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Glucagon-like peptide (GLP)-1 regulation of lipid and lipoprotein metabolism

Medical Review 2024年第4期4卷 301-311页

作者： Simon Hoffman Khosrow Adeli Molecular Medicine Research InstituteThe Hospital for Sick ChildrenUniversity of TorontoTorontoONCanada Cardiovascular&Metabolic Disease Merck Research LaboratoriesSouth San FranciscoCAUSA Molecular Medicine Research InstituteThe Hospital for Sick ChildrenUniversity of Toronto555 University Avenue M5G 1X8TorontoONCanada

Metabolic health is highly dependent on intestinal and hepatic handling of dietary and endogenous lipids and *** of lipid and lipoprotein metabolism are commonly observed in patients with insulin resistant states such as obesity,metabolic syndrome,and type 2 ***-idence from both animal models and human studies indicates that a major underlying factor in metabolic or diabetic dysli-pidemia is the overproduction of hepatic and intestinal apoli-poprotein(apo)B-containing lipoprotein *** particles are catabolized down into highly proatherogenic remnants,which can be taken up into the arterial intima and promote plaque *** gut-derived peptides have been identiﬁed as key regulators of energy metabolism;one such peptide is the incretin hormone glucagon-like peptide(GLP)-*** laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein ***,we have demonstrated that GLP-1 receptor(GLP-1R)agonists can ameliorate diet-induced ***,we published evidence for a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic eﬀ***,we demonstrated a novel role for other gut-derived peptides in regulating intestinal lipoprotein ***,ample evidence supports a key role for GLP-1R on the portal vein aﬀerent neurons and nodose ganglion in modulating intestinal fat absorption and lipoprotein produc-tion and identiﬁes other gut-derived peptides as novel regula-tors of postprandial *** from these data may support identiﬁcation of potential drug targets and the development of new therapeutics targeting treatment of dia-betic dyslipidemia.

关键词： glucagon-like peptide-1 lipid lipoprotein intes-tine neuroendocrine

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Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression

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Research 2024年第3期2023卷 35-50页

作者： June Li Danielle Karakas Feng Xue Yingyu Chen Guangheng Zhu Yeni H.Yucel Sonya A.MacParland Haibo Zhang John W.Semple John Freedman Qizhen Shi Heyu Ni Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada toronto Platelet Immunobiology Group TorontoONCanada Keenan Research Centre for Biomedical Science of St.Michael's hospital TorontoONCanada Canadian Blood Services Centre for Innovation TorontoONCanada Departments of Pediatrics Medical College of WisconsinMilwaukeeWIUSA Blood Research Institute Versiti WisconsinMilwaukeeWIUSA Departments of Ophthalmology and Vision Sciences Medicine University of TorontoTorontoONCanada Faculty of Engineering and Architectural Science Ryerson UniversityTorontoONCanada Multi-Organ Transplant Program Toronto General Hospital Research InstituteTorontoONCanada Department of Immunology University of TorontoTorontoONCanada Critical Care Medicine Department ofAnesthesiology and PainUniversity of TorontoTorontoONCanada Department of Physiology University of TorontoTorontoONCanada Department of Pharmacology University of TorontoTorontoONCanada. Division of Hematology and Transfusion Medicine Lund UniversityLundSweden clinical Immunology and Transfusion Medicine Ofice of Medical ServicesRegion SkaneLundSweden Department of Medicine University of TorontoTorontoONCanada children's Research Institute Children's WisconsinWauwatosaWIUSA Midwest Athletes Against Childhood Cancer Fund Research Center MilwaukeeWIUSA.

Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell–Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+ regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.

关键词： Platelet transfusion homeostasis

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Intermittent fasting-a double edged sword for atherosclerosis

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Life Metabolism 2024年第3期3卷 9-11页

作者： Jacques Togo Hoon-Ki Sung Translational Medicine Program The Hospital for Sick ChildrenTorontoOntario M5G 0A4Canada Department of Laboratory Medicine and Pathobiology University of TorontoTorontoOntario M5S 1A8Canada

The impact of alternate-day fasting(ADF)on atherosclerosis remains poorly understood,particularly in high-risk popula*** a recent paper published in Life Metabolism,Deng et *** that ADF exacerbated both early and advanced atherosclerotic lesion development in Apoe^(-/-)mice through suppression of hepatic activating transcription factor 3(ATF3)and consequent dysregulation of cholesterol metabolism.

关键词： fasting atherosclerosis

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Temporal trends and practice variation of paediatric diagnostic tests in primary care:retrospective analysis of 14 million tests

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Family Medicine and Community Health 2024年第4期12卷 1-8页

作者： Elizabeth T Thomas Diana R Withrow Cynthia Wright Drakesmith Peter J Gill Rafael Perera-Salazar Carl Heneghan Centre for Evidence-Based Medicine Nuffield Department of Primary Care Health SciencesUniversity of OxfordOxfordUK Nuffield Department of Primary Care Health Sciences University of OxfordOxfordUK Department of Pediatrics University of TorontoTorontoOntarioCanada hospital for sick children TorontoOntarioCanada

Objective The primary objective was to investigate temporal trends and between-practice variability of paediatric test use in primary *** and analysis This was a descriptive study of population-based data from Clinical Practice Research Datalink Aurum primary care consultation records from 1 January 2007 to 31 December *** aged 0–15 who were registered to one of the eligible 1464 general practices and had a diagnostic test code in their clinical record were *** primary outcome measures were(1)temporal changes in test rates measured by the average annual percent change,stratified by test type,gender,age group and deprivation level and(2)practice variability in test use,measured by the coefficient of *** 14299598 diagnostic tests were requested over 27.8 million child-years of observation for 2542101 *** test use increased by 3.6%/year(95%CI 3.4 to 3.8%)from 399/1000 child-years to 608/1000 child-years,driven by increases in blood tests(8.0%/year,95%CI 7.7 to 8.4),females aged 11–15(4.0%/year,95%CI 3.7 to 4.3),and children from the most socioeconomically deprived group(4.4%/year,95%CI 4.1 to 4.8).Tests subject to the greatest temporal increases were faecal calprotectin,fractional exhaled nitric oxide and vitamin *** classified as high-use and high-practice variability were iron studies,coeliac testing,vitamin B12,folate,and vitamin *** In this first nationwide study of paediatric test use in primary care,we observed significant temporal increases and practice variability in *** reflects inconsistency in practice and diagnosis rates and a scarcity of evidence-based *** test use generates more clinical activity with significant resource implications but conversely may improve clinical *** research should evaluate whether increased test use and variability are warranted by exploring test indications and test results and directly examine how increased test use impacts

关键词： vitamin nationwide stratified

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A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

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Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn J.W.So Konstantin Feinberg Marina Manoraj Jenny Cheung Jennifer Zhang Kaveh Mirmoeini JPaul Santerre Tessa Gordon Gregory HBorschel sickKids Research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

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SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance:Implications for Antibody Therapy and Vaccinations against COVID-19

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Research 2024年第3期2023卷 1-15页

作者： Xiaoying Ma Jady Liang Guangheng Zhu Preeti Bhoria Aron A.Shoara Daniel T.MacKeigan Christopher J.Khoury Sladjana Slavkovicl Lisha Lin Danielle Karakas Ziyan Chen Viktor Prifti Zhenze Liu Chuanbin Shen Yuchong Li Cheng Zhang Jiayu Dou Zack Rousseau Jiamin Zhang Tiffany Ni Xi Lei Pingguo Chen Xiaoyu Wu Hamed Shaykhalishahi Samira Mubareka Kim AConnelly Haibo Zhang Ori Rotstein Heyu Ni Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada Department of Laboratory Medicine Keenan Research Centre for Biomedical Science of St.Michael’s HospitalTorontoONCanada toronto Platelet Immunobiology Group TorontoONCanada Department of Physiology University of TorontoTorontoONCanada CCOA Therapeutics Inc. TorontoONCanada Canadian Blood Services Centre for Innovation TorontoONCanada The State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina Department of Laboratory Medicine The Second Affliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina Advanced Pharmaceutics&Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoONCanada Department of Medical Microbiology and Infectious Disease Sunnybrook Health Science CentreToronto ONCanada Department of Medicine University of TorontoTorontoONCanada Division of Cardiology.St.Michael's hospital TorontoONCanada Department of Anesthesiology and Pain Medicine and Division of Critical Care Medicine University of TorontoTorontoONCanada interdepartmental Division of Critical Care Medicine University of TorontoTorontoONCanada Department of Surgery University of Toronto TorontoONCanada.

The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health *** cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately *** infection and vaccination utilize the spike protein receptor-binding domain(RBD)of *** found that intravenous injection of recombinant RBD caused significant platelet clearance in *** investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa *** RBD–platelet interaction was partially dependent on theβ3 integrin as binding was significantly reduced inβ3−/−***,RBD binding to human and mouse platelets was significantly reduced with relatedαIIbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 *** data show that the RBD can bind platelets partially thoughαIIbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and *** newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.

关键词： Antibody diagnosis vaccine

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DVsc:An Automated Framework for Efficiently Detecting Viral Infection from Single-cell Transcriptomics Data

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 189-200页

作者： Fei Leng Song Mei Xiaolin Zhou Xuanshi Liu Yefeng Yuan Wenjian Xu Chongyi Hao Ruolan Guo Chanjuan Hao Wei Li Peng Zhang Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute/MOE Key Laboratory of Major Diseases in Children/Rare Disease CenterBeijing Children's HospitalCapital Medical UniversityNational Center for Children's HealthBeijing 100045China Institute of Biomedical Engineering University of TorontoTorontoM5S 3G9Canada

Single-cell RNA sequencing(scRNA-seq)has emerged as a valuable tool for studying cellular heterogeneity in various fields,particularly in virological *** studying the viral and cellular transcriptomes,the dynamics of viral infection can be investigated at a single-cell ***,limited studies have been conducted to investigate whether RNA transcripts from clinical samples contain substantial amounts of viral RNAs,and a specific computational framework for efficiently detecting viral reads based on scRNA-seq data has not been ***,we introduce DVsc,an open-source framework for precise quantitative analysis of viral infection from single-cell transcriptomics *** applied to approximately 200 diverse clinical samples that were infected by more than 10 different viruses,DVsc demonstrated high accuracy in systematically detecting viral infection across a wide array of cell *** innovative bioinformatics pipeline could be crucial for addressing the potential effects of surreptitiously invading viruses on certain illnesses,as well as for designing novel medicines to target viruses in specific host cell subsets and evaluating the efficacy of *** supports the FASTQ format as an input and is compatible with multiple single-cell sequencing ***,it could also be applied to sequences from bulk RNA sequencing *** is available at http://62.***.32.33:5000/DVsc.

关键词： Single-cell RNA sequencing Viral transcriptome Cellular transcriptome Viral infection Quantitative analysis Bulk RNA sequencing

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Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics

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Journal of Pharmaceutical Analysis 2024年第2期14卷 196-210页

作者： Mariola Olkowicz Khaled Ramadan Hernando Rosales-Solano Miao Yu Aizhou Wang Marcelo Cypel Janusz Pawliszyn Department of Chemistry University of WaterlooWaterlooONCanada Jagiellonian Centre for Experimental Therapeutics(JCET) Jagiellonian UniversityKrakowPoland Latner Thoracic Surgery Research Laboratories Toronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada The Jackson Laboratory JAX Genomic MedicineFarmingtonCTUSA Division of Thoracic Surgery Department of SurgeryUniversity Health NetworkUniversity of TorontoToronto Lung Transplant ProgramTorontoONCanada

Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.

关键词： Pulmonary metastases Colorectal cancer Adjuvant chemotherapy In vivo lung chemo-perfusion Solid-phase microextraction(SPME)microprobes Spatial metabolomics

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Hormone based therapy and crosstalk beyond hormones

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Medical Review 2024年第4期4卷 257-261页

作者： Tianru Jin Division of Advanced Diagnostics Toronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada Department of Physiology Temerty Faculty of MedicineUniversity of TorontoTorontoONCanada Banting and Best Diabetes Centre Temerty Faculty of MedicineUniversity of TorontoTorontoONCanada toronto Medical Discovery Tower MaRS101 College StreetM5G 1L7TorontoONCanada

The growing prevalence of non-infectious diseases is now within the major global public health *** them,metabolic disorders,including obesity,type 2 diabetes(T2D),hypertension,cardiovascular diseases(CVD),metabolic dysfunction-associated steatotic liver disease[MASLD,previously known as non-alcoholic fatty liver disease(NAFLD)],have been drawing our attention the *** prevalence is mainly attributed to the consumption of the Western diet or“fast food”,and the sedentary ***,during the past few decades,biomedical researchers from different disciplines have made fundamental advancements of our knowledge on the pathophysiology of those diseases,facilitating the early diagnosis and bringing us novel and potential future novel strategies in the treatment and the prevention of those metabolic disorders.

关键词： prevention diagnosis bringing

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Reconstruction of Postinfarcted Cardiac Functions Through Injection of Tanshinone ⅡA@Reactive Oxygen Species-Sensitive Microspheres Encapsulated in a Thermoreversible Hydrogel

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Energy & Environmental Materials 2024年第2期7卷 187-199页

作者： Ling Yu Yubin Liang Lei Gao Peipei Chen Zhiqiang Yu Minzhou Zhang Aleksander Hinek Shuai Mao Second Clinical College Guangzhou University of Chinese MedicineGuangzhou 510120China Department of Critical Care Medicine Guangdong Provincial Hospital of Chinese MedicineGuangzhou 510120China Guangdong Provincial Branch of National Clinical Research Centre for Chinese Medicine Cardiology Guangzhou 510120China Department of Radiation Medicine and Applied Sciences University of California San DiegoLa JollaCalifornia 92093USA Department of Laboratory Medicine Dongguan Institute of Clinical Cancer ResearchAffiliated Dongguan HospitalSouthern Medical UniversityDongguan 523018China Translational Medicine Hospital for Sick ChildrenToronto M5G 0A4Canada

Myocardial damage resulting from acute myocardial infarction often leads to progressive heart failure and sudden death,highlighting the urgent clinical need for effective ***,tanshinoneⅡA has been identified as a promising therapeutic agent for myocardial ***,efficient delivery remains a major issue that limits clinical *** address this problem,an injectable thermosensitive poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid-co-glycolic acid)gel(PLGA-PEG-PLGA)system encapsulating tanshinoneⅡA-loaded reactive oxygen species-sensitive microspheres(Gel-MS/tanshinoneⅡA)has been designed and synthesized in this *** thermosensitive hydrogel exhibits good mechanical properties after reaching body *** initially immobilized by the gel exhibit excellent reactive oxygen species-triggered release properties in a high-reactive oxygen species environment after myocardial infarction *** a result,encapsulated tanshinoneⅡA is effectively released into the infarcted myocardium,where it exerts local anti-pyroptotic and anti-inflammatory ***,the combined advantages of this technique contribute to the mitigation of left ventricular remodeling and the restoration of cardiac function following tanshinoneⅡ***,this novel,precision-guided intra-tissue therapeutic system allows for customized local release of tanshinoneⅡA,presenting a promising alternative treatment strategy aimed at inducing beneficial ventricular remodeling in the post-infarct heart.

关键词： myocardial infarction ROS-sensitive polymer tanshinoneⅡA thermoreversible hydrogel ventricular remodeling

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