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Resolving the developmental mechanisms of cardiac microthrombosis of SARS-CoV-2 based on single-cell transcriptome analysis

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Science China Life Sciences 2025年第1期68卷 103-115页

作者： Xizi Luo Nan Zhang Yuntao Liu Beibei Du Xuan Wang Tianxu Zhao Bingqiang Liu Shishun Zhao Jiazhang Qiu Guoqing Wang state key laboratory for diagnosis and treatment of Severe Zoonotic infectious diseases Key Laboratory for Zoonosis Research of the Ministry of EducationCollege of Basic MedicineJilin University state key laboratory for diagnosis and treatment of Severe Zoonotic infectious diseases Key Laboratory for Zoonosis Research of the Ministry of EducationCollege of Veterinary MedicineJilin University College of Mathematics Jilin University Bioinformatic Lab School of MathematicsShandong University Department of Cardiology China-Japan Union HospitalJilin University

The coronavirus disease 2019（COVID-19） outbreak caused by the severe acute respiratory syndrome coronavirus-2（SARS-CoV-2） developed into a global health emergency. Systemic microthrombus caused by SARS-CoV-2 infection is a common complication in patients with COVID-19. Cardiac microthrombosis as a complication of SARS-CoV-2 infection is the primary cause of cardiac injury and death in patietns with severe COVID-19. In this study, we performed single-cell sequencing analysis of the right ventricular free wall tissue from healthy donors,patients who died during the hypercoagulable period of characteristic coagulation abnormality（CAC）, and patients who died during the fibrinolytic period of CAC. We collected 61,187 cells enriched in 24 immune cell subsets and 13 cardiac-resident cell subsets. We found that in the course of SARS-CoV-2 infected heart microthrombus, MYO1EhighRASGEF1Bhighmonocyte-derived macrophages promoted hyperactivation of the immune system and initiated the extrinsic coagulation pathway by activating chemokines CCL3, CCL5. This series of events is the main cause of cardiac microthrombi following SARS-CoV-2 infection. In a SARS-CoV-2 infected heart microthrombus, excessive immune activation is accompanied by an increase in cellular iron content, which in turn promotes oxidative stress and intensifies intercellular competition. This induces cells to alter their metabolic environment, resulting in increased sugar uptake via the glycosaminoglycan synthesis pathway. In addition, high levels of reactive oxygen species generated by elevated iron levels promote increased endogenous malondialdehyde synthesis in a subpopulation of cardiac endothelial cells. This exacerbates endothelial cell dysfunction and exacerbates the coagulopathy process.

关键词： SARS-CoV-2 cardiac microthrombosis immune hyperactivation cell competition

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一种基于偶氮键一级断裂与C–C键二级断裂释放药物的β-lapachone高分子纳米前药用于肿瘤选择性治疗（英文）

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Science China Materials 2025年

作者：赵唯栋郑梦飞褚虹宇张景宣王昆杨晨光沈娜汤朝晖 key laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences School of Applied Chemistry and Engineering University of Science and Technology of China Department of Gastrointestinal Colorectal and Anal Surgery China-Japan Union Hospital of Jilin University Department of Pathogenbiology State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases College of Basic Medicine Jilin University

lapachone (β-Lap)是一种极具潜力的邻萘醌类抗肿瘤药物,但β-Lap临床应用受限于低水溶性和严重的毒副作用.前药修饰策略可有效增强药物的肿瘤选择性,但β-Lap受限于缺乏可修饰基团.本文设计了一种新型偶氮键一级断裂和碳碳键(C–C)二...

lapachone (β-Lap)是一种极具潜力的邻萘醌类抗肿瘤药物,但β-Lap临床应用受限于低水溶性和严重的毒副作用.前药修饰策略可有效增强药物的肿瘤选择性,但β-Lap受限于缺乏可修饰基团.本文设计了一种新型偶氮键一级断裂和碳碳键(C–C)二级断裂的β-Lap高分子纳米前药(Azo-Lap NP),自消除的对氨基苯基连接子通过偶氮键连接聚谷氨酸,在高表达NQO1和低pH的肿瘤环境下,实现肿瘤响应性β-Lap释放. Azo-Lap NPs对β-Lap的有效共价负载可显著提高β-Lap的给药剂量,并延长药物的肿瘤停留时间.此外, Azo-Lap NPs通过避免溶血和高铁血红蛋白的产生显著降低β-Lap的毒副作用.通过小鼠抑瘤实验验证了Azo-Lap NPs安全性.在4T1模型中, Azo-Lap NPs组的抑瘤率明显高于β-Lap组.本研究为肿瘤选择性递送β-Lap提供了一种更有效且安全的高分子纳米前药.

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High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid

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Hepatobiliary & Pancreatic diseases International 2015年第3期14卷 287-292页

作者： Yi-Min Zhang Wei Yu Ning Zhou Jian-Zhou Li Li-Chen Xu Zhong-Yang Xie Ying-Feng Lu Lan-Juan Li state key laboratory for diagnosis and treatment of infectious diseases Department of Infectious Diseases the First Affiliated Hospital Zhejiang University School of Medicine Collaborative Innovation Center for diagnosis and treatment of infectious diseases

BACKGROUND： Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of throm- bocytopenia in patients with acute-on-chronic liver failure （ACLF） who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocyto- penia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients.

关键词： acute-on-chronic liver failure linezolid thrombocytopenia

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The immunological roles in acute-on-chronic liver failure:An update

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Hepatobiliary & Pancreatic diseases International 2019年第5期18卷 403-411页

作者： Ping Chen Yun-Yun Wang Chao Chen Jun Guan Hai-Hong Zhu Zhi Chen state key laboratory for diagnosis and treatment of infectious diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital Zhejiang University School of Medicine

Background: Acute-on-chronic liver failure (ACLF) refers to the acute deterioration of liver function that occurs in patients with chronic liver disease. ACLF is characterized by acute decompensation, organ failure and high short-term mortality. Numerous studies have been conducted and remarkable progress has been made regarding the pathophysiology and pathogenesis of this disease in the last decade. The present review was to summarize the advances in this field. Data sources: A comprehensive search in PubMed and EMBASE was conducted using the medical subject words “acute-on-chronic liver failure”,“ACLF”,“pathogenesis”,“predictors”, and “immunotherapy” combined with free text terms such as “systemic inflammation” and “immune paralysis”. Relevant papers published before October 31, 2018, were included. Results: ACLF has two marked pathophysiological features, namely, excessive systemic inflammation and susceptibility to infection. The systemic inflammation is mainly manifested by a significant increase in the levels of plasma pro-inflammatory factors, leukocyte count and C-reactive protein. The underlying mechanisms are unclear and may be associated with decreased immune inhibitory cells, abnormal expression of cell surface molecules and intracellular regulatory pathways in immune cells and increased damageassociated molecular patterns in circulation. However, the main cause of susceptibility to infection is immune paralysis. Immunological paralysis is characterized by an attenuated activity of immune cells. The mechanisms are related to elevations of immune inhibitory cells and the concentration of plasma antiinflammatory molecules. Some immune biological indicators, such as soluble CD163, are used to explore the pathogenesis and prognosis of the disease, and some immunotherapies, such as glucocorticoids and granulocyte colony-stimulating factor, are effective on ACLF. Conclusions: Overwhelming systemic inflammation and susceptibility to infection are two key featur

关键词： Acute-on-chronic liver failure Pathogenesis Predictors Immunotherapy

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Effects of Salmonella infection on hepatic damage following acute liver injury in rats

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Hepatobiliary & Pancreatic diseases International 2016年第4期15卷 399-405页

作者： Yong-Tao Li Cheng-Bo Yu Dong Yan Jian-Rong Huang Lan-Juan Li state key laboratory for diagnosis and treatment of infectious diseases and Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesFirst Affiliated HospitalZhejiang University School of Medicine

BACKGROUND： Acute liver injury is a common clinical disorder associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The purpose of this study was to address this unanswered question using a rat model. METHODS： Oral supplementation with Salmonella enterica serovar enteritidis（S. enteritidis） was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the concentrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver ***： The levels of liver damage and endotoxin were significantly increased in the Salmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury（P〈0.01）; The peyer＇s patch CD3＋ T cell counts were increased significantly when the Salmonella infection with severe injury group was compared with the normal group（P〈0.05）. S. enteritidis pretreatment enhanced intestinal barrier impairment and bacterial ***： Oral S. enteritidis administration exacerbates acute liver injury, especially when injury was *** factors of the exacerbation include inflammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver.

关键词： acute liver injury Salmonella enteritidis endotoxin cytokine bacterial translocation

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Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis

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Hepatobiliary & Pancreatic diseases International 2018年第1期17卷 9-16页

作者： Qing Cao Cheng-Bo Yu Shi-Gui Yang Hong-Cui Cao Ping Chen Min Deng Lan-Juan Li state key laboratory for diagnosis and treatment of infectious diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital Zhejiang University School of Medicine

Background: Minimal hepatic encephalopathy(MHE) is an early and reversible form of hepatic encephalopathy. The documentations on the treatment with probiotics are inconsistent. The present meta-analysis was to verify the role of probiotics in the treatment of cirrhotic patients with *** sources: Seven electronic databases were searched for relevant randomized controlled trials(RCTs)published until July 2015. The effects of probiotics on serum ammonia, endotoxin, and MHE were ***: A total of 14 RCTs(combined n = 1132) were included in the meta-analysis. When probiotics were compared to placebo or no treatment, probiotics were more likely to reduce values in the number connection test(NCT; week 4: MD =-30.25, 95% CI:-49.85 to-10.66), improve MHE(week 4: OR = 0.18,95% CI: 0.07 to 0.47; week 12: OR = 0.15, 95% CI: 0.07 to 0.32), and prevent overt HE progression(week4: OR = 0.22, 95% CI: 0.07 to 0.67) in patients with liver cirrhosis. When probiotics was compared to lactulose, probiotics tended to reduce serum ammonia levels(week 4: MD =-0.33 μmol/L, 95% CI:-5.39 to 4.74; week 8: MD = 6.22 μmol/L, 95% CI:-24.04 to 36.48), decrease NCT(week 8: MD = 3.93, 95% CI:-0.72 to 8.58), improve MHE(week 4: OR = 0.93, 95% CI: 0.45 to 1.91; week 12: OR = 0.73, 95% CI: 0.35 to 1.51) and prevent the development of overt HE(week 4: OR = 0.96, 95% CI: 0.17 to 5.44; week 12:OR = 2.7, 95% CI: 0.50 to 14.64) in patients with liver cirrhosis. However, lactulose appears to be more effective in reducing NCT values as compared to probiotics(week 4: MD = 6.7, 95% CI: 0.58 to 12.82).Conclusion: Probiotics can decrease serum ammonia and endotoxin levels, improve MHE, and prevent overt HE development in patients with liver cirrhosis.

关键词： Randomized controlled trials Probiotics Lactulose Minimal hepatic encephalopathy

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Enhanced subacute ischemic stroke treatment via multistage drug delivery system design for combination therapy

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Science China Chemistry 2025年

作者： Xihan Xu Juan-Juan Li Jiamin Li Hui-Yan Zhang Yilin Qi Bing-Sen Shi Tianqi Li Shan-Shan Su Weitao Zhao Chang Chen Zhongying Gong Huiyu Liu Ke-Rang Wang Dong-Sheng Guo Xue Xue state key laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University College of Chemistry State Key Laboratory of Elemento-Organic Chemistry Key Laboratory of Functional Polymer Materials (Ministry of Education) Frontiers Science Center for New Organic Matter Collaborative Innovation Center of Chemical Science and EngineeringNankai University College of Chemistry and Materials Science State Key Laboratory of New Pharmaceutical Preparations and Excipients Key Laboratory of Medicinal Chemistry and Molecular Diagnosis (Ministry of Education) Key Laboratory of Chemical Biology of Hebei Province Hebei Research Center of the Basic Discipline of Synthetic Chemistry Hebei University Department of Neurology Tianjin First Central Hospital School of Medicine Nankai University Beijing Advanced Innovation Center for Soft Matter Science and Engineering State Key Laboratory of Organic-Inorganic Composites Beijing Laboratory of Biomedical Materials Bionanomaterials & Translational Engineering Laboratory Beijing Key Laboratory of BioprocessBeijing University of Chemical Technology

The management of acute ischemic stroke remains challenging due to its abrupt onset and the narrow treatment window,resulting in high rates of disability and *** therapy for neuroprotection and neurorepair strategies provided new hopes for subacute stroke *** we designed a multistage nanodelivery system that matches the unique microenvironment of the subacute phase of stroke,which utilizes calixarene as a building block to effectively load the neuroprotective drug *** calixarene is designed with glycosidic linkages targeting the glucose transporter 1 (GLUT1)on the blood-brain barrier (BBB) and azo bonds that are responsive to hypoxic ***,the decomposed calixarene molecules themselves possess intrinsic bio-activation to modulate inflammatory responses,achieving a multistage therapeutic approach that transitions from targeting to release and finally to *** approach combines anti-inflammation and neuroprotection,providing a multi-level treatment *** system was validated in a rat model of permanent middle cerebral artery occlusion (pMCAO),demonstrating that intravenous administration of the nanodelivery system repairs brain damage and improves motor function 24 h post-pMCAO *** work offers a precise and integrative strategy for stroke patients missing the acute therapy window to improve functional recovery and enhance the effect of comprehensive treatment.

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Progress in hepatitis B virus-related acute-on-chronic liver failure treatment in China:A large,multicenter,retrospective cohort study using a propensity score matching analysis

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Hepatobiliary & Pancreatic diseases International 2021年第6期20卷 535-541页

作者： Lan-Lan Xiao Xiao-Xin Wu Jia-Jia Chen Dong Yan Dong-Yan Shi Jian-Rong Huang Xiao-Wei Xu Lan-Juan Li state key laboratory for diagnosis and treatment of infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalZhejiang UniversityHangzhou 310003China

Background:Hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF)has a high short-term ***,the treatment progression for HBV-ACLF in China in the past decade has not been well *** present study aimed to determine whether the HBV-ACLF treatment has significantly improved during the past ***:This study retrospectively compared short-term(28/56 days)survival rates of two different nationwide cohorts(cohort I:2008-2011 and cohort II:2012-2015).Eligible HBV-ACLF patients were enrolled *** in the cohorts I and II were assigned either to the standard medical therapy(SMT)group(cohort I-SMT,cohort II-SMT)or artificial liver support system(ALSS)group(cohort IALSS,cohort II-ALSS).Propensity score matching analysis was conducted to eliminate baseline differences,and multivariate logistic regression analysis was used to explore the independent factors for 28-day ***:Short-term(28/56 days)survival rates were significantly higher in the ALSS group than those in the SMT group(Ptreatments(P=0.046).Multivariate logistic regression analysis revealed that ALSS(OR=0.962,95%CI:0.951-0.973,P=0.038),nucleos(t)ide analogs(OR=0.927,95%CI:0.871-0.983,P=0.046),old age(OR=1.028,95%CI:1.015-1.041,Ptreatment for patients with HBV-ACLF has improved

关键词： Hepatitis B virus-related acute-on-chronic liver failure Propensity score matching analysis Short-term survival rate Standard medical therapy Artificial liver support system

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A serum metabolomic analysis for diagnosis and biomarker discovery of primary biliary cirrhosis and autoimmune hepatitis

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Hepatobiliary & Pancreatic diseases International 2015年第4期14卷 413-421页

作者： Jiang-Shan Lian Wei Liu Shao-Rui Hao De-Ying Chen Yin-Yin Wang Jian-Le Yang Hong-Yu Jia Jian-Rong Huang Collaborative Innovation Center for diagnosis and treatment of infectious diseases state key laboratory for diagnosis and treatment of infectious Disease First Affiliated Hospital Zhejiang University School of Medicine Yantai City Hospital for infectious diseases

Because of the diversity of the dinical and laboratory manifestations, the diagnosis of autoimmune liver disease （AILD） remains a challenge in clinical practice. The value of metabolomics has been studied in the diagnosis of many diseases. The present study aimed to determine whether the metabolic profiles, based on ultraperformance liquid chromatography-mass spectrometry （UPLC-MS）, differed between autoimmune hepatitis （AIH） and primary biliary cir- rhosis （PBC）, to identify specific metabolomic markers, and to establish a model for the diagnosis of AIH and PBC. METHODS： Serum samples were collected from 20 patients with PBC, 19 patients with AIH, and 25 healthy individuals. UPLC-MS data of the samples were analyzed using principal component analysis, partial least squares discrimination analysis and or- thogonal partial least squares discrimination analysis. RESULTS： The partial least squares discrimination analysis model （R2y=0.991, Q2=0.943） was established between the AIH and PBC groups and exhibited both sensitivity and speci- ficity of 100%. Five groups of biomarkers were identified, in- eluding bile acids, free fatty acids, phosphatidylcholines, lyso- lecithins and sphingomyelin. Bile acids significantly increased in the AIH and PBC groups compared with the healthy con- trol group. The other biomarkers decreased in the AIH andPBC groups compared with those in the healthy control group. In addition, the biomarkers were downregulated in the AIH group compared with the PBC group. CONCLUSIONS： The biomarkers identified revealed the pathophysiological changes in AILD and helped to discrimi- nate between AIH and PBC. The predictability of this method suggests its potential application in the diagnosis of AILD.

关键词： autoimmune liver disease biomarkers metabolomics autoimmune hepatitis primary biliary cirrhosis overlap syndrome

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In vitro culture of isolated primary hepatocytes and stem cell-derived hepatocyte-like cells for liver regeneration

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Protein & Cell 2015年第8期6卷 562-574页

作者： Chenxia Hu Lanjuan Li Collaborative Innovation Center for diagnosis and treatment of infectious diseases State Key Laboratory for Diagnosis and Treatment of Infectious Diseases School of Medicine First Affiliated Hospital Zhejiang University Hangzhou 310006 China

Various liver diseases result in terminal hepatic failure, and liver transplantation, cell transplantation and artificial liver support systems are emerging as effective therapies for severe hepatic disease. However, all of these treatments are limited by organ or cell resources, so developing a sufficient number of functional hepatocytes for liver regeneration is a priority. Liver regeneration is a complex process regulated by growth factors （GFs）, cytokines, transcription factors （TFs）, hormones, oxidative stress products, metabolic net- works, and microRNA. It is well-known that the function of isolated primary hepatocytes is hard to maintain; when cultured in vitro, these cells readily undergo dedifferentia- tion, causing them to lose hepatocyte function. For this mason, most studies focus on inducing stem cells, such as embryonic stem cells （ESCs）, induced pluripotent stem cells （iPSCs）, hepatic progenitor cells （HPCs）, and mesenchymal stem cells （MSCs）, to differentiate into hepatocyte-like cells （HLCs） in vitro. In this review, we mainly focus on the nature of the liver regeneration process and discuss how to main- tain and enhance in vitro hepatic function of isolated primary hepatocytes or stem cell-derived HLCs for liver regenera- tion. In this way, hepatocytes or HLCs may be applied for clinical use for the treatment of terminal liver diseases and may prolong the survival time of patients in the near future.

关键词： liver regeneration primary hepatocyte,stem cell hepatocyte-like cell in vitro culture

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