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The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

Genes & Diseases 2024年第3期11卷 452-467页

作者： Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang Department of Neurology Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqing 400016China Department of Pediatrics Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurosurgery Affliated Hospital of Jining Medical UniversityJiningShandong 272000China Pediatric research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China

Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent *** lobe epilepsy(TLE)is one of the most common medically intractable seizure ***2-and NcK-interacting kinase(TNIK)has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders,but its role in epilepsy remains *** this study,we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpineinduced rat model of epilepsy by western blotting,immunofluorescence,and immunohistochemistry.A pentylenetetrazole(PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of ***(Co-IP)/mass spectrometry(MS)was used to identify the potential *** Co-IP,we detected and confirmed the main potential TNIK *** fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density(PSD)*** found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with ***-0846 delayed kindling progression and decreased seizure ***-IP/MS identified 63 candidate TNIK interactors in rat hippocampi,notably ***-IP showed that TNIK might correlate with endogenous GRIA1,SYN2,PSD-95,CaMKIV,GABRG1,and *** addition,the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ *** results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

关键词： Epilepsy NCB-0846 Rat TLE TNIK Traf2-and NcK-interacting kinase

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Single-cell transcriptomics systematically discloses the immune-inflammatory responses of peripheral blood mononuclear cells for diabetic nephropathy

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Genes & Diseases 2024年第4期11卷 82-85页

作者： Jiangpeng wu Nan Hu Baochun Guo Hualin Ma Lulin Xie Yisha Huang Siyu Xia Yuke Jiang Zhije Li Jigang Wang Xinzhou Zhang Zhen Liang Department of Nephrology Shenzhen Key Laboratory of Kidney Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong 518020China Department of Geriatrics and Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong 518020China State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China

Diabetic nephropathy(DN)has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes *** functional alterations of renal infiltrating immune cells have been reported as part of the pathological mechanism of DN,the understanding of the immune response underlying peripheral blood mononuclear cells(PBMCs)in DN remains ***,single-cell RNA sequencing(scRNA-seq)was used toprofile the transcriptomic signatures of PBMCs from DN patients.

关键词： nephropathy alterations mortality

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Protective Effects of Phellodendron Species on Bone Health: A Novel Perspective on Their Potentials in Treating Osteoporosis and Osteoarthritis

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Chinese Journal of Integrative Medicine 2024年第4期30卷 379-384页

作者： XIN Li TAN Guo-yao ZHANG Qiang ZHANG Qun Good clinical Practice development Guangdong Provincial Key Laboratory of Bone and Joint Degeneration DiseasesThe Third Affiliated Hospital of Southern Medical UniversityGuangzhou(510630)China Department of Pharmacy Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou(510120)China

Phellodendron(PN)species,traditionally used in Chinese medicine for centuries,hold promise as a potential treatment for osteoporosis(OP)and osteoarthritis(OA)due to their bioactive *** bioactive compounds,including berberine and palmatine,exhibit anti-inflammatory,antioxidant,and bone-protective properties,contributing to their potential therapeutic benefits in promoting bone health and preventing bone ***,challenges such as the need for standardized preparation and dosing,limited clinical studies,and potential interactions with other medications hinder their clinical ***,the rich history of PN species in Chinese medicine provides a promising foundation for future investigation into their potential as alternative treatments for OP and *** research is needed to fully understand the underlying mechanisms of action and explore the clinical implications of PN for bone health.

关键词： Phellodendron species bone health osteoporosis osteoarthritis review

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The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan

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Cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan clinical research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National Cancer Center research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer *** the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and *** CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of *** back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be *** quantity and quality of these samples will be compatible with omics *** biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： Cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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Non-invasive estimation of pulmonary hypertension and clinical deterioration risk in pediatric congenital heart disease:development and validation of predictive tools

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Chinese Medical Journal 2024年第11期137卷 1384-1386页

作者： Ting Wang Dansha Zhou Yuqin Chen Suhua Kuang Yue Xing Qijian Yi Zhengxia Pan Weibin Xu Jiao Rao Yunqi Liu Guoliang Lu Ziying Lin Xiang Li Yi Xie Yulong Wu Peng An Xiaoxiao Deng Jiayue He Jiayi Xie Chenxi Li Gang Geng Daiyin Tian Enmei Liu Jingsi Huang Zhou Fu Jian Wang Department of Respiratory Chongqing Higher Institution Engineering Research Center of Children’s Medical Big Data Intelligent ApplicationNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China State Key Laboratory of Respiratory Diseases National Center for Respiratory MedicineGuangdong Key Laboratory of Vascular DiseasesNational Clinical Research Center for Respiratory DiseasesGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouGuangdong 510120China Department of Cardiac Surgery The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouGuangdong 510120China Department of Cardiovascular Medicine Children’s hospital of Chongqing Medical University National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Thoracic and Cardiac Surgery Children’s hospital of Chongqing Medical University National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Cardiac Center of Guangdong Women and Children hospital Guangzhou GuangzhouGuangdong 511400China Department of Guangzhou Laboratory Guangzhou International Bio IslandGuangzhouGuangdong 510005China

To the Editor:Owing to the heterogeneity of congenital heart disease-associated pulmonary hypertension(CHDPH)disease and the development of the pulmonary vascular system in pediatric patients,the management of CHD-PH in children is signicantly different from that in adults.[1]Early identication and intervention of CHD-PH are of great signicance for disease management in children with CHD,and non-invasive,accurate clinical tools are urgently needed to predict PH risk in children with ***,the applicability of the current risk-scoring system to pediatric CHD-PH remains ***,there are presently no user-friendly,non-invasive online tools available for predicting CHD-PH,and there is a scarcity of related studies in Asian *** study aimed to develop and validate the prediction tools for estimating the risk of pulmonary hypertension and clinical deterioration in children with congenital heart disease.

关键词： pediatric congenital hypertension

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Current understanding of ELF4 deficiency:a novel inborn error of immunity

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World Journal of Pediatrics 2024年第5期20卷 444-450页

作者： Hong-Qiang Du Xiao-Dong Zhao Department of Rheumatology&Immunology National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Child Rare Diseases in Infection and ImmunityChildren’s Hospital of Chongqing Medical UniversityZhongshan Er Road 136Yuzhong DistrictChongqingChina

Background ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity(IEIs),specifically categorized as a“disease of immune dysregulation.”Cases of this condition,reported by our team and others,are very limited *** such,our current knowledge of this new disease remains *** review aims to provide a brief overview of the clinical manifestations,pathogenesis,and treatment strategies for this novel *** sources A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 *** search strategy was“ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor”as of the time of manuscript *** The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer,abdominal pain,and diarrhea in pediatric *** some cases,immunodeficiency and autoimmunity can also be *** Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 *** blotting for ELF4 expression of the patient’s cells can confirm the pathogenic effect of the *** fully confirm the pathogenicity of the variant,further functional test is strongly *** and biologics are the mainstream management of ELF4 deficiency *** Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of *** atypical presentations are prominent,variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 *** of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.

关键词： ELF4 transcription factor Immune dysregulation Inborn errors of immunity Mechanism Recurrent infections

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Translating bacteriophage-derived depolymerases into antibacterial therapeutics:Challenges and prospects

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Acta Pharmaceutica Sinica B 2024年第1期14卷 155-169页

作者： Honglan Wang Yannan Liu Changqing Bai Sharon Shui Yee Leung School of Pharmacy the Chinese University of Hong KongHong Kong SARChina Emergency Medicine clinical research Center Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Department of Respiratory Shenzhen University General HospitalShenzhen University Clinical Medical AcademyGuangdong 518055China

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and *** depolymerases are enzymes responsible for degrading diverse bacterial surface *** are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic *** depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection ***,some formulation approaches have been developed for improved stability and activity of ***,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and *** development must address these obstacles for clinical ***,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant ***,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.

关键词： Phage-derived polysaccharide depolymerases Bacteriophage proteins Bacterial capsules Polysaccharide capsules Antibiotic resistance Biofilms Antibacterial therapy Antimicrobial adjuvants Combination treatment

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Advances in functional MRI research in bipolar disorder:from the perspective of mood states

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General Psychiatry 2024年第1期37卷 33-43页

作者： Yankun Wu Yun-Ai Su Linlin Zhu Jitao Li Tianmei Si Department of clinical Psychopharmacology Peking University Sixth HospitalPeking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)BeijingChina Peking University Sixth hospital Peking University Institute of Mental HealthNHC Key Laboratoryof Mental Health(Peking University)National Clinical Research Centerfor Mental Disorders(Peking University Sixth Hospital)BeijingChina

Bipolar disorder is characterised by recurrent and alternating episodes of mania/hypomania and *** breakthroughs in functional MRI techniques have uncovered the functional neuroanatomy of bipolar ***,the pathophysiology underlying mood instability,mood switching and the development of extreme mood states is less well *** reviewpresents a comprehensive overviewof current evidence from functional MRI studies from the perspective of mood *** first summarise the disrupted brain activation patterns and functional connectivity that have been reported in bipolar disorder,irrespective of the mood *** next focus on research that solely included patients in a single mood state for a better understanding of the pathophysiology of bipolar disorder and research comparing patients with different mood states to dissect mood state-related ***,we briefly summarise current theoretical models and conclude this review by proposing potential avenues for future research.A comprehensive understanding of the pathophysiology with consideration of mood states could not only deepen our understanding of how acute mood episodes develop at a neurophysiological level but could also facilitate the identification of biological targets for personalised treatment and the development of new interventions for bipolar disorder.

关键词： anatomy bipolar functional

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Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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Oncology research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical Oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

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Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

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Oncology research 2024年第2期32卷 325-337页

作者： JIE ZHAO XUANTAO YANG HAIXI ZHANG XUEZHONG GU Department of Hematology The First People’s Hospital of Yunnan ProvinceYunnan Province Clinical Research Center for Hematologic DiseaseYunnan Province Clinical Center for Hematologic DiseaseKunming650032China Department of Pathology The First People’s Hospital of Yunnan ProvinceKunming650032China

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence *** is a new-generation proteasome inhibitor that is used as the first-line therapy for ***,the development of drug resistance is a pervasive obstacle to treating ***,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic *** elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM *** gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion *** upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion ***,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion ***,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor ***,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion *** suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor *** studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

关键词： Multiple myeloma Carfilzomib Drug resistance Major histocompatibility complex TNFRSF1A

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