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Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

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Journal of Pharmaceutical Analysis 2024年第1期14卷 100-114页

作者： Sze Wan Hung Massimiliano Gaetani Yiran Li Zhouyurong Tan Xu Zheng Ruizhe Zhang Yang Ding Gene Chi Wai Man Tao Zhang Yi Song Yao Wang Jacqueline Pui Wah Chung Tak Hang Chan Roman A.Zubarev Chi Chiu Wang Department of Obstetrics&Gynaecology The Chinese University of Hong KongHong KongChina Division of Physiological Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Chemical Proteomics Core Facility Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSE 17177Sweden Unit of Chemical Proteomics Science for Life Laboratory(SciLifeLab)StockholmSE 17177Sweden center for Reproductive medicine Henan Key Laboratory of Reproduction and GeneticsThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450003China Department of Chemistry McGill UniversityMontrealH3A2K6Canada Department of Pharmacological&Technological Chemistry I.M.Sechenov First Moscow State Medical UniversityMoscow119146Russia Reproduction and Development Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina School of Biomedical Sciences The Chinese University of Hong KongHong KongChina chinese university of hong kong-Sichuan university joint Laboratory in Reproductive medicine The Chinese University of Hong KongHong KongChina

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the *** is a major pathophysiology in *** previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain *** this study,we demonstrated that oral ProEGCG can be effective in preventing and treating ***,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,*** simulation and BioLayer interferometry were used to confirm their binding *** results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)*** vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling ***,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

关键词： Molecular targets ProEGCG EGCG Angiogenesis Treatment Endometriosis

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Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment

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chinese Journal of Natural medicines 2024年第6期22卷 501-514页

作者： CHEN Chiwei HUANG Renlun WANG Neng ZHENG Yifeng ZHOU Jianfu YANG Bowen WANG Xuan ZHANG Juping PAN Bo CHEN Zhiqiang WANG Shengqi WANG Zhiyu XIANG Songtao The Research center of Integrative Cancer medicine Discipline of Integrated Chinese and Western Medicinethe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhou 510000China The First Clinical college of Guangzhou university of chinese medicine Guangzhou 510000China Guangdong Provincial Key Laboratory of Clinical Research on Traditional chinese medicine Syndrome Guangdong Provincial Academy of Chinese Medical SciencesGuangdong Provincial Hospital of Chinese MedicineGuangzhou 510000China Guangdong-hong kong-Macao joint Lab on chinese medicine and Immune Disease Research Guangzhou University of Chinese MedicineGuangzhou 510000China The Research center for Integrative medicine School of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhou 510000China State Key Laboratory of Dampness Syndrome of chinese medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510000China

Prostate cancer(PCa)is the second most common malignancy among men *** Fu-Zheng-Yi-Liu(FZYL)Formula has been widely utilized in the treatment of *** study investigates whether the FZYL Formula can inhibit PCa by tar-geting the TAMs/CCL5 *** conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their *** showed that the FZYL Formula significantly reduced the proliferation,colony formation,subpopulations of PCSCs,and sphere-formation efficacy of PCa cells,even in the presence of TAM ***,the Formula markedly decreased the migration,invasion,and epithelial-mesenchymal transition(EMT)of PCa cells induced by *** FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion,with minimal cytotoxicity *** studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula,as the addition of exogen-ous CCL5 partially reversed the formula’s inhibitory effects on PCSCs self-renewal in the co-culture ***,the Formula also significantly inhibited the growth of PCa xenografts,bone metastasis,and PCSCs activity in vivo by targeting the TAMs/CCL5 ***,this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

关键词： Traditional chinese medicine Tumor-associated macrophages Prostate cancer stem cells CCL5 Tumor microenvironment

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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

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Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of chinese medicine rheumatology of Zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Cancer center of Zhejiang university Hangzhou 310029China Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Chongqing International Institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to *** dysregulation of double-negative(DN)T cells is considered as a crucial commander during ***,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune ***,the function of neddylation in SLE is still ***,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus *** investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus *** double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus *** findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus ***,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was ***,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation ***,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE ***,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

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Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

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Neural Regeneration Research 2024年第2期19卷 409-415页

作者： hongmei Duan Shulun Li Peng Hao Fei Hao Wen Zhao Yudan Gao Hui Qiao Yiming Gu Yang Lv Xinjie Bao Kin Chiu Kwok-Fai So Zhaoyang Yang Xiaoguang Li Department of Neurobiology School of Basic Medical SciencesCapital Medical UniversityBeijingChina Beijing Key Laboratory for Biomaterials and Neural Regeneration School of Engineering MedicineBeihang UniversityBeijingChina Department of Epidemiology and Statistics School of Public Health and ManagementNingxia Medical UniversityYinchuanNingxia Hui Autonomous RegionChina Department of Physical Education Capital University of Economics and BusinessmBeijingChina Department of Neurosurgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Psychology State Key Lab of Brain and Cognitive SciencesThe University of Hong KongHong Kong Special Administration RegionChina Guangdong-hongkong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhouGuangdong ProvinceChina Bioland Laboratory(Guangzhou Regenerative medicine and Health Guangdong Laboratory) GuangzhouGuangdong ProvinceChina Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences The University of Hong KongHong Kong Special Administration RegionChina center for Brain Science and Brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhouGuangdong ProvinceChina Co-innovation center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina Department of Biomedical Engineering School of Biological Science and Medical EngineeringBeihang UniversityBeijingChina

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain ***,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still *** this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in *** gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional *** study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

关键词： adult endogenous neurogenesis angiogenesis basic fibroblast growth factor-chitosan gel chitosan functional recovery ischemic stroke neural stem cell newborn neuron

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Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

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Neural Regeneration Research 2024年第3期19卷 680-686页

作者： Jie Wu Yulei Huang Hanrui Yu Kaixiu Li Shifeng Zhang Guoqing Qiao Xiao Liu hongmei Duan Yifei Huang Kwok-Fai So Zhaoyang Yang Xiaoguang Li Liqiang Wang Department of Ophthalmology the Third Medical CenterChinese PLA General HospitalBeijingChina The PLA medical college Department of NephrologyChinese PLA Institute of NephrologyState Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney DiseasesBeijingChina Department of Ophthalmology Hainan Hospital of Chinese PLA General HospitalSanyaHainan ProvinceChina medical School of chinese PLA BeijingChina Department of Neurobiology School of Basic Medical SciencesCapital Medical UniversityBeijingChina Guangdong-hongkong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhouGuangdong ProvinceChina Bioland Laboratory(Guangzhou Regenerative medicine and Health Guangdong Laboratory) GuangzhouGuangdong ProvinceChina Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences The University of Hong KongHong Kong Special Administrative RegionChina center for Brain Science and Brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhouGuangdong ProvinceChina Co-innovation center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina School of Engineering medicine Beijing Key Laboratory for Biomaterials and Neural RegenerationBeihang UniversityBeijingChina Beijing International Cooperation Bases for Science and Technology on Biomaterials and Neural Regeneration Beijing Advanced Innovation Center for Big Data-Based Precision MedicineBeihang UniversityBeijingChina

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of *** treatment options for neurotrophic keratopathy are *** this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic *** the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation ***-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in *** denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic *** received topical CTH-mNGF twice daily for 8 *** sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were *** total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were *** 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by ***,six out of seven eyes had fluorescence staining scores<***,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant *** increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven *** study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release *** effecti

关键词： chitosan corneal reinnervation murine nerve growth factor neurotrophic keratopathy thermosensitive hydrogel

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Treatment of bilateral developmental dysplasia of the hip joint with an improved technique:A case report

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World Journal of Clinical Cases 2024年第7期12卷 1320-1325页

作者： Xing-Xing Yu Jian-Ye Chen hong-Sheng Zhan Ming-Da Liu Yun-Fei Li Yu-Yan Jia college of Traditional chinese medicine Changchun University of Traditional Chinese MedicineChangchun 130117Jilin ProvinceChina Shi's Traumatology medical center Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 201203China college of Traditional chinese medicine The Affiliated Hospital of Changchun University of Chinese MedicineChangchun 130021Jilin ProvinceChina

BACKGROUND Developmental dysplasia of the hip(DDH)is a common osteoarticular deformity in pediatric orthopedics.A patient with bilateral DDH was diagnosed and treated using our improved technique"(powerful overturning acetabuloplasty)"combined with femoral rotational shortening *** SUMMARY A 4-year-old girl who was diagnosed with bilateral DDH could not stand normally,and sought surgical treatment to solve the problem of double hip extension and *** this child had high dislocation of the hip joint and the acetabular index was high,we changed the traditional acetabuloplasty to"powerful turnover acetabuloplasty"combined with femoral rotation shortening *** the short-term postoperative follow-up(1,3,6,9,12,and 15 months),the child had no discomfort in her lower *** the braces and internal fixation plates were removed,formal rehabilitation training was actively carried *** Our"powerful overturning acetabuloplasty"combined with femoral rotational shortening osteotomy is feasible in the treatment of DDH in *** technology may be widely used in the clinic.

关键词： Developmental dysplasia of the hip Improved technique Case report

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DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation

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Science China(Life Sciences) 2024年第8期67卷 1620-1634页

作者： Yunde Dou Rusong Zhao Han Wu Zhiheng Yu Changjian Yin Jie Yang Chaoyan Yang Xiaohua Luan Yixiao Cheng Tao Huang Yuehong Bian Shan Han Yuqing Zhang Xin Xu Zi-Jiang Chen Han Zhao Shigang Zhao Institute of Women Children and Reproductive HealthShandong UniversityJinan 250012China State Key Laboratory of Reproductive medicine and Offspring Health Jinan 250012China Key laboratory of Reproductive Endocrinology of Ministry of Education Shandong UniversityJinan 250012China Shandong Key Laboratory of Reproductive medicine Shandong UniversityJinan 250012China Shandong Provincial Clinical Research center for Reproductive Health Jinan 250012China National Research center for Assisted Reproductive Technology and Reproductive genetics Shandong UniversityJinan 250012China The Affiliated Suzhou Hospital of Nanjing medical university Suzhou Municipal HospitalNanjing Medical UniversitySuzhou 215008China Gusu School Nanjing Medical UniversitySuzhou 215000China Guangdong Provincial People’s Hospital Guangdong Academy of Medical SciencesGuangzhou 510080China Guangdong-hong kong Metabolism&Reproduction joint Laboratory Guangdong Second Provincial General HospitalGuangzhou 510317China Reproductive medicine center Guangdong Second Provincial General HospitalGuangzhou 510317China Research Unit of Gametogenesis and Health of ART-Offspring Chinese Academy of Medical Sciences(No.2021RU001)Jinan 250012China Shanghai Key Laboratory for Assisted Reproduction and Reproductive genetics Shanghai 200127China center for Reproductive medicine Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

Polycystic ovary syndrome(PCOS)is a complex ***-wide association studies(GWAS)have identified several genes associated with this condition,including ***1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular ***,the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly *** this study,we investigated DENND1A expression in ovarian granulosa cells(GCs)from PCOS patients and its correlation with *** results revealed an upregulation of DENND1A expression in GCs from PCOS cases,which was positively correlated with testosterone *** further explore the functional implications of DENND1A,we generated a transgenic mouse model overexpressing Dennd1a(TG mice).These TG mice exhibited subfertility,irregular estrous cycles,and increased testosterone production following PMSG ***,the TG mice displayed diminished responsiveness to FSH,characterized by smaller ovary size,less well-developed follicles,and abnormal expressions of FSH-priming ***,we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor(FSHR),promoting its internalization and inhibiting *** findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms,thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.

关键词： PCOS DENND1A FSHR ovarian granulosa cells

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TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway

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Current medical Science 2024年第3期44卷 589-602页

作者： An-bang SUN Fang-hua LI Lin ZHU Xi-xi ZENG Min ZHU Qing-hua LEI Yan-hong LIAO Department of Anatomy School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Transfusion medicine Wuhan Hospital of Traditional Chinese and Western MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Department of Nephrology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China Department of Thoracic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China National Basic medical Teaching Demonstration center Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Key Laboratory of Neurological Diseases of Ministry of Education Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

Objective Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney ***,the knockout of transient receptor potential channel 6(TRPC6)has shown promise in alleviating renal ***,the regulatory impact of TRPC6 on renal fibrosis remains *** In vivo,TRPC6 knockout(TRPC6−/−)mice and age-matched 129 SvEv(WT)mice underwent unilateral renal ischemia-reperfusion(uIR)injury surgery on the left renal pedicle or sham *** and serum were collected on days 7,14,21,and 28 after *** vitro,primary tubular epithelial cells(PTECs)were isolated from TRPC6−/−and WT mice,followed by treatment with transforming growth factorβ1(TGFβ1)for 72 *** anti-fibrotic effect of TRPC6−/−and the underlying mechanisms were assessed through hematoxylin-eosin staining,Masson staining,immunostaining,qRT-PCR,and Western *** Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFβ***6−/−alleviated renal fibrosis by reducing the expression of fibrotic markers(Col-1,α-SMA,and vimentin),as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in ***,we found that the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/glycogen synthase kinase 3 beta(GSK3β)signaling pathway,a pivotal player in renal fibrosis,was down-regulated following TRPC6 *** These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3β*** TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.

关键词： transient receptor potential channel 6 ischemia-reperfusion injury renal fibrosis renal tubular epithelial cells

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Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer’s disease mice

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Protein & Cell 2024年第4期15卷 261-284页

作者： He-Zhou Huang Wen-Qing Ai Na Wei Ling-Shuang Zhu Zhi-Qiang Liu Chao-Wen Zhou Man-Fei Deng Wen-Tao Zhang Jia-Chen Zhang Chun-Qing Yang Ya-Zhuo Hu Zhi-Tao Han hong-hong Zhang Jian-Jun Jia Jing Wang Fang-Fang Liu Ke Li Qi Xu Mei Yuan Hengye Man Ziyuan Guo Youming Lu Kai Shu Ling-Qiang Zhu Dan Liu Department of Pathophysiology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of medical genetics School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Pathology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450002China Department of Pathology School of Basic MedicineZhengzhou UniversityZhengzhou 450002China The Second Affiliated Hospital Department of NeurologyHengyang Medical SchoolUniversity of South ChinaHengyang 421001China Beijing Key Laboratory of Aging and Geriatrics National Clinical Research Center for Geriatric DiseaseInstitute of GeriatricsChinese PLA General Hospital and Chinese PLA Medical AcademyBeijing 100853China Department of Neurosurgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Neurology Union HospitalHuazhong University of Science and TechnologyWuhan 430022China Department of Biology Boston UniversityBostonMA 02215USA center for Stem Cell and Organoid medicine(CuSTOM) Division of Developmental BiologyCincinnati Children’s Hospital Medical CenterCincinnatiOH 45229USA

Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family *** genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of ***,the underlying mechanisms of social isolation in AD progression remain *** the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD *** also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related ***,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious ***,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its ***,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD *** together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

关键词： Alzheimer’s disease memory impairment synaptic disorder tau pathology

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The non-canonical poly(A)polymerase FAM46C promotes erythropoiesis

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Journal of genetics and Genomics 2024年第6期51卷 594-607页

作者： Ke Yang Tiangi Zhu Jiaying Yin Qiaoli Zhangg Jing Li hong Fan Gajing Han Weiyin Xu Nan Liu Xiang Lv d.e:a Bone Marrow Transplantation center The First Affliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China Liangzhu Laboratory Zhejang UniversityHangzhouZhejang 311121China Institute of HematologyZhejiang UniversityHangzhouZhejiang 311121China The State Key Laboratory for Complex Severeand Rare DiseasesHaihe Laboratory of Cell EcosystemDepartment of PathophysiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China medical Epigenetics Research center Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China

The post-transcriptional regulation of mRNA is a crucial component of gene *** disruption of this process has detrimental effects on the normal development and gives rise to various *** for novel post-transcriptional regulators and exploring their roles are essential for understanding development and *** a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell ***46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific *** demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent ***,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox *** conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.

关键词： FAM46C TENT5C Poly(A)polymerase Erythroblasts Post-transcriptional regulation Erythroid-specific enhancer

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