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A single-cell landscape of triptolide-associated testicular toxicity in mice

药物分析学报:英文版 2023年第8期13卷 880-893页

作者： Wei Zhang Siyu Xia Jinhuan Ou Min Cao guangqing cheng Zhijie Li Jigang Wang Chuanbin Yang Department of Nephrology Shenzhen Key Laboratory of Kidney DiseasesShenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong518020China State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research CenterInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing10700China

Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.

关键词： Single-cell sequence Transcriptomics Triptolide Reproduction toxicity Testis

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Bailing capsule(百令胶囊) alleviates autoimmune thyroiditis via regulating peroxisome proliferator-activated receptor signaling pathway: a multi-omics analysis

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Journal of Traditional Chinese Medicine 2024年

作者： WANG Qixin XU Liting WU Jiangpeng HE Xueling TANG Huan cheng guangqing LU Tianming DAI Chuanhao GUO Qiuyan WANG Jigang State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Center and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences School of Chinese Materia Medica and State Key Laboratory of Component-based Chinese Medicine Tianjin University of Traditional Chinese Medicine

OBJECTIVE: To investigate the efficacy and potential mechanism of Bailing capsule (百令胶囊， BL) anti-autoimmune thyroiditis (AIT). METHODS: Based on the AIT rat model， the effect of BL in alleviating AIT was evaluated by detecting serum thyroid index free triiodothyronine (FT3)， free thyroxine (FT4)， thyroid-stimulating hormone (TSH)， thyroglobulin antibody (TGAb)， thyroid peroxidase antibody (TPOAb)， and inflammatory factors Interferon-gamma (IFN-γ)， Interleukin-4， -10， and -12 (IL-4， IL-10， and IL-12) as well as thyroid tissue Hematoxylin-eosin (HE) staining and ultrastructure observation. The mechanism of BL was explored by combining transcriptome and proteome analysis， and further verified by Western blot (WB). RESULTS: BL effectively reduced serum FT3， FT4， TGAb， and TPOAb levels in AIT rats， restored TSH balance， inhibited the release of pro-inflammatory cytokines IFN-γ and IL-12， promoted the production of anti-inflammatory cytokines IL-4 and IL-10， and significantly reduced IFN-γ/IL-4 and IL-12/IL-10， improved thyroid follicular structure， and protected thyroid tissue from injury. Kyoto Encyclopedia of Genes and Genomes and protein interaction network analysis showed that BL affected the expression of fatty acid-binding protein 4， acyl-CoA synthetase long-chain family member 1， and acyl-CoA dehydrogenase long chain to regulate the peroxisome proliferator-activated receptor signaling pathway， thereby inhibiting the fatty acid metabolism and the inflammatory state of AIT rats. CONCLUSIONS: BL could effectively reduce thyroid inflammation in AIT model rats. The possible BL mechanism was to regulate the peroxisome proliferator-activated receptor signaling pathway and inhibit fatty acid metabolism. This study suggested that BL has the potential to be used in clinical treatment of AIT.

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Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis

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药物分析学报:英文版 2023年第7期13卷 817-829页

作者： Jiayun Chen Xueling He Yunmeng Bai Jing Liu Yin Kwan Wong Lulin Xie Qian Zhang Piao Luo Peng Gao Liwei Gu Qiuyan Guo guangqing cheng Chen Wang Jigang Wang State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China Department of Nephrology Shenzhen Key Laboratory of Kidney Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People's HospitalThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhenGuangdong518020China Department of Gastroenterology Shenzhen HospitalSouthern Medical UniversityShenzhenGuangdong518020China

Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction.Studies on the therapeutic effect and mechanism of immunomodulatory drugs on the sepsis-induced hyperinflammatory or immunosuppression states of various immune cells remain limited.This study aimed to investigate the protective effects and underlying mechanism of artesunate(ART)on the splenic microenvironment of cecal ligation and puncture-induced sepsis model mice using single-cell RNA sequencing(scRNA-seq)and experimental validations.The scRNA-seq analysis revealed that ART inhibited the activation of pro-inflammatory macrophages recruited during sepsis.ART could restore neutrophils’chemotaxis and immune function in the septic spleen.It inhibited the activation of T regulatory cells but promoted the cytotoxic function of natural killer cells during sepsis.ART also promoted the differentiation and activity of splenic B cells in mice with sepsis.These results indicated that ART could alleviate the inflammatory and/or immunosuppressive states of various immune cells involved in sepsis to balance the immune homeostasis within the host.Overall,this study provided a comprehensive investigation of the regulatory effect of ART on the splenic microenvironment in sepsis,thus contributing to the application of ART as adjunctive therapy for the clinical treatment of sepsis.

关键词： Artesunate Sepsis Single-cell RNA sequencing Immunomodulatory activity

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Single-cell transcriptome analysis uncovers underlying mechanisms of acute liver injury induced by tripterygium glycosides tablet in mice

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药物分析学报:英文版 2023年第8期13卷 908-925页

作者： Qiuyan Guo Jiangpeng Wu Qixin Wang Yuwen Huang Lin Chen Jie Gong Maobo Du guangqing cheng Tianming Lu Minghong Zhao Yuan Zhao Chong Qiu Fei Xia Junzhe Zhang Jiayun Chen Feng Qiu Jigang Wang State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing100700China School of Chinese Materia Medica and State Key Laboratory of Component-Based Chinese MedicineTianjin University of Traditional Chinese MedicineTianjin301617China Department of Nephrology Shenzhen Key Laboratory of Kidney DiseasesShenzhen Clinical Research Centre for GeriatricsShenzhen People's HospitalThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhenGuangdong518020China College of Food Science and Engineering Institute of OceanBohai UniversityJinzhouLiaoning121013China State Key Laboratory of Infectious Disease Prevention and Control Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Institute for Communicable Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing102206China Institute of Chinese Materia Medica China Academy of Chinese Medical SciencesBeijing100700China The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine ShenzhenGuangdong518033China

Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,leprosy reaction and autoimmune hepatitis.However,due to its narrow and limited treatment window,TGT-induced organ toxicity(among which liver injury accounts for about 40%of clinical reports)has gained increasing attention.The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing(scRNA-seq)technology.The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators,including alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase and total bilirubin.Using the mouse model,we identified 15 specific subtypes of cells in the liver tissue,including endothelial cells,hepatocytes,cholangiocytes,and hepatic stellate cells.Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations;led to marked inflammatory response,apoptosis and fatty acid metabolism dysfunction in hepatocytes;activated hepatic stellate cells;brought about the activation,inflammation,and phagocytosis of liver capsular macrophages cells;resulted in immune dysfunction of liver lymphocytes;disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways.Thus,these findings elaborate the mechanism underlying TGT-induced acute liver injury,provide new insights into the safe and rational applications in the clinic,and complement the identification of new biomarkers and therapeutic targets for liver protection.

关键词： Tripterygium glycosides tablet Acute liver injury scRNA-seq

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Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma

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Asian Journal of Pharmaceutical Sciences 2023年第6期18卷 157-174页

作者： Piao Luo Qian Zhang Shuo Shen Yehai An Lixia Yuan Yin-Kwan Wong Sizhe Huang Shaohui Huang Jingnan Huang guangqing cheng Jiahang Tian Yu Chena Xiaoyong Zhang Weiguang Li Songqi He Jigang Wang Qingfeng Du School of Traditional Chinese Medicine and School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Department of Biological Sciences National University of SingaporeSingapore 117543Singapore Department of Nephrology Shenzhen key Laboratory of Kidney Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People’s HospitalThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020China Department of Health Technology and Informatics The Hong Kong Polytechnic UniversityHong Kong 100872China Department of Oncology the Affiliated Hospital of Southwest Medical UniversityLuzhou 646000China National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine Jiangxi University of Chinese MedicineNanchang 330006China

Hepatocellular carcinoma(HCC)is one of most common and deadliest malignancies.Celastrol(Cel),a natural product derived from the Tripterygium wilfordii plant,has been extensively researched for its potential effectiveness in fighting cancer.However,its clinical application has been hindered by the unclear mechanism of action.Here,we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and antitumor capacity by developing a Cel-based liposomes in HCC.We demonstrated that Cel selectively targets the voltage-dependent anion channel 2(VDAC2).Cel directly binds to the cysteine residues of VDAC2,and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore(mPTP)function.We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells.Moreover,coencapsulation of Cel into alkyl glucoside-modified liposomes(AGCL)improved its antitumor efficacy and minimized its side effects.AGCL has been shown to effectively suppress the proliferation of tumor cells.In a xenograft nude mice experiment,AGCL significantly inhibited tumor growth and promoted apoptosis.Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death,while the Cel liposomes enhance its targetability and reduces side effects.Overall,Cel shows promise as a therapeutic agent for HCC.

关键词： Celastrol VDAC2 Ferroptosis Apoptosis Hepatocellular carcinoma Liposomes

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Lactiplantibacillus plantarum DPUL-S164 regulate AhR signaling to ameliorate DSS-induced intestinal barrier damage by producing indole-3-lactic acid in a tryptophan-rich diet

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Food Science and Human Wellness 2024年

作者： Arong Wang Dashuai He Tieqi Wang cheng Guan guangqing Mu Yanfeng Tuo School of Food Science and Technology Dalian Polytechnic University Dalian Probiotics Function Research Key Laboratory Dalian Polytechnic University

The aim of this paper was to study the effect of combination of Lactobacillus strains and tryptophan-rich diet on the intestinal barrier function of Balb/c mice exposed to a cocktail of antibiotics (ABX)and dextran sodium sulfate (DSS). Several Lactobacillus strains isolated from the healthy human fecal sample was found to utilize tryptophan(Trp) to produce indole derivatives. The results of Trp metabolism indicated that the ability of Lactobacillus to metabolize Trp to produce Indole-3-lactic Acid (ILA)， indole-3-carboxaldehyde (I3A)， and indole-3-acetic acid (IAA)varies in vitro and in vivo. The effect of Lactobacillus with high-yielding indole derivatives on disease activity index (DAI)， colon length， and intestinal permeability was significantly better than that of Lactobacillus with low-yielding indole derivatives in a high Trp diet. And Lactobacillus combined with Trp intervention also had a certain regulatory effect on the intestinal flora of male Balb/C mice. Among them， Lactiplantibacillus plantarum (L. plantarum) DPUL-S164 produced more ILA both in vivo and in vitro， and the combination of L. plantarum DPUL-S164 and Trp significantly decreased the expression level of the serum pro-inflammatory cytokine interleukin (IL)-6 and increased the expression level of the anti-inflammatory cytokine IL-10， significantly improved the number of goblet cells in the mouse mucous layer and increased mucin and tight junction protein expression. Furthermore， L. plantarum DPUL-S164 combined with Trp intervention activated the aryl hydrocarbon receptors (AhR) signaling pathway. Furthermore， we found that the expression of colonic tight junction protein was positively correlated with the expression of colonic AhR， and the expression of AhR was positively correlated with the concentrations of ILA and I3A in vivo. Therefore， we conclude that the ILA as AhR ligand produced by L. plantarum DPUL-S164 regulated the AhR pathway， thus up-regulating the expression of the tight junction protein and protecting the integrity of the epi

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李长生教授治疗冠心病的临证经验

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当代医药论丛 2022年第6期20卷 152-155页

作者：杨晓妮程广清陈超山东第一医科大学第一附属医院山东省千佛山医院中医科山东济南250014

冠状动脉粥样硬化性心脏病(冠心病)属于中医学中“胸痹”、“胸痹心痛”、“真心痛”等范畴。李长生教授从医近40年,擅长治疗各类心脑血管疾病。李教授认为冠心病的病机以气虚阴虚为本,以痰浊、血瘀为标,应以益气养阴、化痰活血、宣痹... 详细信息

冠状动脉粥样硬化性心脏病(冠心病)属于中医学中“胸痹”、“胸痹心痛”、“真心痛”等范畴。李长生教授从医近40年,擅长治疗各类心脑血管疾病。李教授认为冠心病的病机以气虚阴虚为本,以痰浊、血瘀为标,应以益气养阴、化痰活血、宣痹通阳、通络止痛为治疗原则。本文对李长生教授治疗冠心病的临证经验进行介绍。

关键词：李长生冠心病胸痹临证经验

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新能源电网中微电源并网控制策略研究

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电力系统保护与控制 2015年第12期43卷 55-60页

作者：陈汝昌陈飞张帆程广清云南电力调度控制中心云南昆明650041 易能(中国)电力科技有限公司北京100093

为了保证分布式发电安全并网运行,提高微电网的稳定性能,研究了微电源逆变器接口的鲁棒控制问题。该研究基于三相并网逆变器系统,建立了三阶数学模型。考虑到系统的动态模型参数的不确定性,基于Lyapunov鲁棒稳定方法设计鲁棒控制器,并... 详细信息

为了保证分布式发电安全并网运行,提高微电网的稳定性能,研究了微电源逆变器接口的鲁棒控制问题。该研究基于三相并网逆变器系统,建立了三阶数学模型。考虑到系统的动态模型参数的不确定性,基于Lyapunov鲁棒稳定方法设计鲁棒控制器,并将该鲁棒稳定性问题转换为线性矩阵不等式问题,给出保证系统稳定的充分条件。采用线性矩阵不等式的凸优化技术,可求得最小鲁棒性能指标和鲁棒控制器的参数。仿真结果证明了该控制方案的有效性。

关键词：微电网并网逆变器鲁棒控制稳定性线性矩阵不等式

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基于MAS和Petri-net技术的新能源电网协调控制策略

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电力系统保护与控制 2015年第12期43卷 1-7页

作者：朱涛梁铃宋振涛程广清云南电力调度控制中心云南昆明650041 易能(中国)电力科技有限公司北京100093

为提高新能源微电网电力供应的安全性和经济性,提出了一种基于Multi-Agent和Petri-net技术的协调控制策略。微电网是一个典型的混合系统,包括多种分布式发电和储能单元,它们具有不同行为特征和多种运行模态。考虑到这些分布式单元模态... 详细信息

为提高新能源微电网电力供应的安全性和经济性,提出了一种基于Multi-Agent和Petri-net技术的协调控制策略。微电网是一个典型的混合系统,包括多种分布式发电和储能单元,它们具有不同行为特征和多种运行模态。考虑到这些分布式单元模态运行和逻辑切换的复杂性,构建了Multi-Agent系统(MAS),通过多Agent的交互作用来实现分布式协调控制策略。由于Petri-net模型是表述多模态运行系统的最有效工具之一,所以采用petr-net模型来描述各分布式单元的模态切换行为并以此设计其单元Agent模态切换控制策略。在此基础上,基于Multi-Agent系统框架在上层中心Agent中构建各分布式能源单元之间的模态协调切换控制策略,来实现整个微电网运行模态的有效切换。最后仿真验证了所提出的控制策略的有效性。

关键词：微电网 Multi-Agent系统协调控制策略分布式能源多模态行为 Petri-net

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宁南山区土壤质量对人工植被恢复模式的响应

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农业工程学报 2014年第16期30卷 283-289页

作者：金晶炜苏纪帅白于井赵斌井光花程光庆程积民西北农林科技大学水土保持研究所杨凌712100 中国科学院水利部水土保持研究所杨凌712100 西北农林科技大学动物科技学院杨凌712100

为了评价人工植被恢复模式对土壤质量的影响，该文以宁南山区7种人工植被恢复模式为研究对象，选取0～10和＞10～20 cm土层全氮、全磷、速效磷、速效钾、有机质、pH值和土壤含水量等指标作为土壤质量评价指标，应用灰色关联模型和聚类... 详细信息

为了评价人工植被恢复模式对土壤质量的影响，该文以宁南山区7种人工植被恢复模式为研究对象，选取0～10和＞10～20 cm土层全氮、全磷、速效磷、速效钾、有机质、pH值和土壤含水量等指标作为土壤质量评价指标，应用灰色关联模型和聚类分析方法研究植被恢复对土壤质量的影响，确定最优植被恢复模式。结果表明，不同人工植被恢复模式对土壤质量有很大影响，与对照（农地）相比，恢复年限为5、10、15、20 a紫花苜蓿草地和恢复年限为30 a柠条林地均提高土壤质量，其中30 a柠条林地恢复效果最好。随着“退耕还林还草”的开展，在宁南山区，种植紫花苜蓿、建植柠条是较好的生态重建和植被恢复方式。研究结果为宁南山区植被和生态建设提供理论依据。

关键词：土壤植被聚类分析宁南山区人工植被恢复模式灰色关联模型

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