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Perivascular localized cells commit erythropoiesis in PDGF-B-expressing solid tumors

Cancer Communications 2023年第6期43卷 637-660页

作者： Kayoko Hosaka Chenchen Wang Shiyue Zhang Xue Lv Takahiro Seki Yin Zhang Xu Jing Jieyu Wu Qiqiao Du Xingkang He Yulong Fan Xuan Li Makoto Kondo Masahito Yoshihara Hong Qian Lihong Shi Ping Zhu Yuanfu Xu Yunlong Yang Tao Cheng Yihai Cao Department of Microbiology Tumor and Cell BiologyKarolinska InstituteStockholmSweden State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjinP.R.China Tianjin Institutes of Health Science TianjinP.R.China School of pharmacology Binzhou Medical UniversityYantaiShandongP.R.China Department of Clinical Laboratory the Second Hospital of Shandong UniversityJinanShandongP.R.China Department of Gastroenterology Sir Run Run Shaw HospitalZhejiang University Medical SchoolHangzhouZhejiangP.R.China Center for Hematology and Regenerative Medicine Department of MedicineKarolinska InstituteKarolinska University HospitalStockholmSweden Department of Biosciences and Nutrition Karolinska InstituteHuddingeSweden Department of cellular and Genetic Medicine School of Basic Medical SciencesFudan UniversityShanghaiP.R.China

Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated *** than BM,extramedullary hematopoiesis is discovered in various pathophysiological ***,whether tumors can contribute to hematopoiesis is completely *** evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other ***,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate ***:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived *** tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in ***-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological *** production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and *** investigate BM function in tumor erythropoiesis,BM transplantation mouse models were ***:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid ***-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates *** analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived sub

关键词： cancer hematopoiesis PDGF-B perivascular localized cell stem cell tumor vasculature

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The arresting phase determines the total healing time of a locally irradiated skin wound in swine

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Chinese Journal of Traumatology 2012年第1期15卷 6-12页

作者： LI Ping ZHANG En LIU Xia LIU Jian-zhong PENG Yan XIONG Ren-ping CHEN Xing-yu ZHAO Yan ZHOU Yuan-guo Molecular biology Center State Key Laboratory of Trauma Burn and Combined Injury Research Institute of Surgery and Daping Hospital Third Military Medical University Chongqing 400042 China Molecular biology Center State Key Laboratory of Trauma Burn and Combined Injury Research Institute of Surgery and Daping Hospital Third Military Medical University Chongqing 400042 China Department of pharmacology Second Military Medical University Shanghai 200433 China

Objective：Radiation is an important cause of delayed wound healing,and there still exist many questions regarding the patterns and mechanisms of wound *** study investigated the characteristics of wound healing after varying doses of local radiation and explored possible causes of the delay in healing caused by ***：A full-thickness dorsal longitudinal skin tissue,2 cm in diameter,was excised after local irradiation on one side of the back of swine,and the other side was wounded as a *** size of the wound area was recorded every two days after *** changes,proliferating cell nuclear antigen（PCNA,immunohistochemistry）and apoptosis levels（TUNEL assay）were measured at different time points after ***：The course of wound healing can be divided into four phases,namely：the arresting phase,the healing priming phase,the fast healing phase,and the healed *** the total wound healing time was closely correlated to the dose of irradiation（R2=0.9758）,it was more dependent on the length of the arresting phase（R2=0.9903）because once the arresting phase ended,the wound healed at a similar speed regardless of radiation *** analysis showed that compared with the control side there were more necrotic tissues,slower epithelial crawling,as well as fewer blood vessels and cellular components in the irradiated side at the arresting phase,while other phases revealed no significant difference concerning these *** showed that the irradiated wounds had significantly less PCNA-positive and more TUNEL-positive labeling of cells in the arresting phase than in other ***,the changes were positively related to the radiation doses,but there was no obvious difference in cell proliferation or apoptosis among the healing priming phase,fast healing phase or healed phase,whether on the control side or on the irradiated ***：After local irradiation,the length of the arre

关键词： Apoptosis Cell proliferation Radiation Wound healing

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CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

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Journal of Genetics and Genomics 2024年第5期51卷 531-542页

作者： Danhui Ruan Jiancheng Xu Yang Liu Juan Luo Xuyang Zhao Yuhua Li Guangxi Wang Jiawen Feng Hui Liang Yue Yin Jianyuan Luo Yuxin Yin Institute of Systems Biomedicine Department of PathologySchool of Basic Medical SciencesBeijing Key Laboratory of Tumor Systems BiologyPeking University International Cancer InstitutePeking-Tsinghua Center of Life SciencesPeking University Health Science CenterBeijing 100191China Institute of Precision Medicine Peking University Shenzhen HospitalShenzhenGuangdong 518036China Department of pharmacology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Department of Medical Genetics Center for Medical GeneticsSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Soochow University Cancer Institute SuzhouJiangsu 215127China

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological *** RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or ***,PTEN-related circRNAs are largely ***,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy ***-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in *** down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate *** data demonstrate that circPTEN-MT is an important regulator of cellular energy *** study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

关键词： Circular RNA LRPPRC Mitochondrial energy metabolism mtDNA post-transcriptional regulation

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Hyperhomocysteinemia dysregulates plasma levels of polyunsaturated fatty acids-derived eicosanoids

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Life Research 2022年第2期5卷 32-41页

作者： Mohamed Al-Shabrawey Ahmed Elmarakby Yara Samra Mohamed Moustafa Stephen WLooney Krishna Rao Maddipati Amany Tawfik Department of Foundational Medical Studies and Eye Research Center Oakland University William Beaumont School of MedicineRochesterMichiganUSA Eye Research Institute Oakland UniversityRochesterMichiganUSA Department of Oral biology and Diagnostic Sciences Dental College of GeorgiaAugusta UniversityAugustaGeorgiaUSA departments of pharmacology&Toxicology Faculty of PharmacyMansoura UniversityMansouraEgypt Department of Biochemistry Faculty of PharmacyMansoura UniversityEgypt Department of Population Health Sciences Medical College of GeorgiaAugusta UniversityAugustaGeorgiaUSA Bioactive Lipids Research Program Department of PathologyWayne State UniversityMichiganUSA

Hyperhomocysteinemia(HHcy)contributes to the incidence of many cardiovascular diseases(CVD).Our group have previously established crucial roles of eicosanoids and homocysteine in the incidence of vascular injury in diabetic retinopathy and renal *** cystathionine-β-synthase heterozygous mice(cβs^(+/-))as a model of HHcy,the current study was designed to determine the impact of homocysteine on circulating levels of lipid mediators derived from polyunsaturated fatty acids(PUFA).Plasma samples were isolated from wild-type(WT)and cβs^(+/-)mice for the assessment of eicosanoids levels using LC/*** 12/15-lipoxygenase(12/15-LOX)activity significantly decreased in cβs^(+/-)*** control ***-derived metabolites from both omega-3 and omega-6 PUFA were also reduced in cβs^(+/-)mice compared to WT control(P<0.05).Contrary to LOX metabolites,cytochrome P450(CYP)metabolites from omega-3 and omega-6 PUFA were significantly elevated in cβs^(+/-)mice compared to WT *** acids(EETs)are epoxides derived from arachidonic acid(AA)metabolism by CYP with anti-inflammatory properties and are known to limit vascular injury,however their physiological role is limited by their rapid degradation by soluble epoxide hydrolase(sEH)to their corresponding diols(DiHETrEs).In cβs^(+/-)mice,a significant decrease in the plasma EETs bioavailability was obvious as evident by the decrease in EETs/DiHETrEs ratio relative to WT control ***(COX)metabolites were also significantly decreased in cβs^(+/-)*** control *** data suggest that HHcy impacts eicosanoids metabolism through decreasing LOX and COX metabolic activities while increasing CYP metabolic *** increase in AA metabolism by CYP was also associated with increase in sEH activity and decrease in EETs *** of eicosanoids metabolism could be a contributing factor to the incidence and progression of HHcy-induced CVD.

关键词： homocysteine cystathionine β-synthase eicosanoids cycloxygenase lipoxygenase cytochrome-P450

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Phosphomonoester Phosphoethanolamine Induces Apoptosis in Human Chronic Myeloid Leukemia Cells

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Journal of Pharmacy and pharmacology 2019年第7期7卷 434-450页

作者： Thais de Oliveira Conceicao Manuela Garcia Laveli da Silva Durvanei Augusto Maria Molecular biology Laboratory Butantan InstituteSao PauloSPBrazil

Background:Leukemia is a type of cancer that starts in the blood or blood-forming *** results from the clonal proliferation of hematopoietic cells in the bone marrow and/or lymphoid tissues,which subsequently reach the peripheral circulation and can infiltrate other *** are many different kinds of leukemia,and treatments are different for each *** leukemia is with a slower growing than acute leukemia but could be just as *** are antitumor analogs,such as synthetic phosphoethanolamine,which is a phosphorylated compound capable of controlling cellular proliferation and inducing apoptosis in several types of tumor ***:K562 and K562-Lucena(MDR+)human chronic myeloid leukemia cells were treated with synthetic phosphoethanolamine(Pho-s).The viability was evaluated by sulforhodamine B(SRB)assay and cell cycle phases,apoptosis,markers expression,and mitochondrial potential were assessed by flow ***:Tumor cells formed clusters in suspension and decreased significantly *** concentrations for IC50%were ***-s treated were 43.1 mM(K562)and 145.9 mM(K562-Lucena MDR+)in a period of 24 ***-s induced changes in the distribution of cell population phases of cell cycle which showed an increase in fragmented DNA and increased markers expression envolved apoptosis pathways a decrease in the G1/G0 ***:Treatment of K562 and K562-Lucena(MDR+)chronic myeloid leukemia cells with Pho-s showed dose and time dependent cytotoxic *** cytotoxicity induced a decrease in proliferative capacity,mitochondrial electrical potential,and consequently release of cytochrome C;inhibition of Bcl-2 family protein expression,increase in pro-apoptotic family members Bad and Bax,dependent on p53 ***:This study presented a significant therapeutic potential of Phos-s in this type of leukemia through the apoptotic effects on tumor cells independently of the molecular resistance

关键词： Chronic myeloid leukemia cells synthetic phosphoethanolamine mitochondrial potential apoptosis cell cycle

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Meclizine Chloridrate and Methyl-β-Cyclodextrin Associated with Monophosphoester Synthetic Phosphoethanolamine Modulating Proliferative Potential in Triple-Negative Breast Cancer Cells

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Journal of Pharmacy and pharmacology 2019年第7期7卷 408-420页

作者： Manuela Garcia Laveli da Silva Luciana Bastianelli Knop Durvanei Augusto Maria Molecular biology Laboratory Butantan InstituteSao PauloSPBrazil

Synthetic phosphoethanolamine(Pho-s)is a monophosphoester ester with anti-inflammatory and pro-apoptotic *** chloridrate(MC)is a histamine H1 receptor blocker that is also able to inhibit cellular ***,MC does not inhibit cellular respiration in isolated mitochondria such as antimycin and ***-β-cyclodextrin(MβCD)belongs to theβ-cyclodextrin family,which is capable of removing cholesterol from the plasma *** aim of this study was to evaluate the proliferative effects of meclizine chloridrate and methyl-β-cyclodextrin compounds associated with synthetic phosphoethanolamine in a triple-negative human breast tumor line,MDA-MB-231 Cell viability of the tumor line and normal cells FN1 was evaluated by MTT colorimetric test;the production of free radicals was determined by lipoperoxidation(LPO)test;and the percentage of cell cycle phases and proliferative index was evaluated by flow *** viability demonstrated a significant decrease with the treatments of MβCD,MC and Pho-s associated with *** production of free radicals decreases significantly in all *** addition,a significant increase of DNA fragment and decrease in G0/G1 cell cycle phase were observed in cellular percentage with concentrations of 20 and 30 mM of Pho-s in association with MC and MβCD,respectively.

关键词： Human triple-negative breast cancer MDA-MB-231 synthetic phosphoethanolamine meclizine chloridrate methyl-β-cyclodextrin cell cycle

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Type 1 CD8^+ T Cells are Superior to Type 2 CD8^+ T Cells in Tumor Immunotherapy due to Their Efficient Cytotoxicity,Prolonged Survival and Type 1 Immune Modulation

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cellular & Molecular Immunology 2007年第4期4卷 277-285页

作者： Zhenmin Ye Chaoke Tang Shulin Xu Bei Zhang Xueshu Zhang Terence Moyana Jicheng Yang Jim Xiang Research Unit Saskatchewan Cancer Agency Departments of Oncology and Immunology College of Medicine University of Saskatchewan Saskatoon Saskatchewan S7N4H4 Canada Department of Pathology and Laboratory Medicine University of Ottawa Ottawa Ontario K1H 8L6 Canada Cell and Molecular biology Institute College of Medicine Soochow University Suzhou 215132 China Ye and Tang made the same contribution to the study.

CD8^＋ cytotoxic T （Tc） cells play a crucial role in host immune responses to cancer, and in this context, adoptive CD8^＋ Tc cell therapy has been studied in numerous animal tumor models. Its antitumor efficacy is, to a large extent, determined by the ability of Tc cells to survive and infiltrate tumors. In clinical trials, such in vitro-activated T cells often die within hours to days, and this greatly limits their therapeutic efficacy. CD8^＋ Tc cells fall into two subpopulations based upon their differential cytokine secretion. In this study, we in vitro generated that ovalbumin （OVA）-pulsed dendritic cell （DCovA）-activated CD8^＋ type 1 Tc （Tcl） cells secreting IFN-T, and CD8^＋ type 2 Tc （Tc2） cells secreting IL-4, IL-5 and IL-10, which were derived from OVA-specific T cell receptor （TCR） transgenic OT I mice. We then systemically investigated the in vitro and in vivo effector function and survival of Tcl and Tc2 cells, and then assessed their survival kinetics after adoptively transferred into C57BL/6 mice, respectively. We demonstrated that, when compared to CD8^＋ Tc2, Tcl cells were significantly more effective in perforin-mediated cytotoxicity to tumor cells, had a significantly higher capacity for in vivo survival after the adoptive T cell transfer, and had a significantly stronger therapeutic effect on eradication of well-established tumors expressing OVA in animal models. In addition, CD8^＋ Tcl and Tc2 cells skewed the phenotype of CD4^＋ T cells toward Thl and Th2 type, respectively. Therefore, the information regarding the differential effector function, survival and immune modulation of CD8^＋ Tcl and Tc2 cells may provide useful information when preparing in vitro DC-activated CD8^＋ T cells for adoptive T cell therapy of cancer.

关键词： Tc1 cell Tc2 cell cytokine profile cytotoxicity survival tumor therapy

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Muscle RING-finger protein-1 (MuRFl) functions and cellular localization are regulated by SUMOl post-translational modification

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Journal of Molecular Cell biology 2019年第5期11卷 356-370页

作者： Gabriel Heras Arvind Venkat Namuduri Leonardo Traini Ganna Shevchenko Alexander Falk Sara Bergstrom Lind Mi Jia Geng Tian Stefano Gastaldello Department of Physiology and pharmacology Karolinska Institutet Solnavagen 9 Quarter B5 Stockholm SE-17177 Sweden Department of Chemistry-BMC Analytical Chemistry Uppsala University Box 599 Uppsala SE-75124 Sweden Precision Medicine and Pharmacy Research Center Binzhou Medical University Yantai 264003 China

The muscle RING-finger protein-1 (MuRFl) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRFl gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRFl gene point mutations have been found to generate protein aggregate myopathies defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRFl turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUM01 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASy/4. SUMOylation takes place at lysine 238 localized at the second coiled-coil protein domain that is required for efficient substrate interaction for polyubiquitination. We provided evidence that SUMOylation is essential for MuRFl nuclear translocation and its mitochondria accumulation is enhanced in hyper? glycemic conditions delivering a stabilization of the overall SUMOylated proteins in cultured myocytes. Thus, our findings add this SUM01 post-translational modification as a new concept to understand muscle disorders related to the defect in MuRFl activity.

关键词： TRIM63/MuRFl muscle remodeling SUMO protein degradation hyperglycemia

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PPARαactivation inhibits astrocyte over acti⁃vation by restoring autophagy flux after tran⁃sient brain ischemia

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中国药理学与毒理学杂志 2021年第9期35卷 678-678页

作者： LUO Dou-dou YE Wen-xuan YUAN Xiao-qian ZHANG Ya-li JIN Xin ZHOU Yu Department of Basic Medical Science School of MedicineXiamen UniversityXiamen 361102China Key Laboratory of Chiral Drugs Xiamen361102China State Key Laboratory of cellular Stress biology Xiamen UniversityXiamen 361102China

OBJECTIVE Astrocytes activa⁃tion and glial scar formation are the important causes that hinder the recovery of motor function after cerebral ***,its precise mechanism has not been *** proliferator-activated receptorα(PPARα)is a ligand-activated nuclear transcriptional *** study aims to further clarify the role of PPARαin astrocyte activation after cerebral isch⁃emia and explore the underlying *** Astrocyte activation in vivo model was induced by transient middle cerebral artery occlusion(tMCAO)in mice and in vitro model was induced by oxygen-glucose deprivation/reox⁃ygenation(OGD/R)in primary culture of mouse *** effects of PPARαon astrocyte ac⁃tivation and autophagy flux were observed in the condition of PPARαdysfunction(PPARαnull mice)or PPARαactivation by oleoylethanol⁃amide(OEA).RESULTS PPARαmainly ex⁃pressed in activated astrocytes during the chron⁃ic phase of brain ischemia and PPARαdysfunc⁃tion promoted astrocytes activation after brain ischemia in vivo and in *** cerebral isch⁃emia,the expressions of LC3-Ⅱ/Ⅰand P62 both increased in the brain tissue near the infarct *** vesicles accumulation was ob⁃served by electron microscopy in astrocytes,and mRFP-GFP-LC3 adenovirus infection assay indi⁃cated the block of autophagy ***αdys⁃function aggravated autophagy flux block,while PPARαactivation preserved the lysosome func⁃tion and restored autophagy flux in astrocytes after OGD/*** flux blocker bafilomycin A1 and chloroquine antagonized the effect of OEA on inhibiting astrocyte ***⁃SION PPARαactivation inhibites the over-activa⁃tion of astrocytes by restoring the autophagy flux after cerebral ischemia.

关键词： astrocyte activation autophagy au⁃tophagy flux ischemic stroke peroxisome prolif⁃erator-activated receptorα lysosome

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Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye

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Bioactive Materials 2022年第3期7卷 77-91页

作者： Yi Han Lu Jiang Huihui Shi Chenfang Xu Minting Liu Qingjian Li Lan Zheng Hong Chi Mingyue Wang Zuguo Liu Mingliang You Xian Jun Loh Yun-Long Wu Zibiao Li Cheng Li Fujian Provincial Key Laboratory of Ophthalmology and Visual Science&Ocular Surface and Corneal Diseases Eye Institute&Affiliated Xiamen Eye CenterSchool of MedicineXiamen UniversityXiamen361102China Institute of Materials Research and Engineering A*STAR(Agency for ScienceTechnology and Research)Singapore138634Singapore School of Chemical Sciences University of Chinese Academy of ScienceBeijing100049China Key Laboratory of Marine Materials and Related Technologies Zhejiang Key Laboratory of Marine Materials and Protective TechnologiesNingbo Institute of Material Technology and EngineeringChinese Academy of ScienceNingbo315201China Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of cellular Stress biology School of Pharmaceutical SciencesXiamen UniversityXiamen361102China Hangzhou Cancer Institute Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou Cancer HospitalZhejiang University School of MedicineHangzhou310002China Shandong Provincial Key Laboratory of Molecular Engineering School of Chemistry and Pharmaceutical EngineeringQilu University of Technology(Shandong Academy of Sciences)Jinan250353China Department of Materials Science and Engineering National University of SingaporeSingapore117575Singapore

Dry eye is a common ocular disease that results in discomfort and impaired vision,impacting an individual’s quality of life.A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface,which limits their therapeutic ***,it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular ***,we develop a copolymer from mono-functional POSS,PEG,and PPG(MPOSS-PEG-PPG,MPEP)that exhibits temperature-sensitive sol-gel transition *** thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive,long-acting ocular delivery *** addition,the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular *** comparison with other FK506 formulations and the PEG-PPG-FK506(F127-FK506)hydrogel,this novel MPOSS-PEG-PPG-FK506(MPEP-FK506)hydrogel is a more effective treatment of dry eye in the murine dry eye ***,delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface,which will improve its therapeutic efficacy in the management of dry eye.

关键词： Ocular adhesive Polyhedral oligomeric silsesquioxane FK506 Dry eye

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