Biology subjects

Mei, C.

Publications and source records attributed to Mei, C..

5 recordsLinked to original sources

bioRxiv2025

Oncogenic EGFR rewires STING-TBK1 immune machinery to license DNA damage tolerance

EGFR hotspot mutations (mEGFR), including primary L858R, exon 19 deletion, and secondary T790M, are pivotal oncogenic drivers in human non-small cell lung cancer (NSCLC). Meanwhile, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized immunological mechanism whereby mEGFR exploits cGAS-STING innate immune signaling, conventionally regarded as tumor-suppressive, to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly incorporates into STING signalosomes, directly phosphorylating STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 proteins, and establishing an unexpected and kinase loop critical for DNA damage repair. Disruption of this mEGFR-STING-TBK1 axis, genetically or pharmacologically, profoundly sensitized resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin notably eradicated mEGFR-driven tumors in spontaneous and immunocompetent NSCLC murine models and patient-derived organoids. Our findings suggest a new function of cGAS-STING in the DNA damage repair program, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.

cancer biology↗

bioRxiv2025

Evaluation of distal facial nerve branches contribution to facial nerve paralysis in rodents

Introduction/AimsFacial nerve paralysis is a complex and devastating condition. Translational research of facial paralysis recovery remains largely limited to animal studies, for which there are many potential models employed. When studying facial nerve regeneration in rodents, it is important to understand the converging contributions of the motor supply into the whisker pad. A consensus surgical approach and animal model has yet to be defined. Of particular interest for movement of the nose and whiskers are the buccal and marginal mandibular nerves. This study aims to evaluate how these distal nerve branches contribute to facial nerve paralysis and identify key morphological changes at the neuromuscular junctions (NMJs) in the whisker pad of rodents. MethodsAdult rats underwent isolated transection of the buccal branch of the facial nerve, both the buccal and marginal mandibular branches of the facial nerve, or control sham surgery. ResultsHistological, electrophysiological, and behavior assessments confirmed that the transection of the buccal branch alone did not cease whisker movement in rats, but when combined with a transection of the marginal mandibular branch, it resulted in full paralysis of the whisker and nose movement. DiscussionThese results are indicative of the distinct roles of these nerves branches in facial paralysis repair following a transection injury. Further, our results suggest additional targets for facial nerve repair treatments.

neuroscience↗

bioRxiv2024

D-glucuronyl C5-epimerase binds to EGFR to suppress kidney fibrosis

Renal tubular cells may actively participate in fibrosis processes leading to end-stage renal failure. However, which molecule play pivotal role in the fibrogenesis is still vague. Glucuronyl C5-epimerase (Hsepi, gene name, Glce) is a key enzyme that catalyzes biosynthesis of Heparan sulfate (HS) chains attached to HS proteoglycan which are ubiquitously located on cell membrane. Homozygous Glce-/- mice may cause embryonic lethality and multi-organ defects. However, whether Glce plays a key role in kidney fibrosis is unknown. Here, we show that Glce expression is significant attenuated in kidneys of patients with renal fibrosis and the animal models. Further study shows that renal tubular-specific Glce deletion in mice exacerbate kidney fibrosis while AAV-mediated overexpressing of Glce in UUO-treated mice may ameliorate kidney fibrosis associated with epithelial-mesenchymal transition (EMT) progress via the TGF-{beta}/Smad2/3 signaling pathway. Mechanism study demonstrates that Glce protein may bind to EGFR to inactivate EGFR/ERK signaling and further impede TGF-{beta}/Smad-driven EMT and renal fibrosis in Glce-/- and the wild type mice. Interestingly, the anti-fibrosis function is independent of Glce enzymatic activation. These data uncover a novel function for Glce which plays a key role in kidney tissues against fibrosis.

pathology↗

bioRxiv2024

Circuit mechanisms underlying sexually dimorphic outcomes of early life stress

Stress during early life influences brain development and can affect social, motor, and emotional processes. We describe a striking sex difference in the effects of early life stress (ELS), which produces anhedonia and anxiety-like behaviors in female adolescent mice, as reported previously, but repetitive behavioral pathology and social deficits in male adolescent mice. Notably, this parallels sex differences seen in the prevalence of psychiatric symptoms: depression and anxiety disorders are more common in girls and women, whereas neurodevelopmental disorders like autism spectrum disorder and Tourette syndrome are markedly more common in boys and men. We characterized the effects of ELS on the medial prefrontal cortex (mPFC) and on its projections to the dorsal striatum (dStr) and lateral septum (LS). ELS males, but not females, developed hyperactivity in the cortico-striatal circuit and hypoactivity in the cortico-septal circuit. Chemogenetic manipulation of cortico-striatal projection neurons modulates repetitive behavioral pathology and social behaviors in stressed males, and anhedonia in stressed females. Activation of cortico-septal projection neurons rescues social deficits in stressed males. We conclude that early life stress produces sexually dimorphic behavioral effects, with potential relevance to human psychiatric symptoms, through its differential effects on cortico-striatal and cortico-septal circuits.

neuroscience↗

bioRxiv2023

Levy statistics define anxiety and depression in mice subjected to chronic stress

IntroductionAnxiety and depression are recognized as adaptive responses to external stressors in organisms. Current methods for evaluating anxiety and depression in rodents are both burdensome and stressful. The objective of this investigation is to explore a simplified methodology for identifying stress-induced and stress-free states, as well as anxiety and depression levels, by analyzing the movement patterns of rodents. MethodsTo address this issue, we utilized Levy statistics to examine the movement patterns of stressed rodents and compared them to non-stressed controls. We employed the two-dimensional Kolmogorov-Smirnov test to identify significant differences in the {gamma} and parameters derived from Levy flight (LF) between anxiety, depression, and control mice. Additionally, we employed the support vector machine algorithm to optimize the classification of each group. ResultsOur analysis revealed that stressed mice displayed heavy-tailed distributions of movement velocity in open fields, resembling the movement patterns observed in animal predators searching for scarce food sources in nature. In contrast, non-stressed mice exhibited a normal distribution of speed. Notably, the effectiveness of this methodology in the field of drug discovery was confirmed by the response of stressed mice to fluoxetine, a well-established selective serotonin reuptake inhibitor (SSRI). ConclusionThis study unveils a previously unidentified statistical walking pattern in mice experiencing anxiety and depression. These findings offer a novel and accessible approach for distinguishing between anxiety, depression, and healthy mice. This method provides a one-step gentle approach (free walk in an open field) instead of the traditional multi-step stressful tests.

animal behavior and cognition↗