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In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes

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Stroke & Vascular Neurology 2024年第1期9卷 8-17,I0001-I0033页

作者： Yu Tian Mengxing Wang Yuesong Pan Xia Meng Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Chinese Institute for Brain Research BeijingChina National center for Neurological diseases BeijingChina Advanced Innovation center for Human Brain Protection Capital Medical UniversityBeijingChina China National Clinical Research center for Neurological diseases BeijingChina

Introduction It remains unclear whether enlarged perivascular spaces(EPVS)predict poor clinical outcomes in patients with acute ischaemic stroke(AIS)or transient ischaemic attack(TIA).Method Data were obtained from the Third China National Stroke Registry *** estimated EPVS in basal ganglia(BG)and centrum semiovale(CSO)using a semiquantified scale(Grade from 0 to 4).Using Cox and logistic regression analyses,the associations of EPVS with 3-month and 1-year adverse outcomes(including recurrent stroke,ischaemic stroke,haemorrhagic stroke,combined vascular event,disability and mortality)were *** analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion(SAO)were *** Among 12603 patients with AIS/TIA,median age was 61.7±11.6 years,and 68.2%were *** adjusting for all potential confounders,frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke(HR 0.71,95%CI 0.55 to 0.92,p=0.01)but an increased risk of haemorrhagic stroke(HR 1.99,95%CI 1.11 to 3.58,p=0.02)at 1 year after AIS/TIA,compared with none-to-mild *** with frequent-to-severe CSO-EPVS had a decreased risk of disability(OR 0.76,95%CI 0.62 to 0.92,p=0.004)and all-cause death(HR 0.55,95%CI 0.31 to 0.98,p=0.04)within 3-month but not 1-year follow-ups,compared with those with none-to-mild *** analyses showed that both BG-EPVS(HR 0.43,95%CI 0.21 to 0.87,p=0.02)and CSO-EPVS(HR 0.58,95%CI 0.35 to 0.95,p=0.03)were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year *** BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 ***,caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.

关键词： patients haemorrhagic prevention

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Cognitive impairment in cerebral small vessel disease induced by hypertension

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Neural Regeneration Research 2024年第7期19卷 1454-1462页

作者： Weipeng Wei Denglei Ma Lin Li Lan Zhang Department of Pharmacy Xuanwu Hospital of Capital Medical UniversityBeijingChina Beijing Geriatric Medical Research center Beijing Engineering Research Center for Nervous System DrugsNational Center for Neurological DisordersNational Clinical Research Center for Geriatric DiseasesBeijingChina

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular *** r,the causal relationship between hypertension and cerebral small vessel disease remains *** has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular *** hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and *** is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of *** review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive *** also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

关键词： blood-brain barrier cerebral small vessel disease cognitive impairment dementia endothelial dysfunction enlarged perivascular space hypertension lacunar infarction neuroinflammation treatment white matter high signal intensity

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Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state

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Neural Regeneration Research 2024年第10期19卷 2229-2239页

作者： Yubo Wang Ling Zhang Tianjie Lyu Lu Cui Shunying Zhao Xuechun Wang Meng Wang Yongjun Wang Zixiao Li Vascular Neurology Department of NeurologyBeijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research center for Neurological diseases Beijing Tiantan HospitalCapital Medical UniversityBeijingChina National center for Healthcare Quality Management in Neurological diseases Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Chinese Institute for Brain Research BeijingChina Research Unit of Artificial Intelligence in Cerebrovascular Disease Chinese Academy of Medical SciencesBeijingChina Beijing Engineering Research center of Digital Healthcare for Neurological diseases BeijingChina

Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke

关键词： DNA demethylation DNA methylation DNMT3A functional outcome hyperinflammatory state interleukin neuroinflammation stroke TET2

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A folic acid-decorated nanoparticles loaded JQ1 for oral squamous cell carcinoma therapy

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Chinese Chemical Letters 2024年第3期35卷 332-336页

作者： Dequan Zeng Zhongkai Ma Xin Zan Ting Luo Xiang Wang Xiang Gao Xianghui Fu School of Health Management Xihua UniversityChengdu 610039China State Key Laboratory of Oral diseases National Clinical Research Center for Oral DiseasesWest China College of StomatologySichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Breast Disease center Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality *** poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC *** that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these ***,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor *** then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type *** conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.

关键词： Folic acid Nanoparticles JQ1 Oral squamous cell carcinoma Macrophages

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AAV for Gene Therapy in Ocular diseases:Progress and Prospects

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Research 2024年第3期2023卷 651-670页

作者： Xiaoyu He Yidian Fu Liang Ma Yizheng Yao Shengfang Ge Zhi Yang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai JiaoTong University School of MedicineShanghaiChina Shanghai Key Laboratory of Orbital diseases and Ocular Oncology ShanghaiChina Jiangsu Key Laboratory of Neuropsychiatric diseases and Institute of Neuroscience Soochow UniversityClinical Research Center of Neurological DiseaseThe Second Affiliated Hospital of Soochow UniversitySuzhouChina

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.

关键词： AAV organs treatment

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Percutaneous transhepatic cholangioscopy-assisted biliary polypectomy for local palliative treatment of intraductal papillary neoplasm of the bile duct

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1821-1832页

作者： Xu Ren Yong-Ping Qu Chun-Lan Zhu Xiao-Hong Xu Hong Jiang Yi-Xia Lu Hong-Peng Xue Digestive Disease Hospital of Heilongjiang Provincial Hospital Heilongjiang Provincial Clinical Medical Research Center for Minimally Invasive Diagnosis and Treatment of Pancreaticobiliary DiseasesHarbin 150001Heilongjiang ProvinceChina Digestive Endoscopy center of Heilongjiang Provincial Hospital Heilongjiang Provincial Clinical Medical Research Center for Minimally Invasive Diagnosis and Treatment of Pancreaticobiliary DiseasesHarbin 150001Heilongjiang ProvinceChina Second Department of Gastroenterology Digestive Disease Hospital of Heilongjiang Provincial Hospitaland Heilongjiang Provincial Clinical Medical Research Center for Minimally Invasive Diagnosis and Treatment of Pancreaticobiliary DiseasesHarbin 150001Heilongjiang ProvinceChina Department of Pathology Heilongjiang Provincial HospitalHarbin 150001Heilongjiang ProvinceChina

BACKGROUND Intraductal papillary neoplasm of the bile duct(IPNB)is a premalignant biliarytype epithelial neoplasm with intraductal papillary or villous *** reported local palliative therapeutic modalities,including endoscopic nasobiliary drainage,stenting and biliary curettage,endoscopic biliary polypectomy,percutaneous biliary drainage,laser ablation,argon plasma coagulation,photodynamic therapy,and radiofrequency ablation to relieve mechanical obstruction are limited with weaknesses and *** have applied percutaneous transhepatic cholangioscopy(PTCS)-assisted biliary polypectomy(PTCS-BP)technique for the management of IPNB including mucin-hypersecreting cast-like and polypoid type tumors since *** To assess the technical feasibility,efficacy,and safety of PTCS-BP for local palliative treatment of *** Patients with mucin-hypersecreting cast-like or polypoid type IPNB and receiving PTCS-BP between September 2010 and December 2019 were ***-BP was performed by using a half-moon type snare with a soft stainless-steel wire,and the tumor was snared and resected with *** primary outcome was its feasibility,indicated by technical *** secondary outcomes were efficacy,including therapeutic success,curative resection,and clinical success,and *** Five patients(four with mucin-hypersecreting cast-like type and one with polypoid type IPNB)were ***-and high-grade intraepithelial neoplasia(HGIN)and recurrent IPNB with invasive carcinoma were observed in one,two,and two patients,*** cholangitis and/or obstructive jaundice were presented in all four patients with mucin-hypersecreting cast-like type *** five patients achieved technical success of *** patients(three with mucin-hypersecreting cast-like type and one with polypoid type IPNB)obtained therapeutic success;one with mucin-hypersecreting cast-like type tumors in the intrahepatic small bile duct and HGIN h

关键词： Intraductal papillary neoplasm of the bile duct Percutaneous transhepatic cholangioscopy Biliary polypectomy Feasibility Efficacy

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MiR-107-3p/Atp6v0e1 contributes to protective effects of two selenium-containing peptides,TSeMMM and SeMDPGQQ on lead-induced neurotoxicity

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Food Science and Human Wellness 2024年第4期13卷 2060-2067页

作者： Yong Fang Tianhang Huang Jian Wu Xieqi Luo Fengjiao Fan Peng Li Jian Ding Xinyang Sun College of Food Science and Engineering Nanjing University of Finance and Economics/Collaborative Innovation Center for Modern Grain Circulation and SafetyNanjing 210023China Laboratory of Neurodegenerative and Neuroinjury diseases Wuxi School of MedicineJiangnan UniversityWuxi 214122China

Two selenium(Se)-containing peptides from Se-enriched rice,TSeMMM and SeMDPGQQ,possess neuroprotective potency against lead(Pb2+)-induced ***,the crosstalk between mRNA and microRNAs(miRNA)involved in the neuroprotection mechanism remains to be *** this study,RNA-sequencing and miRNA-sequencing were used to independently identify differentially expressed mRNAs and small RNAs profiles in Pb^(2+)-treated primary fetal rat cortical neurons and then the correlated miRNA-mRNA target pairs were *** was found that 34 mRNAs related to oxidative phosphorylation could be reversed by pretreatment of TSeMMM and *** protective effect of TSeMMM and SeMDPGQQ was mediated by upregulation of miR-107-3p,which downregulates the ATPase H+transporting V0 subunit e1(Atp6v0e1)mRNA level.A zebrafish model was applied to verify the relevance between the targeted mRNA and miRNA by real-time quantitative *** results indicated that miR-107-3p was a potential therapeutic target to achieve neuroprotection of Se-containing peptides via stimulation of Atp6v0e1.

关键词： Lead Se-containing peptides Neuroprotection miRNA

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Cdc42 deletion yielded enamel defects by disrupting mitochondria and producing reactive oxygen species in dental epithelium

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Genes & diseases 2024年第5期11卷 335-349页

作者： Jinxuan Zheng Rongcheng Yu Yiqi Tang Sihui Su Sainan Wang Chenxi Liao Xuecong Li Jiabin Liao Dongsheng Yu Tingting Ai Wei Zhao Vicky Yau Chufeng Liu Liping Wu Yang Cao Hospital of Stomatology Guanghua School of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhouGuangdong 510055China Guangdong Provincial Key Laboratory of Oral diseases GuangzhouGuangdong 510055China Department of Cariology and Endodontology Peking University School and Hospital of Stomatology&National Center for Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical DevicesBeijing 100081China Department of Oral and Maxillofacial Surgery University at BuffaloBuffaloNY 14214USA Department of Orthodontics Stomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280China

Developmental defects of enamel are common due to genetic and environmental factors before and after ***42,a Rho family small GTPase,regulates prenatal tooth development in ***,its role in postnatal tooth development,especially enamel formation,remains ***,we investigated Cdc42 functions in mouse enamel development and tooth repair after ***42 showed highly dynamic temporospatial patterns in the developing incisors,with robust expression in ameloblast and odontoblast ***,epithelium-specific Cdc42 deletion resulted in enamel defects in *** differentiation was inhibited,and hypomineralization of enamel was observed upon epithelial Cdc42 *** analysis showed that abnormal mitochondrial components,phosphotransferase activity,and ion channel regulator activity occurred in the Cdc42 mutant dental *** oxygen species accumulation was detected in the mutant mice,suggesting that abnormal oxidative stress occurred after Cdc42 ***,Cdc42 mutant mice showed delayed tooth repair and generated less calcified *** dysfunction and abnormal oxygen consumption were evidenced by reduced Apool and Timm8a1 expression,increased Atp5j2 levels,and reactive oxygen species overproduction in the mutant repair ***-specific Cdc42 deletion attenuated ERK1/2 signaling in the labial cervical *** Sox2 expression in the mutant labial cervical loop after clipping might lead to delayed tooth *** findings suggested that mitochondrial dysfunction,up-regulated oxidative stress,and abnormal ion channel activity may be among multiple factors responsible for the observed enamel defects in Cdc42 mutant ***,Cdc42 exerts multidimensional and pivotal roles in enamel development and is particularly required for ameloblast differentiation and enamel matrix formation.

关键词： Cdc42 Enamel defects Mitochondrial dysfunction Rho GTPase Tooth repair

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Jun12682,a potent SARS-CoV-2 papain-like protease inhibitor with exceptional antiviral efficacy in mice

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4189-4192页

作者： Mianling Yang Meehyein Kim Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJi’nan 250012China Infectious diseases Therapeutic Research center Korea Research Institute of Chemical Technology(KRICT)Daejeon 34114Republic of Korea

Recently,a collaborative research study published in Science,led by Jun Wang,Xufang Deng,Eddy Arnold,and Francesc Xavier Ruiz1,identified a series of potent small molecule inhibitors that specifically target SARS-CoV-2 papain-like protease(PLpro).The study demonstrated nanomolar PLpro inhibitory potency with Ki values ranging from 13.2 to 88.2 nmol/*** employing a structure-based drug design strategy,the researchers discovered an exceptionally promising compound,named Jun12682,that effectively targets both the newly discovered ubiquitin Val70(Val70Ub)-binding site and the known blocking loop(BL2)groove near the S4 subsite of ***,studies on the mechanism of action revealed that Jun12682 inhibits the deubiquitinating and deISGylating activities of PLpro,which are crucial for antagonizing the host’s innate immune response upon viral *** biology studies confirmed the“two-pronged”binding mode of Jun12682,aligning perfectly with their drug design ***,Jun12682 exhibited potent antiviral activity against SARS-CoV-2 and its variants,including nirmatrelvir-resistant mutants,in Caco-2 cells(EC50:0.44e2.02 mmol/L).It is noteworthy that its oral administration significantly improved survival rates and alleviated both lung virus loads and histopathological lesions in a lethal SARS-CoV-2 mouse *** conclusion。

关键词： SARS-CoV-2 Papain-like protease Broad-spectrum Anti-drug resistance Drug candidate

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Relationship of Retinal Nerve Fiber Layer Thickness and Retinal Vessel Calibers with Cognitive Impairment in the Asymptomatic Polyvascular Abnormalities Population

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Biomedical and Environmental Sciences 2024年第2期37卷 196-203页

作者： WANG Dan Dan WANG An Xin ZHANG Xiao Li WEI Wen Bin WU Shou Ling ZHAO Xing Quan Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China China National Clinical Research center for Neurological diseases Beijing 100070China Beijing Tongren Eye center Beijing Key Laboratory of Ophthalmology and Visual ScienceBeijing Tongren HospitalCapital Medical UniversityBeijing 100005China Department of Cardiology Kailuan HospitalTangshan 063001HebeiChina

Objective Cognitive impairment(CI)in older individuals has a high morbidity rate worldwide,with poor diagnostic methods and susceptible population *** study aimed to investigate the relationship between different retinal metrics and CI in a particular population,emphasizing polyvascular *** We collected information from the Asymptomatic Polyvascular Abnormalities Community Study on retinal vessel calibers,retinal nerve fiber layer(RNFL)thickness,and cognitive function of 3,785participants,aged 40 years or *** regression was used to analyze the relationship between retinal metrics and cognitive *** stratified by different vascular statuses were also *** RNFL thickness was significantly thinner in the CI group(odds ratio:0.973,95%confidence interval:0.953–0.994).In the subgroup analysis,the difference still existed in the non-intracranial arterial stenosis,non-extracranial carotid arterial stenosis,and peripheral arterial disease subgroups(Psmall vessel change in RNFL and CI should be investigated in the future.

关键词： Retinal nerve fiber layer Cognitive impairment Polyvascular abnormality

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