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Anthrax lethal toxin and tumor necrosis factor-a synergize on intestinal epithelia to induce mouse death

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Protein & Cell 2024年第2期15卷 135-148页

作者： Xinhe Gao Teng Teng Yifei Liu Tingting Ai Rui Zhao Yilong Fu Peipei Zhang Jiahuai Han Yingying Zhang State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China Research Unit of Cellular Stress of CAMS Xiang'an Hospital of Xiamen UniversityCancer Research Center of Xiamen UniversitySchool of MedicineFaculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China Laboratory Animal Center Faculty of Medicine and Life SciencesXiamen UniversityXiamen 361102China

Bacillus anthracis lethal toxin(LT)is a determinant of lethal *** function in myeloid cells is required for bacterial dissemination,and LT itself can directly trigger dysfunction of the cardiovascular *** interplay between LT and the host responses is important in the pathogenesis,but our knowledge on this interplay remains *** necrosis factor-a(TNF-a)is a pleiotropic pro-inflammatory cytokine induced by bacterial *** LT accumulates and cytokines,predominantly TNF,amass during *** infection,co-treatment of TNF+LT in mice was used to mimic in vivo conditions for LT to function in inflamed *** marrow transplantation and genetically engineered mice showed unexpectedly that the death of intestinal epithelial cells(IECs)rather than that of hematopoietic cells led to LT+TNF-induced *** of p38a mitogen-activated protein kinase(MAPK)signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs,leading to intestinal damage and mouse ***,p38a inhibition by LT enhanced TNF-mediated cell death in human colon epithelial HT-29 *** intestinal damage is one of the leading causes of lethality in anthrax patients,the IEC damage caused by LT+TNF would most likely be a mechanism underneath this clinical manifestation and could be a target for interventions.

关键词： lethal toxin TNF p38a intestinal epithelial cell cell death

Black phosphorus quantum dots induce myocardial inflammatory responses and metabolic disorders in mice

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Journal of Environmental sciences 2024年第3期137卷 53-64页

作者： Chao Shen Xiaoyan Ding Jinpeng Ruan Fengkai Ruan Weiping Hu Jiyi Huang Chengyong He Yi Yu Zhenghong Zuo Department of Nephrology State Key Laboratory of Cellular Stress BiologySchool of Life SciencesFaculty of Medicine and Life SciencesFujian Clinical Research Center for Chronic Glomerular DiseaseThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361102China

As an ultrasmall derivative of black phosphorus(BP)sheets,BP quantum dots(BP-QDs)have been effectively used in many ***,information on the cardiotoxicity induced by BP-QDs remains *** aimed to evaluate BP-QD-induced cardiac toxicity in *** examination of heart tissue sections was *** sequencing,real-time quantitative PCR(RT–qPCR),western blotting,and enzyme-linked immunosorbent assay(ELISA)assays were used to detect the m RNA and/or protein expression of proinfammatory cytokines,nuclear factor kappa B(NF-κB),phosphatidylinositol3 kinase-protein kinase B(PI3K-AKT),peroxisome proliferator-activated receptor gamma(PPARγ),and glucose/lipid metabolism pathway-related *** found that heart weight and heart/body weight index(HBI)were significantly reduced in mice after intragastric administration of 0.1 or 1 mg/kg BP-QDs for 28 *** addition,obvious infammatory cell infiltration and increased cardiomyocyte diameter were observed in the BP-QD-treated *** expression of proinfammatory cytokines and genes related to the NF-κB signaling pathway further confirmed that BP-QD exposure induced infammatory *** addition,BP-QD treatment also affected the PI3K-AKT,PPARγ,thermogenesis,oxidative phosphorylation,and cardiac muscle contraction signaling *** expression of genes related to glucose/lipid metabolism signaling pathways was dramatically affected by BP-QD exposure,and the effect was primarily mediated by the PPAR signaling *** study provides new insights into the toxicity of BP-QDs to human health.

关键词： BP-QDs Cardiac toxicity Infammatory responses NF-κB signaling pathway PPARγsignaling pathway Glucose/lipid metabolism

Picroside II promotes HSC apoptosis and inhibits the cholestatic liver fibrosis in Mdr2^(−/−)mice by polarizing M1 macrophages and balancing immune responses

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Chinese Journal of Natural medicines 2024年第7期22卷 582-598页

作者： JIA Kexin MA Zhi ZHANG Yinhao XIE Kaihong LI Jianan WU Jianzhi QU Jiaorong LI Fanghong LI Xiaojiaoyang school of life sciences Beijing University of Chinese MedicineBeijing 100029China school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar *** play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune *** II(PIC II),extracted from Picrorhizae Rhizoma,has demonstrated therapeutic potential for various liver ***,the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis,and whether this process can be influenced by PIC II,remain *** the current study,RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC II against liver fibrosis in multidrug-resistance protein 2 knockout(Mdr2^(−/−))*** findings indicate that PIC II activates M1-polarized macrophages to recruit natural killer cells(NK cells),potentially via the CXCL16-CXCR6 ***,PIC II promotes the apoptosis of activated hepatic stellate cells(aHSCs)and enhances the cytotoxic effects of NK cells,while also reducing the formation of neutrophil extracellular traps(NETs).Notably,the anti-hepatic fibrosis effects associated with PIC II were largely reversed by macrophage depletion in Mdr2^(−/−)***,our research suggests that PIC II is a potential candidate for halting the progression of liver fibrosis.

关键词： Liver fibrosis Picroside II M1 macrophage Hepatic stellate cell Natural killer cell Neutrophil

Immune states:integrated views of immunity by combining traditional Chinese medicine and modern medicine

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Science China life sciences 2024年

作者： Anlong Xu Yuxing Zhi school of life sciences and Qi-Huang school of Chinese medicine Beijing University of Chinese Medicine school of life sciences Sun Yat-sen University

Human immune system is an extraordinarily complex physiological system composed of multiple anatomical systems,diverse tissues and molecules from macroscopic to microscopic level. Numerous cells and molecules collectively participate in immune defense and immune surveillance to maintain homeostasis. More than two thousand years ago, the traditional Chinese medicine(TCM) practitioner has recognized that there are factors in the human body responsible for resisting various exogenous and endogenous pathogens, and referred these factors as“Zheng Qi”(healthy Qi), but referred various pathogenic factors as “Xie Qi”(un-healthy Qi).

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Integrated analyses of transcriptomics and network pharmacology reveal leukocyte characteristics and functional changes in subthreshold depression,elucidating the curative mechanism of Danzhi Xiaoyao powder

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Journal of Traditional Chinese Medical sciences 2024年第1期11卷 3-20页

作者： Kunyu Li Leiming You Jianhua Zhen Guangrui Huang Ting Wang Yanan Cai Yunan Zhang Anlong Xu school of life sciences Bejing University of Chinese MedicineBeijing 102488China school of life sciences Sun Yat-Sen UniversityGuangzhou 510006Chin

Objective:To investigate the molecular mechanism and identify potential drugs for subthreshold depression(SD),and elucidate the detalied mechanism of Danzhi Xiaoyao powder(DZXY)in ***:Using RNA-sequencing,we identified differentially expressed genes(DEGs)in leukocytes of SD compared to healthy controls,deciphered their functions and pathways,and identified the hub genes of *** also assessed changes in leukocyte transcription factor activity in patients with SD using the TELis *** Connectivity Map database was retrieved to screen candidate drugs for *** on network pharmacology,we elucidated the"multi-component,multi-target,and multi-pathway"mechanism of DZXY in the treatment of ***:We identified 1080 DEGs(padj<0.05 and|log2(fold change)l≥1&protein coding)in the leukocytes of patients with *** DEGs,including hub genes,were primarily involved in immune and inflammatory response-related *** factor activity analysis revealed similarities between the leukocyte transcriptome profile in SD and the conserved transcriptional response to adversities in immune *** Map analysis identified 28 potential drugs for SD treatment,particularly SB-202190 and *** the"Direct Compounds-Direct Targets-Pathways"network for DZXY and SD revealed the curative mechanisms of DZXY in SD,primarily including inflammatory response,lipid metabolism,immune response,and other ***:These results provide new insights into the characteristics and functional changes of leukocytes in SD,partially illustrate the pathogenesis of SD,and suggest potential drugs for *** curative mechanisms of DZXY in SD are also partially elucidated.

关键词： Subthreshold depression Leukocyte mRNAbiomarker CTRA Transcription factor activity CMap Danzhi Xiaoyaopowder Networkpharmacology

Targeting CD47-SIRPα axis for Hodgkin and non-Hodgkin lymphoma immunotherapy

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Genes & Diseases 2024年第1期11卷 205-217页

作者： Pengcheng Zhao Longyan Xie Lei Yu Ping Wang school of life sciences and medicine Shandong University of TechnologyZiboShandong 255000China Tongji University Cancer Center Shanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai 200092China

The interaction between cluster of differentiation 47(CD47)and signal regulatory proteinα(SiRPa)protects healthy cells from macrophage attack,which is crucial for maintain-ing immune *** of CD47 occurs widely across various tumor cell types and transmits the"don't eat me"signal to macrophages to avoid phagocytosis through binding to *** of the CD47-SIRPa axis is therefore a promising approach for cancer *** is the most common hematological malignancy and is an area of unmet clin-ical *** review mainly described the current strategies targeting the CD47-SIRPa axis,including antibodies,SiRPaFc fusion proteins,small molecule inhibitors,and peptides both in preclinical studies and clinical trials with Hodgkin lymphoma and non-Hodgkin lymphoma.

关键词： Cancer treatment CD47-SIRPαaxis Hodgkin lymphoma Immunotherapy Non-Hodgkin lymphoma

Non-pancreatic hyperlipasemia:A puzzling clinical entity

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World Journal of Gastroenterology 2024年第19期30卷 2538-2552页

作者： Krisztina Eszter Feher David Tornai Zsuzsanna Vitalis Laszlo Davida Nora Sipeki Maria Papp Division of Gastroenterology Department of Internal MedicineFaculty of MedicineUniversity of DebrecenDebrecen H-4032Hajdu-BiharHungary Kalman Laki doctoral school of Biomedical and Clinical sciences Faculty of MedicineUniversity of DebrecenDebrecen H-4032Hungary

BACKGROUND Increased lipase level is a serological hallmark of the diagnosis of acute pancreatitis(AP)but can be detected in various other diseases associated with lipase leakage due to inflammation of organs surrounding the pancreas or reduced renal clearance and/or hepatic *** non-pancreatic hyperlipasemia(NPHL)is puzzling for attending physicians during the diagnostic procedure for *** would be clinically beneficial to identify the clinical and laboratory variables that hinder the accuracy of lipase diagnosis with the aim of improve it.A more precise description of the NPHL condition could potentially provide prognostic factors for adverse outcomes which is currently *** To perform a detailed clinical and laboratory characterization of NPHL in a large prospective patient cohort with an assessment of parameters determining disease *** A Hungarian patient cohort with serum lipase levels at least three times higher than the upper limit of normal(ULN)was prospectively evaluated over 31 *** were identified using daily electronic laboratory reports developed to support an ongoing observational,multicenter,prospective cohort study called the EASY trial(ISRCTN10525246)to establish a simple,easy,and accurate clinical scoring system for early prognostication of *** of NPHL was established based on≥3×ULN serum lipase level in the absence of abdominal pain or abdominal imaging results characteristic of *** A total of 808 patients[male,n=420(52%);median age(IQR):65(51-75)years]were diagnosed with≥3×ULN serum lipase levels.A total of 392 patients had AP,whereas 401 had NPHL with more than 20 different *** and acute kidney injury(AKI)were the most prevalent etiologies of NPHL(27.7%and 33.2%,respectively).The best discriminative cut-off value for lipase was≥666 U/L(sensitivity,71.4%;specificity,88.8%).The presence of AKI or sepsis negatively affected the diagnostic performance of *** w

关键词： Non-pancreatic hyperlipasemia Acute pancreatitis Glycoprotein 2 Acute kidney injury Sepsis Mortality

Immune checkpoint inhibitors:breakthroughs in cancer treatment

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Cancer Biology & medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China Department of Biology School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China

Over the past two decades,immunotherapies have increasingly been considered as first-line treatments for most *** such treatment is immune checkpoint blockade(ICB),which has demonstrated promising results against various solid tumors in clinical *** antibodies(mAbs)are currently available as immune checkpoint inhibitors(ICIs).These ICIs target specific immune checkpoints,including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4)and programmed cell death protein 1(PD-1).Clinical trial results strongly support the feasibility of this immunotherapeutic ***,a substantial proportion of patients with cancer develop resistance or tolerance to treatment,owing to tumor immune evasion mechanisms that counteract the host immune ***,substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1,anti-programmed cell death ligand 1(anti-PD-L1),and anti-CTLA-4 ***,several immune checkpoint molecular targets have been identified,such as T cell immunoreceptor with Ig and ITIM domains(TIGIT),mucin domain containing-3(TIM-3),lymphocyte activation gene-3(LAG-3),V-domain immunoglobulin suppressor of T cell activation(VISTA),B and T lymphocyte attenuator(BTLA),and signal-regulatory proteinα(SIRPα).Functional m Abs targeting these molecules are under ***-4,PD-1/PD-L1,and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of *** review discusses these structures,as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： Immunotherapy cancer ICIs PD-1 CTLA-4

Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals

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National Science Review 2024年第2期11卷 124-134页

作者： Jingyu Li Weibo Hou Qi Zhao Wei Han Hongdi Cui Songling Xiao Ling Zhu Jiadan Qu Xiaoyu Liu Weitao Cong Jingling Shen Yuzheng Zhao Shaorong Gao Guoning Huang Qingran Kong Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive Medicine Chongqing Health Center for Women and ChildrenWomen and Children's Hospital of Chongqing Medical University Oujiang Laboratory Zhejiang Provincial Key Laboratory of Medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life Sciences Wenzhou Medical University Frontier Science Center for Stem Cell Research School of Life Sciences and Technology Tongji University school of Pharmaceutical Science Wenzhou Medical University Institute of life sciences College of Life and Environmental Sciences Wenzhou University Optogenetics&Synthetic Biology Interdisciplinary Research Center State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism School of Pharmacy East China University of Science and Technology

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation(ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-Co A and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.

关键词： mammalian preimplantation development lactate epigenetic remodeling histone lactylation zygotic genome activation