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The role of inflammasomes in human diseases and their potential as therapeutic targets

Signal Transduction and Targeted Therapy 2024年第2期9卷 479-508页

作者： Jing Yao Keenan Sterling Zhe Wang Yun Zhang Weihong Song The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053China townsend family laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Key Laboratory of Neurodegenerative Diseases Ministry of EducationBeijingP.R.China Zhejiang Clinical Research Center for Mental Disorders Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and The Affiliated Kangning HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325000China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiang 325000China

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response.Each inflammasome complex has three major components:an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC.Inflammasome formation typically occurs in response to infectious agents or cellular damage.The active inflammasome then triggers caspase-1 activation,followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death.Aberrant inflammasome activation and activity contribute to the development of diabetes,cancer,and several cardiovascular and neurodegenerative disorders.As a result,recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation,as well as the potential of targeting inflammasomes to treat various diseases.Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies.Therefore,understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies.In this article,we provide a summary of the biological and pathological roles of inflammasomes in health and disease.We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

关键词： inflam therapeutic potential

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miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2024年第2期14卷 635-652页

作者： Man Luo Yayan Pang Junjie Li Lilin Yi Bin Wu Qiuyun Tian Yan He Maoju Wang Lei Xia Guiqiong He Weihong Song Yehong Du Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing 400016China townsend family laboratories Department of PsychiatryThe University of British ColumbiaVancouver BC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceZhejiang Clinical Research Center for Mental DisordersSchool of Mental Health and the Affiliated Kangning HospitalWenzhou Medical UniversityWenzhou 325000China Institute for Brain Science and Disease of Chongqing Medical University Chongqing 400016China

Alzheimer ’s disease(AD) is a leading cause of dementia in the elderly.Mitogen-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in AD.However,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA translation.Here,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model cells.We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation.More importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

关键词： Alzheimer's disease MKP-1 miR-429-3p AMPAreceptor Learning and memory Long-term potentiation

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Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1625-1636页

作者： Qing Zhang Mengen Xing Zhengkai Bao Lu Xu Yang Bai Wanqi Chen Wenhao Pan Fang Cai Qunxian Wang Shipeng Guo Jing Zhang Zhe Wang Yili Wu Yun Zhang Jia-Da Li Weihong Song Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Zhejiang Key Laboratory of Alzheimer's DiseaseZhejiang Provincial Clinical Research Center for Mental DisordersSchool of Mental Health and Wenzhou Kangning HospitalThe Second Affiliated Hospital and Yuying Children's HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325035China townsend family laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders Ministry of Education Key Laboratory of Child Development and DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Medical Genetics Hunan Key Laboratory of Animal Models for Human DiseasesHunan Key Laboratory of Medical GeneticsHunan International Scientific and Technological Cooperation Base of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangsha 410078 HunanChina The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053Chin

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its function.However,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive.In this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent y-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in mice.Finaly,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout mice.This data demonstrates that the a-secretase is essential for CNTNAP2 processing and its function.Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

关键词： NAP2 cleavage subsequent

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The current situation of semen analysis in China,based on a survey of 296 laboratories

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Asian Journal of Andrology 2024年第2期26卷 220-221页

作者： Long-Long Fu Ying Liu Xiao-Wei Wang Fang Zhou Ying Guo Wen-Hong Lu Yi-Qun Gu National Health Commission Key Laboratory of Male Reproductive Health Reproductive Health Research CenterNational Research Institute for Family PlanningBeijing 100081China Institute of Pediatric Research Children's Hospitalof Soochow UniversitySuzhou 215025China

Dear Editor,Semen analysis is a basic test to assess male fertility and is a fundamental test in assisted reproductive technology.From the first publication of World Health Organization(WHO)Laboratory Manual of Human Semen and Sperm-Cervical Mucus Interaction in 1980,to the publication of the WHO Manual,6th edition in 2021,these 40 years have been recognized as providing a global standard that is widely used in research and clinical laboratories worldwide.The WHO Manual,6th edition in Chinese,which we have been authorized by the WHO to translate,will be published soon.

关键词： technology. analysis translate

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Discovery of a potent and selective cell division cycle 7 inhibitor from 6-(3-fluoropyridin4-yl)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as an orally active antitumor agent

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Acta Pharmaceutica Sinica B 2024年第2期14卷 893-896页

作者： Mingwei Fu Min Ge Wanxiang Yang Chunchen Hu Xiaowei Li Yuanjiang Wang Shaohua Gou Pharmaceutical Research Center and School of Chemistry and Chemical Engineering Southeast UniversityNanjing 211189China Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research Southeast UniversityNanjing 211189China Zenji Research laboratories Nanjing 211189China

To the Editor:Kinase cell division cycle 7(CDC7),a cell division cycle protein,takes a vital role in mediating DNA replication1.CDC7 complexes in the nucleus can phosphorylate the minichromosome maintenance complex(MCM)family members that bind to chromosomes.In addition,CDC7 kinase,as a molecular switch regulating DNA replication,can mediate DNA damage signaling pathways to stimulate cell cycle termination as well as DNA replication2.Studies have shown that CDC7 is overexpressed in many types of cancer cells,and its overexpression was related to poor patient survival,tumor grade,genetic instability,aneuploidy and so on3.Therefore,CDC7 is a promising target for antitumor therapy.

关键词： Cell division cycle 7 DNA replication CDC7 inhibitor Anti-tumor

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Gonadotropin releasing hormone(GnRH):a hormone therapy boosts cognition in Down syndrome and dementia

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Signal Transduction and Targeted Therapy 2023年第3期8卷 869-871页

作者： Keenan Sterling Ruixue Cao Weihong Song townsend family laboratories Department of PsychiatryThe University of British Columbia2255 Wesbrook MallVancouverBCCanada The Second Affiliated Hospital and Yuying Children’s Hospital Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceWenzhou Medical UniversityWenzhouChina Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouChina

A recent study published in Science by Manfredi-Lozano and colleagues suggests that the gonadotropin-releasing hormone(GnRH)could potentially restore cognition in patients with Down syndrome(DS).1 The findings reveal a new molecular link between dementia and the loss of smell,and a promising therapeutic avenue to combat age-related cognitive decline in DS and other neurodegenerative diseases.

关键词： releasing Down boost

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Do Systemic Infections Contribute to the Pathogenesis of Dementia?

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Neuroscience Bulletin 2022年第3期38卷 331-333页

作者： Keenan Sterling Mengen Xing Weihong Song townsend family laboratories Department of PsychiatryThe University of British ColumbiaVancouverBCV6T 1Z3Canada Institute of Aging Key Laboratory of Alzheimer’s Disease of Zhejiang ProvinceSchool of Mental Health and Kangning HospitalThe Second Affiliated Hospital and Yuying Children’s HospitalWenzhou Medical UniversityWenzhou325035China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou325000China

With over 50 million people currently living with dementia and numbers expected to double every twenty years,the world is currently facing a dementia epidemic.Nevertheless,a poor understanding of the etiology of dementia has resulted in the inability to develop any successful disease-modifying treatment.Over the past year,several researchers have highlighted the role of systemic infections in increasing the risk of developing dementia.These findings are particularly troubling given the ongoing coronavirus 19(COVID-19)pandemic,adding yet another cause for concern over the long-term impact of COVID-19 on the public’s mental health.

关键词： adding etiology finding

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A bHLH transcription factor,CsSPT,regulates high-temperature resistance in cucumber

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Horticultural Plant Journal 2024年第2期10卷 503-514页

作者： Yonggui Liang Chenyu Yang Fangyan Ming Bingwei Yu Zhihua Cheng Yixi Wang Zhengkun Qiu Xiaolan Zhang Bihao Cao Shuangshuang Yan Key Laboratory of Biology and Genetic Improvement of Horticultural Crops(South China) Ministry of Agriculture and Rural AffairsGuangdong Vegetable Engineering and Technology Research CenterCollege of HorticultureSouth China Agricultural UniversityGuangzhouGuangdong 510642China State Key laboratories of Agrobiotechnology Beijing Key Laboratory of Growth and Developmental Regulation for Protected Vegetable CropsMOE Joint Laboratory for International Cooperation in Crop Molecular BreedingChina Agricultural UniversityBeijing 100193China

High-temperature stress threatens the growth and yield of crops. Basic helix-loop-helix(bHLH) transcription factors(TFs) have been shown to play important roles in regulating high-temperature resistance in plants. However, the bHLH TFs responsible for high-temperature tolerance in cucumbers have not been identified. We used transcriptome profiling to screen the high temperature-responsive candidate bHLH TFs in cucumber. Here, we found that the expression of 75 CsbHLH genes was altered under high-temperature stress. The expression of the CsSPT gene was induced by high temperatures in TT(Thermotolerant) cucumber plants. However, the Csspt mutant plants obtained by the CRISPR-Cas9 system showed severe thermosensitive symptoms, including wilted leaves with brown margins and reduced root density and cell activity.The Csspt mutant plants also exhibited elevated H_(2)O_(2) levels and down-regulated photosystem-related genes under normal conditions.Furthermore, there were high relative electrolytic leakage(REC), malondialdehyde(MDA), glutathione(GSH), and superoxide radical(O_(2)^(·-)) levels in the Csspt mutant plants, with decreased Proline content after the high-temperature treatment. Transcriptome analysis showed that the photosystem and chloroplast activities in Csspt mutant plants were extremely disrupted by the high-temperature stress compared with wildtype(WT) plants. Moreover, the plant hormone signal transduction, as well as MAPK and calcium signaling pathways were activated in Csspt mutant plants under high-temperature stress. The HSF and HSP family genes shared the same upregulated expression patterns in Csspt and WT plants under high-temperature conditions. However, most bHLH, NAC, and bZIP family genes were significantly down-regulated by heat in Csspt mutant plants. Thus, these results demonstrated that CsSPT regulated the high-temperature response by recruiting photosynthesis components, signaling pathway molecules, and transcription factors. Our results provide important insights into the heat response m

关键词： Cucumber bHLH CsSPT Photosynthesis High temperature

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Amyloidβ-based therapy for Alzheimer’s disease:challenges,successes and future

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Signal Transduction and Targeted Therapy 2023年第7期8卷 3374-3399页

作者： Yun Zhang Huaqiu Chen Ran Li Keenan Sterling Weihong Song National Clinical Research Center for Geriatric Disorders Xuanwu HospitalCapital Medical UniversityBeijingChina The Second Affiliated Hospital and Yuying Children’s Hospital Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceWenzhou Medical UniversityWenzhouZhejiangChina townsend family laboratories Department of PsychiatryThe University of British ColumbiaVancouverBC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)WenzhouZhejiangChina

Amyloidβprotein(Aβ)is the main component of neuritic plaques in Alzheimer’s disease(AD),and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression.Aβhas been the prime target for the development of AD therapy.However,the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course.

关键词： Alzheimer Aβ clinical

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Cell-type-specific memory consolidation driven by translational control

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Signal Transduction and Targeted Therapy 2021年第2期6卷 206-208页

作者： Qing Zhang Isabel Bestard-Lorigados Weihong Song townsend family laboratories Department of PsychiatryThe University of British ColumbiaVancouverBCCanada Institute of Aging School of Mental Health and Kangning HospitalThe Second Affiliated Hospital and Yuying Children’s HospitalWenzhou Medical UniversityWenzhouChina

Dr.Sonenberg’s group has significantly contributed to the understanding of translational control in learning and memory.In a recent Nature article,they further reported the cell-typespecific translational control underlying memory consolidation.1 Long-term potentiation(LTP)has been widely acknowledged as one of the main cellular models of learning and memory.Generally,there are two components of LTP driven by different stimulations and mechanisms.The early phase of LTP(E-LTP)and short-term memory(STM)are evoked for short periods and are temporary,relying primarily on modifications of pre-existing proteins.The late phase of LTP(L-LTP)and consequent longterm memory(LTM)are elicited by strong and repetitive stimulation and are long-lasting,requiring new protein synthesis.

关键词： synthesis. translational stimulation

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