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Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis(INSPIRES)

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Stroke & Vascular Neurology 2023年第3期8卷 249-258,I0096-I0110页

作者： Ying Gao Yuesong Pan Shangrong Han Weiqi Chen Jing Jing Chunjuan Wang Yingying Yang Tingting Wang Xia Meng Xingquan Zhao Liping Liu Hao Li S Claiborne Johnston Pierre Amarenco Philip M Bath Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research center for Neurological Diseases Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Dean's Office Dell Medical SchoolUniversity of Texas at AustinAustinTexasUSA Department of Neurology and Stroke center Assistance Publique-Hôpitaux de Paris(APHP)Bichat HospitalINSERM LVTS-U1148University of ParisParisFrance Population Health Research Institute McMaster UniversityHamiltonOntarioCanada Stroke Trials Unit Mental Health&Clinical NeuroscienceUniversity of NottinghamNottinghamUK Advanced Innovation center for Human Brain Protection Capital Medical UniversityBeijingChina National center for Neurological Diseases BeijingChina Research Unit of Artificial Intelligence in Cerebrovascular Disease Chinese Academy of Medical SciencesBeijingChina Chinese Institute for Brain Research BeijingChina

Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or *** The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the *** subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin *** primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after *** primary safety endpoint is moderate to severe bleeding at 90 *** The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.

关键词： intracranial atherosclerosis random

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m^(6)A demethylase ALKBH5 is required for antibacterial innate defense by intrinsic motivation of neutrophil migration

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2608-2622页

作者： Yang Liu Renjie Song Lu Zhao Zhike Lu Yini Li Xinyi Zhan Fengjiao Lu Jiang Yang Yamei Niu Xuetao Cao Department of Immunology Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina Frontier Research center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai University300071 TianjinChina School of Life Sciences Westlake University310024 HangzhouChina Department of Pathology Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina.

Neutrophil migration into the site of infection is necessary for antibacterial innate defense,whereas impaired neutrophil migration may result in excessive inflammation and even *** neutrophil migration directed by extracellular signals such as chemokines has been extensively studied,yet the intrinsic mechanism for determining neutrophil ability to migrate needs further investigation.N6-methyladenosine(m^(6)A)RNA modification is important in immunity and inflammation,and our preliminary data indicate downregulation of RNA m^(6)A demethylase alkB homolog 5(ALKBH5)in neutrophils during bacterial *** m^(6)A modification and ALKBH5 might intrinsically modulate neutrophil innate response remain *** we report that ALKBH5 is required for antibacterial innate defense by enhancing intrinsic ability of neutrophil *** found that deficiency of ALKBH5 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture(CLP),and Alkbh5-deficient CLP mice exhibited higher bacterial burden and massive proinflammatory cytokine production in the peritoneal cavity and blood because of less neutrophil ***5-deficient neutrophils had lower CXCR2 expression,thus exhibiting impaired migration toward chemokine ***,ALKBH5-mediated m^(6)A demethylation empowered neutrophils with high migration capability through altering the RNA decay,consequently regulating protein expression of its targets,neutrophil migration-related molecules,including increased expression of neutrophil migration-promoting CXCR2 and NLRP12,but decreased expression of neutrophil migration-suppressive PTGER4,TNC,and *** findings reveal a previously unknown role of ALKBH5 in imprinting migrationpromoting transcriptome signatures in neutrophils and intrinsically promoting neutrophil migration for antibacterial defense,highlighting the potential application of targeting neutrophil m^(6)A modification in controlling bacterial infec

关键词： neutrophil impaired immunity

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Electronic transport properties of Co cluster-decorated graphene

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Chinese Physics B 2018年第6期27卷 81-86页

作者： Chao-Yi Cai Jian-Hao Chen International center for Quantum Materials Peking UniversityCollaborative Innovation Center of Quantum Matte

Interactions of magnetic elements with graphene may lead to various electronic states that have potential *** report an in-situ experiment in which the quantum transport properties of graphene are measured with increasing cobalt coverage in continuous ultra-high vacuum environment. The results show that e-beam deposited cobalt forms clusters on the surface of graphene, even at low sample temperatures. Scattering of charge carriers by the absorbed cobalt clusters results in the disappearance of the Shubnikov–de Haas（Sd H） oscillations and the appearance of negative magnetoresistance（MR）which shows no sign of saturation up to an applied magnetic field of 9 T. We propose that these observations could originate from quantum interference driven by cobalt disorder and can be explained by the weak localization theory.

关键词： in situ quantum transport negative magnetoresistance weak localization

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Total flavonoids of hawthorn leaves promote motor function recovery via inhibition of apoptosis after spinal cord injury

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Neural Regeneration Research 2021年第2期16卷 350-356页

作者： Qiong Zhang Yin Xiong Bo Li Gui-Ying Deng Wen-Wen Fu Bai-Chuan Cao Shao-Hui Zong Gao-Feng Zeng School of Public Health Guangxi medical university NanningGuangxi Zhuang Autonomous RegionChina Department of Spine Osteopathic Surgery The First Affiliated Hospital of Guangxi Medical UniversityGuangxi Zhuang Autonomous RegionChina Research center for Regenerative Medicine Guangxi Key Laboratory of Regenerative MedicineGuangxi Medical UniversityNanningGuangxi Zhuang Autonomous RegionChina

Flavonoids have been reported to have therapeutic potential for spinal cord *** leaves have abundant content and species of total flavonoids,and studies of the effects of the total flavonoids of hawthorn leaves on spinal cord injury have not been published in or outside ***,Sprague-Dawley rats were used to establish a spinal cord injury model by Allen's *** were intraperitoneally injected with 0.2 m L of different concentrations of total flavonoids of hawthorn leaves(5,10,and 20 mg/kg)after spinal cord *** were administered once every 6 hours,three times a day,for 14 *** treatment with various concentrations of total flavonoids of hawthorn leaves,the Basso,Beattie,and Bresnahan scores and histological staining indicated decreases in the lesion cavity and number of apoptotic cells of the injured spinal cord tissue;the morphological arrangement of the myelin sheath and nerve cells tended to be regular;and the Nissl bodies in neurons *** Basso,Beattie,and Bresnahan scores of treated spinal cord injury rats were *** blot assays showed that the expression levels of pro-apoptotic Bax and cleaved caspase-3 were decreased,but the expression level of the anti-apoptotic Bcl-2 protein was *** improvement of the above physiological indicators showed a dose-dependent relationship with the concentration of total flavonoids of hawthorn *** above findings confirm that total flavonoids of hawthorn leaves can reduce apoptosis and exert neuroprotective effects to promote the recovery of the motor function of rats with spinal cord *** study was approved by the Ethics Committee of the Guangxi medical university of China(approval No.201810042)in October 2018.

关键词： apoptosis Bax protein Bcl-2 protein cleaved caspase-3 inflammation motor function recovery neuroprotection Nissl bodies spinal cord injury total flavonoids of hawthorn leaves

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Disease-based Toxicology on Safety Assessment Strategy and Application for Herbal and Traditional Medicines

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World Journal of Traditional Chinese Medicine 2019年第3期5卷 139-144页

作者： Jia-Bo Wang Zhuo Shi Xiao-He Xiao The Fifth medical center China Military Institute of Chinese MedicineGeneral Hospital of PLA Clinical Pharmacokinetics Laboratory School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjingChina Integrative medical center The Fifth Medical CenterGeneral Hospitalof PLABeijing

The safety issue on herbal and traditional medicines(H&TM) is one of the most challenging problems and serious concern worldwide. With scientific endeavor and further exploration, we came to realize that there are great differences between H&TM and synthetic drugs in many aspects, such as medical theory, medication experience, compatibility, processing, toxicological characteristics, and safety evaluating requirements. In the current preclinical models for synthetic drugs, the safety assessment results of some conventional deemed 'nontoxic' H&TM were not well consistent with clinical situations, which resulted in major difficulties to understand the mechanisms and guide the safe and rational uses of these H&TM. Thus, based on the traditional Chinese medicine toxicity theory called You Gu Wu Yun, this paper introduces a novel safety assessment strategy for H&TM, named as disease-based toxicology. It aims to cognize the relativity and susceptibility of the toxicity of H&TM, and then to enhance controllability in new drug development and clinical applications. It also provides a theoretical practice for the traditional Chinese medicine toxicity theory and a methodological promotion for the future development of the precision toxicology for H&TM.

关键词： Disease-based toxicology idiosyncratic toxicity safety of herbal and traditional medicines susceptibility syndrome differentiation-based toxicity attenuation

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Phosphatidylinositol 4-kinase β is required for the ciliogenesis of zebrafish otic vesicle

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Journal of Genetics and Genomics 2020年第10期47卷 627-636页

作者： Yufei Feng Ping Yu Jingyu Li Ying Cao Jingjing Zhang Affiliated Hospital of Guangdong medical university&Key Laboratory of Zebrafish Model for Development and Disease of Guangdong medical university Zhanjiang 524001China Clinical and Translational Research center Shanghai First Maternity and Infant HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate *** motility of cilia is necessary for various developmental and physiological ***(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and *** an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase ***,its potential roles in organ development remain to be *** investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 *** homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other ***,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb *** the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 *** addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb *** together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.

关键词： Ciliogenesis Pi4kb Hair cell Hearing loss Zebrafish

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A PTEN translational isoform has PTEN-like activity

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Chinese Journal of Cancer Research 2015年第5期27卷 524-532页

作者： Xie Zhang Bowei Yin Fangfang Zhu Guochang Huang Hong Li Department of Gastroenterology Ningbo Medical CenterLiHuiLi Hospital School of Medicine Ningbo University Ningbo medical center Ningbo Medical CenterLiHuiLi hospital Minimally Invasive Abdominal Surgery Ningbo Medical CenterLiHuiLi hospital

Background： To identify PTEN isoform and explore its potential role in tumor suppression. Methods： Western blotting, over-expression, shRNA mediated knocking-down, and bioinformatic analysis were used to identify PTEN isoform and test its effect on PI3K-Akt signaling pathway. Cell proliferation, apoptosis, and migration assays were used to test PTEN isoform＇s biological activities. Results： The PTEN isoform is about 15 kDa bigger than PTEN and its expression is dependent on PTEN status. Immunoprecipitation for PTEN isoform followed by screening with antibodies against ISG15, SUMO1/2/3, Ubiquitin, and Nedd8 showed the identified PTEN isoform is not a general proteinaceous post-translational modification. In addition, overexpression of PTEN cDNA in cells did not generate PTEN isoform whereas knocking-down of PTEN reduced the protein levels of both PTEN and PTEN isoform in a proportional manner. Analysis of PTEN DNA sequence disclosed an alternative translational starting code （CTG） upstream of canonical PTEN coding sequence. Expression of cloned PTEN isoform generated a protein with a size about 15 kDa bigger than PTEN and suppressed PI3K-Akt signaling pathway in cells. Overexpression of PTEN isoform also led to decrease in cell growth and enhanced serum starvation--and UV irradiation--induced apoptosis through activation of Caspase 3. Finally, expression of PTEN isoform inhibited cell migration in scratch assay. Conclusions： PTEN isoform has PTEN-Iike activity and might be a new tumor suppressor.

关键词： PTEN PTEN isoform rumor suppressor PI3K-Akt cell growth apoptosis cell migration

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Effect of structure and function of paraoxonase-1(PON-1)on organophosphate pesticides metabolism

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BIOCELL 2020年第3期44卷 363-370页

作者： HAZAEL RAMIRO CEJA-GÁLVEZ ERANDIS DHENI TORRES-SÁNCHEZ JUAN HERIBERTO TORRES-JASSO ARTURO VILLALOBOS ORNELAS JOEL SALAZAR-FLORES Department of medical and Life Sciences University Center of La CiénegaUniversity of Guadalajara(CUCI-UdeG)OcotlánCP 47810Mexico Department of Biological Sciences University Center of the CoastUniversity of Guadalajara(CUCosta-UdeG)Puerto VallartaCP 48280Mexico

Paraoxonase-1(PON1)is an important enzyme in various pathologies such as pesticide poisoning,diabetes,atherosclerosis,neuronal disorders,and cancer,due to its multifunctional activity since it acts on different ***,one of its main functions is the hydrolysis of organophosphate(OP)compounds from pesticides that cause fatal poisoning at the level of the central nervous system(CNS).The objective of this review was to investigate whether the structure,genetics,and function of PON1 affect the metabolism of organophosphate pesticides or other *** was selected from articles in the database PubMed–NCBI(https://***/pubmed/)with a publication date between 2011 and *** enzymatic activity of PON1 can be modified depending on its chemical structure since there are different genetic polymorphisms that change PONI morphologies or the levels of expression in the *** leads to differences in susceptibilities to organophosphate pesticide *** results of this review reveal that phenotypic variants of PON1 have differences in affinities for OP substrates.

关键词： PON1 Pesticides Organophosphorus toxicity

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Increased mtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer

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Signal Transduction and Targeted Therapy 2018年第1期3卷 246-254页

作者： Xiacheng Sun Lei Zhan Yibing Chen Gang Wang Linjie He Qian Wang Feng Zhou Fang Yang Jin Wu Yousheng Wu Jinliang Xing Xianli He Qichao Huang State Key Laboratory of Cancer Biology and Experimental Teaching center of Basic Medicine Fourth Military Medical University710032 Xi’anChina Department of Gastroenterology Second Affiliated Hospital of Harbin Medical University150086 HarbinChina center of Genetic&Prenatal Diagnosis First Affiliated HospitalZhengzhou University450052 ZhengzhouChina Department of General Surgery Tangdu HospitalFourth Military Medical University710032 Xi’anChina Department of General Surgery Huaihai HospitalXuzhou Medical UniversityXuzhou 221004China

Colorectal cancer is one of the leading causes of cancer death *** to global genomic status,colorectal cancer can be classified into two main types:microsatellite-stable and microsatellite-instable ***,the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular ***,mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal ***,the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer,which accounts for the majority of colorectal cancer,remain *** this study,we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer ***,the underlying molecular mechanisms were also *** results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellitestable colorectal cancer cells both in vitro and in ***,we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer ***,the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative ***,treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy *** study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism,which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer.

关键词： colorectal metastasis inhibited

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Mitochondria-mediated apoptosis in mammals

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Protein & Cell 2014年第10期5卷 737-749页

作者： Shunbin Xiong Tianyang Mu Guowen Wang Xuejun Jiang Department of Genetics The University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA Institute of Cancer Stem Cell Dalian Medical University Cancer Center 9 Lvshun Road South Dalian 116044 China Department of Bone and Soft Tissue Tumors Tianjin Medical University Cancer Institute & Hospital Tianjin 300060 China Cell Biology Program Memorial SIoan-Kettering Cancer Center New York NY 10065 USA

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization （MOMP） and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, main- tenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehen- sively studied, yet a great deal of new evidence indi- cates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the tar- geted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.

关键词： apoptosome Bcl-2 family lAPs lAPantagonists cancer therapy

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