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FXR suppresses colorectal cancer by inhibiting the Wnt/β-catenin pathway via activation of TLE3

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Genes & Diseases 2023年第3期10卷 719-722页

作者： Xingchen Dong Chunmiao Cai Ting Fu Pharmaceutical Sciences Division School of PharmacyUniversity of Wisconsin Carbone Cancer Center(UWCCC)University of Wisconsin–MadisonMadisonWI 53705USA

Colorectal cancer(CRC)is the third most common and lethal cancer worldwide.1 Farnesoid X receptor(FXR)is a regulator of bile acid(BA)homeostasis and its expression is inversely correlated with the incidence of CRC.2,3 Moreover,our recent study discovered that dietary factors and dysregulated Wnt signaling independently alter BA profiles,some of which antagonize intestinal FXR,such as Tauro-β-muricholic acid(T-βMCA)and deoxycholic acid(DCA).

关键词： cancer inhibiting homeostasis

In Vivo Tumor-Targeted Dual-Modality PET/Optical Imaging with a Yolk/Shell-Structured Silica Nanosystem

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Nano-Micro Letters 2018年第4期10卷 111-121页

作者： Sixiang Shi Feng Chen Shreya Goel Stephen A.Graves Haiming Luo Charles P.Theuer Jonathan W.Engle Weibo Cai Department of Materials Science and Engineering University of Wisconsin-Madison Department of Radiology University of Wisconsin-Madison Department of Medical Physics University of Wisconsin-Madison TRACON Pharmaceuticals Inc. university of wisconsin carbone cancer center

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic *** combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

关键词： Hollow mesoporous silica nanoparticle(HMSN) Quantum dot(QD) Molecular imaging Positron emission tomography(PET) Optical imaging CD105/endoglin

PRMT5 in gene regulation and hematologic malignancies

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Genes & Diseases 2019年第3期6卷 247-257页

作者： Fen Zhu Lixin Rui Department of Medicine and carbone cancer center University of Wisconsin School of Medicine and Public HealthMadisonWI53792USA

Arginine methylation is a common posttranslational modification that governs important cellular processes and impacts development,cell growth,proliferation,and *** methylation is catalyzed by protein arginine methyltransferases(PRMTs),which are classified as type I and type II enzymes responsible for the formation of asymmetric and symmetric dimethylarginine,***5 is the main type II enzyme that catalyzes symmetric dimethylarginine of histone proteins to induce gene silencing by generating repressive histone marks,including H2AR3me2s,H3R8me2s,and ***5 can also methylate nonhistone proteins such as the transcription factors p53,E2F1 and *** of these proteins by PRMT5 are involved in diverse cellular processes,including transcription,translation,DNA repair,RNA processing,and metabolism.A growing literature demonstrates that PRMT5 expression is upregulated in hematologic malignancies,including leukemia and lymphoma,where PRMT5 regulates gene expression to promote cancer cell *** PRMT5 by specific inhibitors has emerged as a potential therapeutic strategy to treat these diseases.

关键词： Gene regulation Hematologic malignancies Metabolism Pathogenesis PRMT5

Nano-STING agonist-decorated microrobots boost innate and adaptive anti-tumor immunity

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Nano Research 2023年第7期16卷 9848-9858页

作者： Yixin Wang Zhaoting Li Yu Chen Allie Barrett Fanyi Mo Quanyin Hu Pharmaceutical Sciences Division School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA carbone cancer center School of Medicine and Public HealthUniversity of Wisconsin-MadisonMadisonWI 53705USA wisconsin center for NanoBioSystems School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA

Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains ***,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor *** ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative *** exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling ***,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep *** demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.

关键词： drug delivery mitochondrial DNA(mtDNA) Fenton reaction stimulator of interferon genes(STING) tumor immunotherapy bacteria

Double-layer probiotic encapsulation for enhanced bacteriotherapy against inflammatory bowel disease

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Nano Research 2024年第10期17卷 9103-9110页

作者： Yixin Wang Jun Liu Sichen Yuan Yawen You Quanyin Hu Pharmaceutical Sciences Division School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA carbone cancer center School of Medicine and Public HealthUniversity of Wisconsin-MadisonMadisonWI 53705USA wisconsin center for NanoBioSystems School of PharmacyUniversity of Wisconsin-MadisonMadisonWI 53705USA

Inflammatory bowel disease(IBD)is inflammatory intestinal disorders associated with dysregulated gut *** that leverages bacteria as therapeutics has shown tremendous promise in resolving gut dysbiosis and reducing inflammatory mediators to treat *** delivered probiotics,such as Escherichia coli Nissle 1917(EcN),can produce beneficial ingredients,competitively inhibit the proliferation of pathogens,and promote the restoration of gut microbiome ***,environmental stresses(such as gastric acids)in the gastrointestinal(GI)tract pose an enormous challenge to the probiotics following oral administration,leading to decreases in viability and activity of ***,the inferior mucoadhesive capability of probiotics results in low colonization efficacy,further compromising their therapeutic *** probiotics with functional biomaterials may protect them from elimination and prolong their retention in the GI ***,we developed a facile double-layer electrostatic assembly technique to encapsulate EcN bacteria in protective layers of mucoadhesive chitosan(CS)and immunomodulatory hyaluronic acid(HA)to generate *** biomaterials confer the coated EcN resistance to environmental assault and enhanced mucoadhesion in the GI *** probiotics equipped with the multifunctional shield can thus suppress inflammation and reshape the intestinal microenvironment to enhance therapeutic efficacy for the prevention and treatment of ***,this study presents a novel probiotic coating strategy to augment the outcome of bacteriotherapy to combat IBD.

关键词： probiotics biomaterial coating inflammatory bowel disease mucoadhesion oral administration

DNA methyltransferases in hematological malignancies

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Journal of Genetics and Genomics 2020年第7期47卷 361-372页

作者： Nguyet-Minh Hoang Lixin Rui Department of Medicine University of Wisconsin School of Medicine and Public HealthMadisonWI53792USA carbone cancer center University of Wisconsin School of Medicine and Public HealthMadisonWI53792USA

DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine *** mammalian DNMT family includes three major members that have functional methylation activities,termed DNMT1,DNMT3A,and ***3A and DNMT3B are responsible for methylation establishment,whereas DNMT1 maintains methylation during DNA *** evidence demonstrates that regulation of DNAmethylation by DNMTs is critical for normal *** DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies,such as DNMT3A mutations in acute myeloid *** this reviewwe first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation,We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation *** also discuss DNMT mu-tations and pathogenic roles in human leukemia and *** summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor *** highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.

关键词： DNA methyltransferases Leukemia Lymphoma Tumor suppressor DNA methylation

Convergence of nanomedicine and neutrophils for drug delivery

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Bioactive Materials 2024年第5期35卷 150-166页

作者： Sichen Yuan Quanyin Hu Pharmaceutical Sciences Division School of PharmacyUniversity of Wisconsin-MadisonMadisonWI53705United States carbone cancer center School of Medicine and Public HealthUniversity of Wisconsin-MadisonMadisonWI53705United States wisconsin center for NanoBioSystems School of PharmacyUniversity of Wisconsin-MadisonMadisonWI53705United States

Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation,chemotaxis,and *** integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects,neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes,loading nanoparticles inside living cells,or engineering chimeric antigen receptor(CAR)-*** neutrophil-inspired therapies have shown superior biocompatibility,targeting ability,and therapeutic *** this review,we summarized the benefits of combining neutrophils and nanotechnologies,the design principles and underlying mechanisms,and various applications in disease *** challenges and prospects for neutrophil-based drug delivery systems were also discussed.

关键词： Nanotechnology Neutrophil Drug delivery Cell therapy

Adoptive transfer of IL-10^(+) regulatory B cells decreases myeloid-derived macrophages in the central nervous system in a transgenic amyotrophic lateral sclerosis model

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Cellular & Molecular Immunology 2018年第7期15卷 727-730页

作者： Andrea Pennati Seneshaw Asress Jonathan D Glass Jacques Galipeau Department of Medicine University of Wisconsin School of Medicine and Public Health and University of Wisconsin Carbone Cancer CenterMadisonWI 53706USA Department of Neurology Emory UniversityAtlantaGA 30322USA

I mmunosuppressive therapies have meaningful effects on the treatment of multiple sclerosis(MS),a classical inflammatory autoimmune disease of the central nervous system.1 In mice with experimental autoimmune encephalomyelitis(EAE),a murine model of human MS,we showed that an adoptive transfer of GM-CSF and Interleukin-15 Fusion Transgene(GIFT15)-derived regulatory B cells(GIFT15 Bregs)sustained a durable remission of the disease.2,3 These regulatory B cells require the expression of MHC class II and IL-10 for suppressive activity.

关键词： sustained sclerosis autoimmune

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

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Asian Journal of Urology 2019年第1期6卷 57-64页

作者： Tyler Etheridge Shivashankar Damodaran Adam Schultz Kyle A.Richards Joseph Gawdzik Bing Yang Vincent Cryns David F.Jarrard Department of Urology University of Wisconsin-MadisonMadisonWIUSA Department of Medicine University of Wisconsin-MadisonMadisonWIUSA university of wisconsin-Madison Carbone Cancer CenterUniversity of Wisconsin-MadisonMadisonWIUSA

Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely *** clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved *** mechanisms surrounding this improved cancer outcomes are incompletely *** response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains *** laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these *** senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic *** features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are *** tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal *** review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

关键词： Prostate cancer Cellular senescence Androgen deprivation therapy Combination therapy Synthetic lethal targeting Metformin Statins