Over the last several decades, radiotherapy has been considered the primary treatment option for a broad range of cancer types, aimed at prolonging patients’ survival and slowing down tumor regression. However, therapeutic outcomes of radiotherapy remain limited, and patients suffer from relapse shortly after radiation. Neutrophils can initiate an immune response to infection by releasing cytokines and chemokines to actively combat pathogens. In tumor immune microenvironment, tumor-derived signals reprogram neutrophils and induce their heterogeneity and functional versatility to promote or inhibit tumor growth. In this review, we present an overview of the typical phenotypes of neutrophils that emerge after exposure to low- and high-dose radiation. These phenotypes hold potential for developing synergistic therapeutic strategies to inhibit immunosuppressive activity and improve the antitumor effects of neutrophils to render radiation therapy as a more effective strategy for cancer patients, through tumor microenvironment modulation.

Enhancing stress resilience constitutes a pivotal strategy in mitigating the risk of depression, making it a critical component of both prevention and treatment. In the current work, we identified a compound, gastrodin (GAS), as capable of enhancing stress resilience, as demonstrated by its ability to protect against depression following chronic stress exposure. To elucidate the potential of GAS to promote neurogenesis under chronic stress, along with the associated cellular and molecular processes involved. We evaluated the effect of GAS on NSPC proliferation and differentiation using both in vitro and in vivo investigations. Neurogenesis was inhibited using temozolomide to verify GAS's impact on stress resilience. Comprehensive methodologies, including hippocampal transcriptome analysis and western blotting, were utilized to identify the involvement of the Wnt/β-catenin pathway. Immunolocalization was conducted to confirm β-catenin's nuclear translocation in SOX2⁺ cells within the hippocampal dentate gyrus subgranular zone. GAS demonstrated robust stimulation of NSPC proliferation and neuronal differentiation, enhancing adult hippocampal neurogenesis under conditions of chronic stress. Inhibition of neurogenesis negated GAS's protective effects on stress resilience. Integrated analysis pointed to the Wnt/β-catenin signaling pathway within NSPCs as a crucial mechanism facilitating GAS-promoted neurogenesis. Inhibiting Wnt expression or blocking β-catenin's nuclear translocation abolished GAS's neurogenic and stress-resilience enhancing effects. These results suggested that GAS directly activates the Wnt/β-catenin signaling pathway, which promotes the proliferation and neuronal differentiation of NSPCs, thereby enhancing adult hippocampal neurogenesis and promoting stress resilience to mitigate the risk of depression.

Depression is a common mental disorder affecting hundreds of millions worldwide. Targeting microglial peroxisome proliferator-activated receptor gamma (PPARγ) is regarded as one of the strategies to improve depression. However, a PPARγ activator capable of targeting brain microglia is currently lacking. To screen novel natural PPARγ agonists targeting brain microglia from phytomedicine and analyze their antidepressant mechanisms. Natural PPARγ agonists targeting brain microglia were identified from phytomedicine through molecular docking, kinetic simulations, surface plasmon resonance, and in vitro and in vivo approaches. The depression animal model was established using chronic unpredictable mild stress (CUMS). Depressive-like behaviors were evaluated using systematic behavioral analysis. Immunohistochemistry and Golgi staining were employed to evaluate the microglial phenotype and synaptic plasticity. The role of microglial PPARγ in improvement of neuroinflammation, synaptic impairment and depression was investigated in transgenic mice with conditional Pparg deletion in microglia. A total of 18 potential compounds capable of activating microglial PPARγ were identified. Among them, asperosaponin VI (ASA-VI) showed stable binding affinity for multiple PPARγ subtypes and promoted PPARγ nuclear translocation in microglia. ASA-VI driven the phenotypic transformation of microglia toward a neuroprotective phenotype and inhibited neuroinflammation in vitro and in vivo. ASA-VI also improved hippocampal synaptic impairment and depressive-like behaviors in CUMS-exposed mice. Critically, conditional knockout of Pparg in microglia abolished the therapeutic effects of ASA-VI on neuroinflammation, synaptic impairment and depression. Our findings identify ASA-VI as a microglial PPARγ activator that remodels microglial phenotype, suppresses neuroinflammation and alleviates stress-induced depression and synaptic impairment.