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Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

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Neural Regeneration Research 2024年第9期19卷 2068-2074页

作者： Carolina Aguado Sara Badesso JoséMartínez-Hernández Alejandro Martín-Belmonte Rocío Alfaro-Ruiz Miriam Fernández Ana Esther Moreno-Martínez Mar Cuadrado-Tejedor Ana García-Osta Rafael Luján Synaptic Structure Laboratory Instituto de Investigación en Discapacidades Neurológicas(IDINE)Department of Medical SciencesFacultad de MedicinaUniversidad de Castilla-La ManchaCampus BiosanitarioAlbaceteSpain Gene Therapy for Neurological Disease program Center for Applied Medical Research(CIMA)University of NavarraInstituto de Investigación Sanitaria de Navarra(IdiSNA)PamplonaSpain pharmacology Unit Department of Pathology and Experimental TherapeuticsFaculty of Medicine and Health SciencesInstitute of NeurosciencesUniversity of BarcelonaBarcelonaSpain Neuropharmacology and Pain Group Neuroscience ProgramInstitut d’InvestigacióBiomèdica de BellvitgeIDIBELLL’Hospitalet de LlobregatSpain department of Pathology Anatomy and PhysiologySchool of MedicineUniversity of NavarraPamplonaSpain UniversitéGrenoble Alpes Grenoble Institut des NeurosciencesGrenobleFrance

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive *** the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic *** hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD *** the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 *** the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant *** further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic *** findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic ***,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate ***,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic ***,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic *** subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play cr

关键词： aging Alzheimer´s disease cognitive hippocampus immunoelectron microscopy resilience synapse

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Beyond reproduction:unraveling the impact of sex hormones on cardiometabolic health

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Medical Review 2024年第4期4卷 284-300页

作者： Viktoria Xega Jun-Li Liu MeDiC program The Research Institute of McGill University Health CentreMontrealCanada Division of Endocrinology and Metabolism Department of MedicineMcGill UniversityMontrealCanada

This review thoroughly explores the multifaceted roles of sexual hormones,emphasizing their impact beyond reproductive functions and underscoring their signiﬁcant inﬂuence on cardiometabolic *** analyzes the broader physiological implications of estrogen,testosterone,and progesterone,highlighting their eﬀects on metabolic syndrome,lipid metabolism,glucose homeostasis,and car-diovascular *** from diverse molecular,clin-ical,and therapeutic studies,the paper delves into the intricate interplay between these hormones and car-diometabolic *** presenting a comprehensive analysis that goes beyond traditional perspectives,and recognizing sexual hormones as more than reproductive agents,the review sheds light on their broader signiﬁcance in health and disease management,advocating for holistic and personalized medical approaches.

关键词： estrogens progesterone androgens metabolic syndrome cardiovascular diseases

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The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities

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Genes & Diseases 2024年第3期11卷 155-187页

作者： Michael Yu Kevin Qin Jiaming Fan Guozhi Zhao Piao Zhao Wei Zeng Connie Chen Annie Wang Yonghui Wang jiamin Zhong Yi Zhu William Wagstaff Rex C.Haydon Hue H.Luu Sherwin Ho Michael J.Lee Jason Strelzow Russell R.Reid Tong-Chuan He School of medicine Rosalind Franklin University of Medicine and ScienceNorth ChicagoIL 60064USA molecular Oncology Laboratory Department of Orthopedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA Ministry of Education Key Laboratory of Diagnostic medicine and Department of Clinical BiochemistryThe School of Laboratory MedicineChongqing Medical UniversityChongqing 400016China department of Orthopedic Surgery The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China department of Urology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China department of Clinical Laboratory medicine Shanghai Jiaotong University School of MedicineShanghai 200000China department of Orthopaedic Surgery Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Laboratory of Craniofacial Suture Biology and Development Department of Surgery Section of Plastic SurgeryThe University of Chicago Medical CenterChicagoIL 60637USA department of Neurology The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523475China

The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across *** proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling *** behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling *** signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various *** includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem *** signaling has also been implicated in tumor cells that exhibit stem cell-like *** signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone *** surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including *** of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and ***,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt *** with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

关键词： β-Catenin Cancer Canonical Wnt Disease Non-canonical Wnt Stem cells Targeted therapy Wnt signaling

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The prolactin receptor(PRLR)gene is linked to and associated with the comorbidity of depression and type 2 diabetes in Italian families

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Genes & Diseases 2024年第3期11卷 15-17页

作者： Mutaz Amin Rongling Wu Teodor T.Postolache Claudia Gragnoli INSERM US14-OrphanetParis 75014France University of Paris Paris 75013France department of Biochemistryand molecular Biology Faculty of MedicineAl-Neelain UniversityKhartoum 11121Sudan department of Public Health Sciences Penn State College of MedicineHersheyPA 17033USA department of Statistics Penn State College of MedicineHersheyPA 17033USA Mood and Anxiety program Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreMD 21201USA Rocky Mountain Mental Illness Research Education and Clinical Center(MIRECC) Veterans Integrated Service Network(VISN)19Military and Veteran Microbiome:Consortium for Research and Education(MVM-CoRE)DenverCO80246USA Mental illness Research Education and Clinical Center(MIRECC) Veterans Integrated Service Network(VISN)5VA Capitol Health Care NetworkBaltimoreMD 21090USA Division of Endocrinology Department of MedicineCreighton University School of MedicineOmahaNE 68124USA molecular Biology Laboratory Bios Biotech Multi-Diagnostic Health CenterRome 00197Italy

Major depressive disorder(MDD)and type 2 diabetes(T2D)are two common complex multifactorial disorders that share several genetic and environmental risk factors such as hypercortisolism and related genes'riskvariants within the stress response and the neuroendocrine hypothalamicpituitary *** stress,the pituitary gland releases prolactin(PRL),whose effects are pleiotropic and include mood control and insulin secretion from the beta cells.1 Variations in the prolactin receptor(PRLR)gene are associated in rodent models with stress level,depressionlike behavior,2 and hepatic insulin sensitivity3 and in humans with maternal glucose homeostasis and gestational diabetes.

关键词： diabetes prolactin pituitary

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Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

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Cellular & molecular Immunology 2024年第3期21卷 227-244页

作者： Kang-Gu Lee Bong-Ki Hong Saseong Lee Naeun Lee Seung-Whan Kim Donghyun Kim Wan-Uk Kim Center for Integrative Rheumatoid Transcriptomics and Dynamics The Catholic University of KoreaSeoul 06591Republic of Korea department of Biomedicine&Health Sciences The Catholic University of KoreaSeoul 06591Republic of Korea department of pharmacology Asan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea Bio-Medical Institute of Technology University of UlsanSeoul 05505Republic of Korea department of Microbiology and Immunology Seoul National University College of MedicineSeoul 03080Republic of Korea Institute of Infectious Diseases Seoul National University College of MedicineSeoul 03080Republic of Korea Division of Rheumatology Department of Internal MedicineThe Catholic University of KoreaSeoul 06591Republic of Korea

Transcriptional coactivators regulate the rate of gene expression in the *** receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains ***,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory ***,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic ***,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active *** note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in *** ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in *** with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling ***,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

关键词： Nuclear receptor coactivator 6 Nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis

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Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition:Harnessing the power of nanotheranostics

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Asian Journal of Pharmaceutical Sciences 2024年第3期19卷 79-101页

作者： Sagnik Nag Oishi Mitra Bhanu Maturi Simran Preet Kaur Ankita Saini Muskan Nama Soumik Roy Souvik Samanta Leena Chacko Rohan Dutta Suresh Babu Sayana Vetriselvan Subramaniyan Jasvinder Singh Bhatti Ramesh Kandimalla Jeffrey Cheah School of medicine and Health Sciences Monash University MalaysiaJalan Lagoon Selatan47500 Bandar SunwaySelangorMalaysia department of Bio-Sciences School of Bio-Sciences&Technology(SBST)Vellore Institute of Technology(VIT)Tiruvalam RoadVellore 632014Tamil NaduIndia department of Internal medicine University of Alabama at BirminghamBirminghamALUSA department of Microbiology University of Delhi(South Campus)Benito Juarez RoadNew Delhi 110021India department of Biotechnology Indian Institute of TechnologyHyderabad(IIT-H)SangareddyTelangana 502284India BioAnalytical Lab Meso Scale Discovery1601 Research BlvdRockvilleMDUSA department of pharmacology Government Medical CollegeSuryapetTelanganaIndia Laboratory of Translational medicine and Nanotherapeutics Department of Human Genetics and Molecular MedicineSchool of Health SciencesCentral University of PunjabBathindaIndia department of Biochemistry Kakatiya Medical CollegeWarangal 506007India

Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition(DHC),which encompasses a complex range of cardiovascular issues linked to diabetes and associated *** significant progress in reducing mortality rates from cardiovascular diseases(CVDs),heart failure remains a major cause of increased morbidity among diabetic *** cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components,and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and *** a variety of conventional diagnostic and therapeutic strategies are available,DHC continues to present a significant ***-of-care diagnostics,supported by nanobiosensing techniques,offer a promising alternative for these complex *** conventional medications have been widely used in DHC patients,they raise several concerns regarding various physiological *** medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC,offering a promising approach to deliver drugs beyond the limitations of traditional *** article aims to explore the potential connections between autophagy,mitophagy and DHC,while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

关键词： Autophagy Diabetes Diabetic heart condition Mitophagy Nanotheranostics Nanomedicine

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Single-domain antibodies as therapeutics for solid tumor treatment

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2854-2868页

作者： Mingkai Wang Tianlei Ying Yanling Wu MOE/NHC/CAMS Key Laboratory of Medical molecular Virology School of Basic Medical SciencesDepartment of Pulmonary and Critical Care MedicineDepartment of Liver Surgery and TransplantationZhongshan HospitalFudan UniversityShanghai 200032China Shanghai Engineering Research Center for Synthetic Immunology Shanghai 200032China

Single-domain antibodies(sdAbs),initially identified in camelids or sharks and commonly referred to as nanobodies or VNARs,have emerged as a promising alternative to conventional therapeutic *** sdAbs have many superior physicochemical and pharmacological properties,including small size,good solubility and thermostability,easier accessible epitopes,and strong tissue ***,the inherent challenges associated with the animal origin of sdAbs limit their clinical *** recent years,various innovative humanization technologies,including complementarity-determining region(CDR)grafting or complete engineering of fully human sdAbs,have been developed to mitigate potential immunogenicity issues and enhance their *** review provides a comprehensive exploration of sdAbs,emphasizing their distinctive features and the progress in humanization *** addition,we provide an overview of the recent progress in developing drugs and therapeutic strategies based on sdAbs and their potential in solid tumor treatment,such as sdAbedrug conjugates,multispecific sdAbs,sdAb-based delivery systems,and sdAb-based cell therapy.

关键词： Single-domain antibody Nanobody Humanization Fully human singledomain antibody Solid tumor

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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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Inverse relationship between platelet Akt activity and hippocampal atrophy:A pilot case-control study in patients with diabetes mellitus

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World Journal of Clinical Cases 2024年第2期12卷 302-313页

作者： Haruhiko Tokuda Takamitsu Hori Daisuke Mizutani Tomoyuki Hioki Kumi Kojima Takashi Onuma Yukiko Enomoto Tomoaki Doi Rie Matsushima-Nishiwaki Shinji Ogura Hiroki Iida Toru Iwama Takashi Sakurai Osamu Kozawa department of Metabolic Research Research InstituteNational Center for Geriatrics and GerontologyObu 474-8511Japan department of Clinical Laboratory National Center for Geriatrics and GerontologyObu 474-8511Japan department of pharmacology Gifu University Graduate School of MedicineGifu 501-1194Japan department of Neurosurgery Gifu University Graduate School of MedicineGifu 501-1194Japan department of Dermatology Central Japan International Medical CenterMinokamo 505-8510Japan department of Anesthesiology and Pain medicine Gifu University Graduate School of MedicineGifu 501-1194Japan department of Emergency medicine Faculty of MedicineUniversity of ToyamaToyama 930-0194Japan department of Emergency and Disaster medicine Gifu University Graduate School of MedicineGifu 501-1194Japan Research Institute National Center for Geriatrics and GerontologyObu 474-8511Japan

BACKGROUND Akt plays diverse roles in *** is involved in the pathogenesis of type 2 diabetes mellitus(T2DM),which is caused by insulin *** also plays a vital role in human platelet ***,the hippocampus is closely associated with memory and learning,and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without *** To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM *** Platelet-rich plasma(PRP)was prepared from the venous blood of patients with T2DM or age-matched *** pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt,p38 mitogen-activated protein(MAP)kinase and glyceraldehyde 3-phosphate dehydrogenase(GAPDH).Phosphorylation levels were quantified by densitometric *** volume was analysed using a voxel-based specific regional analysis system for Alzheimer’s disease on magnetic resonance imaging,which proposes the Z-score as a parameter that reflects hippocampal *** The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects,whereas the levels of phosphorylated Akt corrected with GAPDH were ***,this relationship was not observed in the control *** These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM *** findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.

关键词： Akt Platelet Hippocampal atrophy Magnetic resonance imaging Diabetes mellitus

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Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease(GSD)mouse model

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 38-50页

作者： Dongfang ZHANG Hao XU Chi QIN Kangming CAI Jing ZHANG Xinqiu XIA Jingwen BI Li ZHANG Lianping XING Qianqian LIANG Wensheng WANG Laboratory of molecular medicine College of Life Science and State Key Laboratory of Cell Differentiation and RegulationHenan Normal UniversityXinxiang453007China Longhua Hospital&Spine Institute Shanghai University of Traditional Chinese MedicineShanghai200032China Key Laboratory of Theory and Therapy of Muscles and Bones Ministry of Education(Shanghai University of Traditional Chinese Medicine)Shanghai201203China department of Pathology and Laboratory medicine University of Rochester Medical CenterRochester14642USA

Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow *** the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely *** this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of *** to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in *** the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in *** an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in *** found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like *** staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the *** on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

关键词： Semaphorin 3A Gorham-Stout disease Osteoclast Osteolysis Lymphatic endothelial cell

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