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Protein neddylation and its role in health and diseases

Signal Transduction and Targeted Therapy 2024年第5期9卷 1869-1904页

作者： Shizhen zhang qing Yu Zhijian Li Yongchao Zhao yi Sun Department of Breast Surgery the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Institute of Translational Medicine Zhejiang University School of MedicineHangzhou 310029China Department of Thyroid Surgery Zhejiang Cancer HospitalInstitute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou 310022China Key Laboratory of Head&Neck Cancer Translational Research of Zhejiang Province Hangzhou 310022China Department of Hepatobiliary and Pancreatic Surgery Zhejiang University School of MedicineHangzhou 310029China Zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Zhejiang University Cancer Center Hangzhou 310029China Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang Hangzhou 310024China Research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin proteins.Neddylation of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular localization.Significantly,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among others.Thus,targeting neddylation becomes an attractive strategy for the treatment of these diseases.In this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates.We further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach.Finally,few perspectives were proposed for extensive future investigations.

关键词： NEDD8 attached attractive

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Research on a TOPSIS energy efficiency evaluation system for crude oil gathering and transportation systems based on a GA-BP neural network

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Petroleum Science 2024年第1期21卷 621-640页

作者： Xue-Qiang zhang qing-Lin Cheng Wei Sun yi Zhao Zhi-Min Li Key Lab of Ministry of Education for Enhancing the Oil and Gas Recovery Ratio Northeast Petroleum UniversityDaqing163318HeilongjiangChina China Petroleum Pipeline Material and Equipment Co. LtdLangfang065000HebeiChina Research Institute of Petroleum Engineering and Technology Sinopec Northwest Oilfield CompanyUrumqi830011XinjiangChina

As the main link of ground engineering,crude oil gathering and transportation systems require huge energy consumption and complex structures.It is necessary to establish an energy efficiency evaluation system for crude oil gathering and transportation systems and identify the energy efficiency gaps.In this paper,the energy efficiency evaluation system of the crude oil gathering and transportation system in an oilfield in western China is established.Combined with the big data analysis method,the GA-BP neural network is used to establish the energy efficiency index prediction model for crude oil gathering and transportation systems.The comprehensive energy consumption,gas consumption,power consumption,energy utilization rate,heat utilization rate,and power utilization rate of crude oil gathering and transportation systems are predicted.Considering the efficiency and unit consumption index of the crude oil gathering and transportation system,the energy efficiency evaluation system of the crude oil gathering and transportation system is established based on a game theory combined weighting method and TOPSIS evaluation method,and the subjective weight is determined by the triangular fuzzy analytic hierarchy process.The entropy weight method determines the objective weight,and the combined weight of game theory combines subjectivity with objectivity to comprehensively evaluate the comprehensive energy efficiency of crude oil gathering and transportation systems and their subsystems.Finally,the weak links in energy utilization are identified,and energy conservation and consumption reduction are improved.The above research provides technical support for the green,efficient and intelligent development of crude oil gathering and transportation systems.

关键词： Crude oil gathering and transportation system GA-BP neural network Energy efficiency evaluation TOPSIS evaluation method Energy saving and consumption reduction

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AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 43-51页

作者： qing-Qi zhang Qian Chen Pan Cao Chun-Xia Shi Lu-yi zhang Lu-Wen Wang Zuo-Jiong Gong Department of Infectious Diseases Renmin Hospital of Wuhan UniversityWuhan 430060China

Background:Acute liver failure(ALF)is an unpredictable and life-threatening critical illness.The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure.Methods:Animals were divided into 3 groups,normal,thioacetamide(TAA,ALF model)and TAA+AGK2.Cultured L02 cells were divided into 5 groups,normal,TAA,TAA+mitofusin 2(MFN2)-siRNA,TAA+AGK2,and TAA+AGK2+MFN2-siRNA groups.The liver histology was evaluated with hematoxylin and eosin staining,inositol-requiring enzyme 1(IRE1),activating transcription factor 6β(ATF6β),protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)and phosphorylated-PERK(p-PERK).C/EBP homologous protein(CHOP),reactive oxygen species(ROS),MFN2 and glutathione peroxidase 4(GPX4)were measured with Western blotting,and cell viability and liver chemistry were also measured.Mitochondriaassociated endoplasmic reticulum membranes(MAMs)were measured by immunofluorescence.Results:The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis,which were reduced by AGK2 pre-treatment.In comparison to the normal group,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+in the TAA-induced ALF model group were significantly increased,which were decreased by AGK2 pre-treatment.The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group,which were enhanced by AGK2 pretreatment.Compared with the TAA-induced L02 cell,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group.AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell.Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells.Conclusions:The d

关键词： SIRT2 inhibitor AGK2 Acute liver failure MFN2 Ferroptosis

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Numerical study of submerged bending vegetation under unidirectional flow

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Water Science and Engineering 2024年第1期17卷 92-100页

作者： Pei-pei zhang yi-qing Gong Ken Vui Chua Jie Dai Jing-qiao Mao College of Water Conservancy and Hydropower Engineering Hohai UniversityNanjing 210098China Institute of Water Science and Technology Hohai UniversityNanjing 210098China School of Engineering Cardiff UniversityCardiff CF243AAUK

Submerged vegetation commonly grows and plays a vital role in aquatic ecosystems,but it is also regarded as a barrier to the passing flow.Numerical simulations of flow through and over submerged vegetation were carried out to investigate the effect of vegetation density on flow field.Numerical simulations were computationally set up to replicate flume experiments,in which vegetation was mimicked with flexible plastic strips.The fluid-structure interaction between flow and flexible vegetation was solved by coupling the two modules of the COMSOL packages.Two cases with different vegetation densities were simulated,and the results were successfully validated against the experimental data.The contours of the simulated time-averaged streamwise velocity and Reynolds stress were extracted to highlight the differences in mean and turbulent flow statistics.The turbulence intensity was found to be more sensitive to vegetation density than the time-averaged velocity.The developing length increased with the spacing between plants.The snapshots of the bending vegetation under instantaneous velocity and vorticity revealed that flexible vegetation responded to the effects of eddies in the shear layer by swaying periodically.The first two rows of vegetation suffered stronger approaching flow and were prone to more streamlined postures.In addition,the origin of tip vortices was investigated via the distribution of vorticity.The results reveal the variation of flow properties with bending submerged vegetation and provide useful reference for optimizationofrestorationprojects.

关键词： Computational fluid dynamics Fluid-structure interaction Turbulence Flexible and submerged vegetation

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Will partial splenic embolization followed by splenectomy increase intraoperative bleeding?

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World Journal of Gastrointestinal Surgery 2024年第2期16卷 318-330页

作者： Long Huang qing-Lin Li qing-Sheng Yu Hui Peng Zhou Zhen yi Shen Qi zhang Department of No.1 Surgery The First Hospital Affiliated to Anhui University of Traditional Chinese MedicineHefei 230031Anhui ProvinceChina Anhui University of Traditional Chinese Medicine Anhui University of Traditional Chinese MedicineHefei 230038Anhui ProvinceChina Department of Surgery The Second Hospital Affiliated to Anhui University of Traditional Chinese MedicineHefei 230061Anhui ProvinceChina

BACKGROUND Partial splenic embolization(PSE)has been suggested as an alternative to splenectomy in the treatment of hypersplenism.However,some patients may experience recurrence of hypersplenism after PSE and require splenectomy.Currently,there is a lack of evidence-based medical support regarding whether preoperative PSE followed by splenectomy can reduce the incidence of complications.AIM To investigate the safety and therapeutic efficacy of preoperative PSE followed by splenectomy in patients with cirrhosis and hypersplenism.METHODS Between January 2010 and December 2021,321 consecutive patients with cirrhosis and hypersplenism underwent splenectomy at our department.Based on whether PSE was performed prior to splenectomy,the patients were divided into two groups:PSE group(n=40)and non-PSE group(n=281).Patient characteristics,postoperative complications,and follow-up data were compared between groups.Propensity score matching(PSM)was conducted,and univariable and multivariable analyses were used to establish a nomogram predictive model for intraoperative bleeding(IB).The receiver operating characteristic curve,Hosmer-Lemeshow goodness-of-fit test,and decision curve analysis(DCA)were employed to evaluate the differentiation,calibration,and clinical performance of the model.RESULTS After PSM,the non-PSE group showed significant reductions in hospital stay,intraoperative blood loss,and operation time(all P=0.00).Multivariate analysis revealed that spleen length,portal vein diameter,splenic vein diameter,and history of PSE were independent predictive factors for IB.A nomogram predictive model of IB was constructed,and DCA demonstrated the clinical utility of this model.Both groups exhibited similar results in terms of overall survival during the follow-up period.CONCLUSION Preoperative PSE followed by splenectomy may increase the incidence of IB and a nomogram-based prediction model can predict the occurrence of IB.

关键词： Partial splenic embolization Splenectomy Hypertension,Portal Liver Cirrhosis Intraoperative bleeding

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Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

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Fundamental Research 2024年第1期4卷 188-198页

作者： yi-Ting Zhou Da-Dao An yi-Xin Xu ying Zhou qing-qing Li Hai-Bin Dai Xiang-Nan zhang yi Wang Min Lou Zhong Chen Wei-Wei Hu Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital NHC and CAMS Key Laboratory of Medical NeurobiologySchool of Basic Medical SciencesCollege of Pharmaceutical SciencesZhejiang University School of MedicineHangzhou 310058China Department of Pharmacy Sir Run Run Shaw HospitalHangzhou 310012China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China Department of Neurology the Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310003China

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical structure.In a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral hypoperfusion.The therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ischemia.Mechanistically,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons.Additionally,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral hypoperfusion.In summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion.It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

关键词： Chronic cerebral hypoperfusion Optogenetic stimulation Oligodendrocyte progenitor cellIschemic vascular dementia Glutamatergic neuron Remyelination

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Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening

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Virologica Sinica 2024年第2期39卷 301-308页

作者： Qiu-Yan zhang Jia-Qi Li Qi Li Yang zhang Zhe-Rui zhang Xiao-Dan Li Hong-qing zhang Cheng-Lin Deng Feng-Xia Yang yi Xu Bo zhang The Joint Center of Translational Precision Medicine Department of Infections and DiseasesGuangzhou Institute of PediatricsGuangzhou Women and Children's Medical CenterGuangzhou510623China Key Laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China University of Science and Technology of China Department of Life Sciences and MedicineHefei230026China Hunan Normal University School of MedicineChangsha410081China

Hand,foot,and mouth disease(HFMD)is a common pediatric illness mainly caused by enteroviruses,which are important human pathogens.Currently,there are no available antiviral agents for the therapy of enterovirus infection.In this study,an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed.Using this screening system,we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors.Fangchinoline(FAN),a bis-benzylisoquinoline alkaloid,exhibits potential inhibitory effects against various enteroviruses that cause HFMD,such as EV-A71,CV-A10,CV-B3 and CV-A16.Further investigations revealed that FAN targets the early stage of the enterovirus life cycle.Through the selection of FAN-resistant EV-A71 viruses,we demonstrated that the VP1 protein could be a potential target of FAN,as two mutations in VP1(E145G and V258I)resulted in viral resistance to FAN.Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

关键词： Hand,foot,and mouth disease(HFMD) Enterovirus EV-A71 High-content screening Fangchinoline(FAN)

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Mediating role of social support in dysphoria,despondency,and quality of life in patients undergoing maintenance hemodialysis

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World Journal of Psychiatry 2024年第3期14卷 409-420页

作者： Xiang Zhou Hong Jiang yi-Peng Zhou Xiao-Yu Wang Hai-Yan Ren Xue-Fei Tian qing-qing zhang Department of Nephrology People’s Hospital of Xinjiang Uygur Autonomous RegionXinjiang Clinical Research Center for Kidney DiseaseUrumqi 832000Xinjiang Uygur Autonomous RegionChina Department of Endocrinology and Metabolism People’s Hospital of Xinjiang Uygur Autonomous RegionUrumqi 832000Xinjiang Uygur Autonomous RegionChina Section of Nephrology Department of Internal MedicineYale University School of MedicineNew HavenCT 06510United States

BACKGROUND Dysphoria and despondency are prevalent psychological issues in patients undergoing Maintenance Hemodialysis(MHD)that significantly affect their quality of life(QOL).High levels of social support can significantly improve the physical and mental well-being of patients undergoing MHD.Currently,there is limited research on how social support mediates the relationship between dysphoria,despondency,and overall QOL in patients undergoing MHD.It is imperative to investigate this mediating effect to mitigate dysphoria and despondency in patients undergoing MHD,ultimately enhancing their overall QOL.AIM To investigate the mediating role of social support in relationships between dysphoria,despondency,and QOL among patients undergoing MHD.METHODS Participants comprised 289 patients undergoing MHD,who were selected using a random sampling approach.The Social Support Rating Scale,Self-Rating Anxiety Scale,Self-Rating Depression Scale,and QOL Scale were administered.Correlation analysis was performed to examine the associations between social support,dysphoria,despondency,and QOL in patients undergoing MHD.To assess the mediating impact of social support on dysphoria,despondency,and QOL in patients undergoing MHD,a bootstrap method was applied.RESULTS Significant correlations among social support,dysphoria,despondency,and quality in patients undergoing MHD were observed(all P<0.01).Dysphoria and despondency negatively correlated with social support and QOL(P<0.01).Dysphoria and despondency had negative predictive impacts on the QOL of patients undergoing MHD(P<0.05).The direct effect of dysphoria on QOL was statistically significant(P<0.05).Social support mediated the relationship between dysphoria and QOL,and this mediating effect was significant(P<0.05).Similarly,the direct effect of despondency on QOL was significant(P<0.05).Moreover,social support played a mediating role between despondency and QOL,with a significant mediating effect(P<0.05).CONCLUSION These findings suggest that social support plays a signifi

关键词： Maintenance hemodialysis Social support Dysphoria Despondency Quality of life Mediating effect

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Cordyceps as potential therapeutic agents for atherosclerosis

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Journal of Integrative Medicine 2024年第2期22卷 102-114页

作者： yi zhang Si-jing Liu School of Marxism Chengdu University of Traditional Chinese MedicineChengdu 61137Sichuan ProvinceChina College of Medical Technology Chengdu University of Traditional Chinese MedicineChengdu 611137Sichuan ProvinceChina Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases with Integrated Chinese and Western Medicine Chengdu University of Traditional Chinese MedicineChengdu 611137Sichuan ProvinceChina

Atherosclerosis is a leading cause of mortality and morbidity worldwide.Despite the challenges in managing atherosclerosis,researchers continue to investigate new treatments and complementary therapies.Cordyceps is a traditional Chinese medicine that has recently gained attention as a potential therapeutic agent for atherosclerosis.Numerous studies have demonstrated the effectiveness of cordyceps in treating atherosclerosis through various pharmacological actions,including anti-inflammatory and antioxidant activities,lowering cholesterol,inhibiting platelet aggregation,and modulating apoptosis or autophagy in vascular endothelial cells.Notably,the current misuse of the terms cordyceps and Ophiocordyceps sinensis has caused confusion among researchers,and complicated the current academic research on cordyceps.This review focuses on the chemical composition,pharmacological actions,and underlying mechanisms contributing to the anti-atherosclerotic effects of cordyceps and the mycelium of Ophiocordyceps spp.This review provides a resource for the research on the development of new drugs for atherosclerosis from cordyceps.

关键词： Atherosclerosis Cordyceps Ophiocordyceps sinensis

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Gene therapy for monogenic disorders: challenges, strategies, and perspectives

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Journal of Genetics and Genomics 2024年第2期51卷 133-143页

作者： yi zhang Zhi-ying Wu Department of Medical Genetics and Center for Rare Diseases Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Department of Neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Key Laboratory of Medical Neurobiology of Zhejiang Province HangzhouZhejiang 310009China

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

关键词： Gene therapy Monogenic diseases Geneediting Genedelivery Challenges

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