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A new silicon phthalocyanine dye induces pyroptosis in prostate cancer cells during photoimmunotherapy

Bioactive Materials 2024年第11期41卷 537-552页

作者： Isis Wolf Jonas Storz Susanne Schultze-Seemann Philipp REsser Stefan FMartin Susan Lauw Peer Fischer Wolfgang Melchinger robert zeiser Oliver Gorka Olaf Groß Christian Gratzke Reinhard Brückner Philipp Wolf Department of Urology Medical Center–University of Freiburg79106FreiburgGermany Faculty of Medicine University of Freiburg79106FreiburgGermany Faculty of Biology University of Freiburg79104FreiburgGermany Institute for Organic Chemistry University of Freiburg79104FreiburgGermany Allergy Research Group Department of DermatologyMedical Center–University of Freiburg79104FreiburgGermany Core Facility Signalling Factory&Robotics University of Freiburg79104FreiburgGermany BIOSS Centre for Biological Signalling Studies University of Freiburg79104FreiburgGermany Max Planck Institute for Medical Research 69120HeidelbergGermany Institute for Molecular Systems Engineering and Advanced Materials Heidelberg University69120HeidelbergGermany Department of Internal Medicine I Medical Center-University of Freiburg79106FreiburgGermany k Institute of Neuropathology Medical Center-University of Freiburg79106FreiburgGermany CIBSS Centre for Integrative Biological Signalling Studies University of Freiburg79104FreiburgGermany Received 12 Septembe

Photoimmunotherapy(PIT)combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers(PS)and is a promising new cancer *** designed and synthesized,in a highly convergent manner,the silicon phthalocyanine dye WB692-CB2,which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to *** the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen(PSMA).The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red *** cells exhibited morphological characteristics associated with *** studies revealed the generation of reactive oxygen species,triggering a cascade of intracellular events involving lipid peroxidation,caspase-1 activation,gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular *** first in vivo experiments,PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor *** study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer,including local prostate tumor lesions,and systemic activation of anti-tumor immune responses by the induction of pyroptosis.

关键词： Silicon phthalocyanine Photoimmunotherapy Cancer Pyroptosis Immunogenic cell death

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Retinoic acid signaling acts as a rheostat to balance Treg function

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Cellular & Molecular Immunology 2022年第7期19卷 820-833页

作者： Govindarajan Thangavelu Gabriela Andrejeva Sara Bolivar-Wagers Sujeong Jin Michael C.Zaiken Michael Loschi Ethan G.Aguilar Scott N.Furlan Chrysothemis C.Brown Yu-Chi Lee Cameron McDonald Hyman Colby J.Feser Angela Panoskaltsis-Mortari Keli L.Hippen Kelli P.MacDonald William J.Murphy Ivan Maillard Geoffrey R.Hill David H.Munn robert zeiser Leslie S.Kean Jeffrey C.Rathmell Hongbo Chi Randolph J.Noelle Bruce R.Blazar Department of Pediatrics Center for ImmunologyUniversity of MinnesotaMinneapolisMNUSA Center for Immunobiology Vanderbilt University Medical CenterNashville TNUSA Department of Pediatrics University of WashingtonSeattleWAUSA Fred Hutchinson Cancer Research Center SeattleWAUSA Howard Hughes Medical Institute Immunology Program and Ludwig CenterSloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Department of Microbiology and Immunology.Geisel School of Medicine at Dartmouth Norris Cotton Cancer CenterLebanonUSA Department of Immunology Queensland Institute of Medical Research(QIMR)Berghofer Medical Research Institute and School of MedicineUniversity of QueenslandBrisbaneQLDAustralia Departmentof Dermatology School of MedicineUniversity of California DavisSacramentoCAUSA Division of Hematology/Oncology Department of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPAUSA Georgia Cancer Center Augusta UniversityAugustaGAUSA Department of Haematology Oncology and Stem Cell TransplantationFaculty of MedicineFreiburg University Medical CentreFreiburgGermany Boston Children's Hospital and the Dana-Farber Cancer Institute BostonMAUSA Department of Immunology St.Jude Children's ResearchHospitalMemphisTNUSA

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory *** certain inflammatory conditions,Tregs can lose their lineage stability and *** studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and ***,it is unknown how RA receptor signaling in Tregs influences these processes in ***,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T *** the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor ***,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic *** function was observed when wild-type mice were treated with a pharmacologic pan-RAR ***,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and *** loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive *** mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA *** findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

关键词： Retinoic acid Tregulatory cells Autoimmunity Metabolism mTORC1 STAT5

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