiac dysfunction, fibrosis and senescence marker induction, whereas recombinant Wnt5a and cardiomyocyte-targeted Wnt5a overexpression were sufficient to promote cardiomyocyte senescence and cardiac dysfunction. Mechanistically, DOX activated a Wnt5a-Fzd2 feed-forward axis that amplified Wnt5a expression in cardiomyocytes and propagated senescence to neighboring fibroblasts. Genetic disruption of this pathway in cardiomyocytes, fibroblasts or senescent cells reduced DOX-induced cardiomyopathy. Pharmacological inhibition of Wnt5a signaling with secreted frizzled-related protein 5 suppressed DOX-induced cardiac injury without compromising the anticancer efficacy of DOX. These findings identify Wnt5a-Fzd2 signaling as a senescence-amplifying mechanism in anthracycline cardiomyopathy and suggest a therapeutic strategy to mitigate DOX cardiotoxicity.

cell biology↗

bioRxiv2025

Pattern separation in cerebellar-targeted whisking pre-motor nuclei

The cerebellar output can trigger whisker movement through indirect projections that pass via several brainstem pre-motor nuclei before reaching the facial nucleus, which directly controls whisker movements in rodents. Although the central pattern generator function of the intermediate reticular formation has been recently clarified, the roles of the other whisker pre-motor nuclei remain unclear. Here, we set out to compare the whisker movement kinematics of the main pre-motor whisker nuclei connecting the cerebellum and the facial nucleus. We optogenetically stimulated neurons located in the cerebellar cortex Purkinje cells (PCs), the cerebellar nuclei (CN), the red nucleus (RN), the superior colliculus (SC), the spinal trigeminal nucleus (SV), and the reticular formation (RF); in head-fixed awake mice while monitoring the bilateral whisker movement. Here, we find that optogenetic stimulation of the RN, SC, and SV resulted in a predominant midpoint change, whereas optogenetic stimulation of the PCs, CN, and RF resulted in faster whisker movements. In addition, the excitation of PCs, the RN, and SC resulted in symmetric bilateral whisking. In contrast, the excitation of CN, the RF, and SV resulted in initial asymmetric movement, followed by a more dominantly symmetrical bilateral whisking. Our results suggest that several pre-motor nuclei receiving cerebellar output modulate different aspects of whisking, suggesting pattern separation takes place in the brain-wide network downstream of the cerebellum.

neuroscience↗

bioRxiv2025

Evolutionary Trade-off Between Stomatal Defense and Gas Exchange in Brassicaceae

Stomatal opening is crucial for gas exchange, but it unavoidably offers invasion by pathogens. In response, plants close stomata to prevent pathogen entry, while the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pto) produces coronatine (COR), a jasmonate (JA) mimic, to counteract this plant response. Here, we demonstrate that by COR, Pto exploits CYP707A1 activation in Arabidopsis thaliana, encoding an enzyme that degrades abscisic acid, essential for stomatal closure. Notably, COR-induction of CYP707A1 is absent in other Brassicaceae species, such as Capsella rubella and Eutrema salsugineum, rendering them resistant to Pto invasion. In contrast, in A. thaliana, CYP707A1 enables rapid stomatal opening at dawn in a JA-dependent manner, enhancing gas exchange and chlorophyll content, unlike C. rubella and E. salsugineum. Promoter-swap experiments confirm that the regulatory region of CYP707A1 underlies these evolutionary diversifications. Together, our study presents a mechanism underlying an evolutionary trade-off between stomatal defense and gas exchange.

plant biology↗

bioRxiv2024

Suppression of autophagy induces senescence in the heart

Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function. Suppression of general autophagy in cardiac-specific Atg7 knockout (Atg7cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation of Atg7 was also observed in chimeric Atg7 cardiac-specific KO mice and cultured cardiomyocytes in vitro, suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function in Atg7cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where activation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction. O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/595978v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@dd3551org.highwire.dtl.DTLVardef@d78a85org.highwire.dtl.DTLVardef@c7505aorg.highwire.dtl.DTLVardef@16c84b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family is induced for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

neuroscience↗