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Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

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Neuroscience Bulletin 2024年第2期40卷 218-240页

作者： feifei li Chou Wu Gelin Wang School of Pharmaceutical Sciences Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijing 100084China Tsinghua-Peking Joint Center for life Sciences Tsinghua UniversityBeijing 100084China

As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.

关键词： Ageing Neuroprotection NAD metabolism Therapeutic strategy Neurodegenerative diseases

Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment

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Signal Transduction and Targeted Therapy 2022年第1期7卷 131-160页

作者： Wen li feifei li Xia Zhang Huikuan lin Chuan Xu Integrative Cancer Center&Cancer Clinical Research Center Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of China610042 ChengduP.R.China Guangxi Collaborative Innovation Center for Biomedicine(Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment) Guangxi Medical University530021 NanningGuangxiChina Institute of Pathology and Southwest Cancer Center Southwest Hospital Third Military Medical University(Army Medical University)400038 ChongqingChina Department of Cancer Biology Wake Forest Baptist Medical CenterWake Forest UniversityWinston SalemNC 27101USA

More and more in-depth studies have revealed that the occurrente and development of tumors depend on gene mutation and tumor *** most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment(TME)*** depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor *** has resulted in novel therapeutic in terve ntions as a place beyond tumor *** malig nant can cer cells,tumor in filtrate immune cells,angiogenic vascular cells,lymphatic endothelial cells,cancer-associated fibroblastic cells,and the released factors including intracellular metabolites,hormonal signals and inflammatory mediators all contribute actively to cancer *** post-translational modification(PTM)is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological *** in quantitative transcriptomics,proteomics,and nuclease-based gene editing are now paving the global ways for exploring *** this review,we focus on recent developments in the PTM area and speculate on their importanee as a critical functional readout for the regulation of TME.A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.

关键词： homeostasis translational maintain

Evidence of constraint in the 3D genome for trans-splicing in human cells

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Science China(life Sciences) 2020年第9期63卷 1380-1393页

作者： Cong liu Yiqun Zhang Xiaoli li Yan Jia feifei li Jing li Zhihua Zhang CAS Key Laboratory of Genome Sciences and Information Beijing Institute of Genomicsand China National Center for BioinformationChinese Academy of SciencesBeijing 100101China School of life Science University of Chinese Academy of SciencesBeijing 100049China

Fusion transcripts are commonly found in eukaryotes, and many aberrant fusions are associated with severe diseases, including cancer. One class of fusion transcripts is generated by joining separate transcripts through trans-splicing. However, the mechanism of trans-splicing in mammals remains largely elusive. Here we showed evidence to support an intuitive hypothesis that attributes trans-splicing to the spatial proximity between premature transcripts. A novel trans-splicing detection tool(TSD) was developed to reliably identify intra-chromosomal trans-splicing events(i TSEs) from RNA-seq data. TSD can maintain a remarkable balance between sensitivity and accuracy, thus distinguishing it from most state-of-the-art tools. The accuracy of TSD was experimentally demonstrated by excluding potential false discovery from mosaic genome or template switching during PCR. We showed that i TSEs identified by TSD were frequently found between genomic regulatory elements, which are known to be more prone to interact with each other. Moreover, i TSE sites may be more physically adjacent to each other than random control in the tested human lymphoblastoid cell line according to Hi-C data. Our results suggest that trans-splicing and 3 D genome architecture may be coupled in mammals and that our pipeline, TSD, may facilitate investigations of trans-splicing on a systematic and accurate level previously thought impossible.

关键词： trans-splicing chromatin interaction 3D genome spatial clustering

Aberrant NF-κB activation in odontoblasts orchestrates inflammatory matrix degradation and mineral resorption

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International Journal of Oral Science 2022年第1期14卷 80-90页

作者： Fanyuan Yu Fengli Huo feifei li Yanqin Zuo Chenglin Wang ling Ye State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases West China Hospital of StomatologySichuan UniversityChengduChina Department of Endodontics West China Stomatology HospitalSichuan UniversityChengduChina

Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues *** a specialized inflammatory pathological process,dental internal resorption(IR)includes both soft and hard tissues deconstruction within the dentin-pulp complex,which has been one of the main reasons for inflammatory tooth *** of inflammatory matrix degradation and tissue resorption in IR are largely *** this study,we used a combination of Cre-loxP reporter,flow cytometry,cell transplantation,and enzyme activities assay to mechanistically investigate the role of regenerative cells,odontoblasts(ODs),in inflammatory mineral resorption and matrices *** report that inflamed ODs have strong capabilities of matrix degradation and tissue ***,ODs are regarded as hard-tissue regenerative cells;however,our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue ***,we uncovered that nuclear factor-kappa b(NF-κB)signaling orchestrated Tumor necrosis factorα(TNF-α)-induced matrix metalloproteinases(Mmps)and Cathepsin K(Ctsk)functions in ODs to enhance matrix degradation and tissue ***,TNF-αincreases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level,which utterly makes ODs cell line 17IIA11(A11)become Trap^(+) and Ctsk^(+) multinucleated cells to perform resorptive *** of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and ***,via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in *** data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.

关键词： inflammatory matrix utilizing

Deep learning for predictive mechanical properties of hot-rolled strip in complex manufacturing systems

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International Journal of Minerals,Metallurgy and Materials 2023年第6期30卷 1093-1103页

作者： feifei li Anrui He Yong Song Zheng Wang Xiaoqing Xu Shiwei Zhang Yi Qiang Chao liu National Engineering Research Center for Advanced Rolling and Intelligent Manufacturing University of Science and Technology BeijingBeijing 100083China China Academy of Machinery Science and Technology Beijing 100044China

Higher requirements for the accuracy of relevant models are put throughout the transformation and upgrade of the iron and steel sector to intelligent *** has been difficult to meet the needs of the field with the usual prediction model of mechanical properties of hotrolled *** data and difficult parameter adjustment limit deep learning models based on multi-layer networks in practical applications;besides,the limited discrete process parameters used make it impossible to effectively depict the actual strip processing *** order to solve these problems,this research proposed a new sampling approach for mechanical characteristics input data of hot-rolled strip based on the multi-grained cascade forest(gcForest)*** to the characteristics of complex process flow and abnormal sensitivity of process path and parameters to product quality in the hot-rolled strip production,a three-dimensional continuous time series process data sampling method based on time-temperature-deformation was *** basic information of strip steel(chemical composition and typical process parameters)is fused with the local process information collected by multi-grained scanning,so that the next link’s input has both local and global ***,in the multi-grained scanning structure,a sub sampling scheme with a variable window was designed,so that input data with different dimensions can get output characteristics of the same dimension after passing through the multi-grained scanning structure,allowing the cascade forest structure to be trained ***,actual production data of three steel grades was used to conduct the experimental *** results revealed that the gcForest-based mechanical property prediction model outperforms the competition in terms of comprehensive performance,ease of parameter adjustment,and ability to sustain high prediction accuracy with fewer samples.

关键词： hot-rolled strip prediction of mechanical properties deep learning multi-grained cascade forest time series feature extraction variable window subsampling

Xianling lianxia formula improves the efficacy of trastuzumab by enhancing NK cell-mediated ADCC in HER2-positive BC

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Journal of Pharmaceutical Analysis 2024年第10期14卷 1450-1467页

作者： feifei li Youyang Shi Mei Ma Xiaojuan Yang Xiaosong Chen Ying Xie Sheng liu Department of Breast Surgery Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai200030China Institute of Chinese Traditional Surgery Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai200030China Institute of Toxicology School of Public HealthLanzhou UniversityLanzhou730000China Department of General Surgery Comprehensive Breast Health CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200001China

Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment *** killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of *** Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune *** lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive ***,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention ***,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)***,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.

关键词： HER2-positive breast cancer Traditional chinese medicine Trastuzumab NK cell ADCC effect

***:An augmented reality-based visualization platform for 3D genome

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The Innovation 2021年第3期2卷 19-20页

作者： Bixia Tang Xiaoxing li Guan li Dong Tian feifei li Zhihua Zhang CAS Key Laboratory of Genome Sciences and Information Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China National Genomics Data Center Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Computer Network Information Center Chinese Academy of SciencesBeijing 100190China School of life Science University of Chinese Academy of SciencesBeijing 100049China School of Artificial Intelligence University of Chinese Academy of SciencesBeijing 100049China

Many visualization tools have been developed for 3D genome data integration using two-dimensional(2D)devices such as PC monitors or ***,the 2D surface is only suitable for displaying linear data,and it has done little to inform our understanding of the complex interconnections between 3D genome architecture and its various associated-omics *** breakthrough in immersive display technologies,e.g.,virtual reality(VR)and augmented reality(AR),has opened a completely new model for data *** visualization has proved a powerful way to enhance 3D structure-related research,e.g.,protein structure and drug ***,visualization in immersive mode,coupled with the integration of 3D genome and its associated-omics data,is *** a few attempts have been made for single features,e.g.,Juicebox VR,which projects a Hi-C contact matrix into a virtual mountain field,and the WashU Epigenome Browser,which provides a 3D scene for epigenome tracks.A visualization tool for immersive integration of 3D genome architecture with high-dimensional-omics data has not yet been published.

关键词： integration breakthrough visualization

CsABF3-activated CsSUT1 pathway is implicated in pre-harvest water deficit inducing sucrose accumulation in citrus fruit

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Horticultural Plant Journal 2024年第1期10卷 103-114页

作者： Xiaochuan Ma Yuanyuan Chang feifei li Junfeng Yang li Ye Tie Zhou Yan Jin ling Sheng Xiaopeng Lu College of Horticulture Hunan Agricultural UniversityChangshaHunan 410128China National Center for Citrus Improvement ChangshaHunan 410128China Institute of Horticulture Hunan Academy of Agricultural ScienceChangshaHunan 410125China

Pre-harvest water deficit(PHWD)plays an important role in sugar accumulation of citrus ***,the mechanism is not known ***,it was confirmed that PHWD promoted sucrose accumulation of citrus fruit,but had limited effect on fructose,glucose and total acid.A sucrose transporter,Cs SUT1,which localizes to the plasma membrane,was demonstrated to function in sucrose transport induced by *** to wild-type,Cs SUT1 overexpression in citrus calli stimulated sucrose,fructose and glucose accumulation,while its silencing in juice sacs reduced sucrose *** sugar accumulation in transgenic lines enhanced plant drought tolerance,and resulted in decreased electrolyte leakage,malondialdehyde and hydrogen peroxide contents,as well as increased superoxide dismutase activity and proline *** abscisic acid(ABA)-responsive transcription factor,Cs ABF3,was found with a same expression pattern with Cs SUT1 under *** one-hybrid,electrophoretic mobility shift assay and dual-luciferase assays all revealed that Cs ABF3 directly bound with the Cs SUT1 promoter by ABA responsive *** Cs ABF3 was overexpressed in citrus calli,the sucrose,fructose and glucose concentration increased ***,transgenic studies demonstrated that Cs ABF3 could affect sucrose accumulation by regulating Cs ***,this study revealed a regulation of Cs ABF3 promoting Cs SUT1 expression and sucrose accumulation in response to *** results provide a detail insight into the quality formation of citrus fruit.

关键词： Citrus Water deficit Pre-harvest Sucrose CsABF3 CsSUT1

Identifying human-induced influence on microbial community:A comparative study in the effluent-receiving areas in Hangzhou Bay

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Frontiers of Environmental Science & Engineering 2019年第6期13卷 103-113页

作者： Yuhan Zheng Zhiguo Su Tianjiao Dai feifei li Bei Huang Qinglin Mu Chuanping Feng Donghui Wen School of Water Resource and Environmental Science China University of Geosciences(Beijing)Beijing 100083China College of Environmental Sciences and Engineering Peking UniversityBeijing 100871China Zhejiang Provincial Zhoushan Marine Ecological Environmental Monitoring Station Zhoushan 316021China

Microbial community structure is afiected by both natural processes and human *** coastal area,anthropegenetic activity can usually lead to the discharge of the effluent from wastewater treatment plant(WWTP)to sea,and thus the water quality chronically turns worse and marine ecosystem becomes *** play key roles in pollutants degradation and ecological restoration;however,there are few studies about how the WWTP effluent disposal influences coastal microbial *** this study,sediment samples were collected from two WWTP effluentreceiving areas(abbreviated as JX and SY)in Hangzhou ***,based on the high-throughput sequencing of 16S rRNA gene,microbial community structure was ***,several statistical analyses were conducted to reveal the microbial community characteristics in response to the effluent *** PCoA,the significant difference of in microbial community structure was determined between JX and SY;using RDA,water COD and temperature,and sediment available phosphate and ammonia nitrogen were identified as the key environmental factors for the community difference;using LDA effect size analysis,the most distinctive microbes were found and their correlations with environmental factors were investigated;and according to detrended beta-nearesttaxon-index,the sediment microbial communities were found to follow"niche theory".An interesting and important finding was that in SY that received more and toxic COD,many distinctive microbes were related to the groups that were capable of degrading toxic organic *** study provides a clear illustration of eco-environmental deterioration under the long-term human pressure from the view of microbial ecology.

关键词： Microbial community structure Effluent-receiving area High-throughput sequencing Costal sediments Wastewater treatment plant(WWTP)