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| 1 | Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis显示文摘Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide,but the molecular basis underlying its development remains unclear.An accumulating body of evidence supports gasdermin D(GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases.However,there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis.In this work,we investigated the role of GSDMD-mediated pyroptosis in silicosis.Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression.Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica.Measurement of interleukin-1βrelease,lactic dehydrogenase activity,and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages.Additionally,we verified that both canonical(caspase-1-mediated)and non-canonical(caspase-4/5/11-mediated)signaling pathways mediated silica-induced pyroptosis activation,in vivo and in vitro.Notably,Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes,which highlighted the pivotal role of pyroptosis in this disease.Taken together,our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis. | Meiyue Song Jiaxin Wang Youliang Sun Junling Pang Xiaona Li Yuan Liu Yitian Zhou Peiran Yang Tianhui Fan Ying Liu Zhaoguo Li Xianmei Qi Baicun Li Xinri Zhang Jing Wang Chen Wang | 2022 | Acta Pharmaceutica Sinica B2022，12，3： | 5 |
| 2 | Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis:a multi-omics study with drug exploration显示文摘Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to fully decipher the intricated pathogenesis.Thus,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed.In this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents.By utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were emphasized.Notably,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of silicosis.To inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis.Overall,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis. | Mingyao Wang Zhe Zhang Jiangfeng Liu Meiyue Song Tiantian Zhang Yiling Chen Huiyuan Hu Peiran Yang Bolun Li Xiaomin Song Junling Pang Yanjiang Xing Zhujie Cao Wenjun Guo Hao Yang Jing Wang Juntao Yang Chen Wang | 2022 | Signal Transduction and Targeted Therapy2022，7，6： | 1 |
| 3 | Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma显示文摘Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380). | Yingqiang Liu Zhengsheng Zhan Zhuang Kang Mengyuan Li Yongcong Lv Shenglan Li Linjiang Tong Fang Feng Yan Li Mengge Zhang Yaping Xue Yi Chen Tao Zhang Peiran Song Yi Su Yanyan Shen Yiming Sun Xinying Yang Yi Chen Shanyan Yao Hanyu Yang Caixia Wang Meiyu Geng Wenbin Li Wenhu Duan Hua Xie Jian Ding | 2023 | Acta Pharmaceutica Sinica B2023，13，12： | 0 |
| 4 | Automated optical inspection of FAST’s reflector surface using drones and computer vision显示文摘The Five-hundred-meter Aperture Spherical radio Telescope(FAST)is the world’s largest single-dish radio telescope.Its large reflecting surface achieves unprecedented sensitivity but is prone to damage,such as dents and holes,caused by naturally-occurring falling objects.Hence,the timely and accurate detection of surface defects is crucial for FAST’s stable operation.Conventional manual inspection involves human inspectors climbing up and examining the large surface visually,a time-consuming and potentially unreliable process.To accelerate the inspection process and increase its accuracy,this work makes the first step towards automating the inspection of FAST by integrating deep-learning techniques with drone technology.First,a drone flies over the surface along a predetermined route.Since surface defects significantly vary in scale and show high inter-class similarity,directly applying existing deep detectors to detect defects on the drone imagery is highly prone to missing and misidentifying defects.As a remedy,we introduce cross-fusion,a dedicated plug-in operation for deep detectors that enables the adaptive fusion of multi-level features in a point-wise selective fashion,depending on local defect patterns.Consequently,strong semantics and fine-grained details are dynamically fused at different positions to support the accurate detection of defects of various scales and types.Our AI-powered drone-based automated inspection is time-efficient,reliable,and has good accessibility,which guarantees the long-term and stable operation of FAST. | Jianan Li Shenwang Jiang Liqiang Song Peiran Peng Feng Mu Hui Li Peng Jiang Tingfa Xu | 2023 | Light(Advanced Manufacturing)2023，4，1： | 0 |
| 5 | Bioactive elements manipulate bone regeneration显示文摘While bone tissue is known for its inherent regenerative abilities,various pathological conditions and trauma can disrupt its meticulously regulated processes of bone formation and resorption.Bone tissue engineering aims to replicate the extracellular matrix of bone tissue as well as the sophisticated biochemical mechanisms crucial for effective regeneration.Traditionally,the field has relied on external agents like growth factors and pharmaceuticals to modulate these processes.Although efficacious in certain scenarios,this strategy is compromised by limitations such as safety issues and the transient nature of the compound release and half-life.Conversely,bioactive elements such as zinc(Zn),magnesium(Mg)and silicon(Si),have garnered increasing interest for their therapeutic benefits,superior stability,and reduced biotic risks.Moreover,these elements are often incorporated into biomaterials that function as multifaceted bioactive components,facilitating bone regeneration via release on-demand.By elucidating the mechanistic roles and therapeutic efficacy of the bioactive elements,this review aims to establish bioactive elements as a robust and clinically viable strategy for advanced bone regeneration. | Long Bai Peiran Song Jiacan Su | 2023 | Biomaterials Translational2023，4，4： | 0 |
| 6 | Systems analysis of the“weights”of Bcl-2 and Mcl-1 in mitochondrial apoptosis pathway establishes a predictor for best drug combination ratio显示文摘Background:Inhibitors of B-cell CLL/Iymphoma 2(Bcl-2)family proteins have shown hope as antitumor drugs.While the notion that it is efficient to coordinate,balance,and neutralize both arms of the anti-apoptotic Bcl-2 family has been validated in many cancer cells,the weights of the two arms contributing to apoptosis inhibition have not been explored.This study analyzed the best combination ratio for different Bcl-2 selective inhibitors.Methods:We used a previously established mathematical model to study the weights of Bcl-2(representing both Bcl-2 and BcI-xL in this study)and myeloid cell leukemia-1(Mcl-1).Correlation and single-parameter sensitivity analysis were used to find the major molecular determinants for Bcl-2 and Mcl-1 dependency,as well as their weights.Biological experiments were used to verify the mathematical model.Results:Bcl-2 protein level and Mcl-1 protein level,production,and degradation rates were the major molecular determinants for Bcl-2 and Mcl-1 dependency.The model gained agreement with the experimental assays for ABT-737/A-1210477 and ABT-737/compound 5 combination effect in MCF-7 and MDA-MB-231.Two sets of equations composed of Bcl-2 and Mcl-1 levels were obtained to predict the best combination ratio for Bcl-2 inhibitors with Mcl-1 inhibitors that stabilize and downregulate Mcl-1,respectively.Conclusions:The two sets of equations can be used as tools to bypass time-consuming and laborious experimental screening to predict the best drug combination ratio for treatment. | Zongwei Guo Fangkui Yin Peiran Wang Ting Song Zhichao Zhang | 2021 | Quantitative Biology2021，9，3： | 0 |
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