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NAD⁺ modulation of intestinal macrophages renders anti-inflammatory functionality and ameliorates gut inflammation

Biomedicine and Pharmacotherapy 2025年 185卷 117938-117938页

作者： Kim, Young-In Ko, Inseok Yi, Eun-Je Kim, Jusik Hong, Yong Rae Lee, Wheeseong Chang, Sun-Young Laboratory of Microbiology Department of Pharmacy and Research Institute of Pharmaceutical Science and Technology (RIPST) Ajou University Suwon 16499 South Korea Korea Initiative for fostering University of Research and Innovation (KIURI) Program Ajou University School of Medicine Suwon 16499 South Korea Lmito Therapeutics Yongin-si 16827 South Korea Department of Chemistry Education Graduate Department of Chemical Materials Pusan National University Busan South Korea

Macrophages can maintain gut immune homeostasis by driving clearance of infection, but also can prevent chronic inflammation and induce tissue repair. Reduced nicotinamide adenine dinucleotide (NAD⁺) levels in macrophages have been reported to be associated with the onset of severe colitis. Given that dysregulation of gut macrophages plays a significant role in inflammatory bowel disease (IBD), they represent a potential target for novel therapies. Here we show an IBD therapeutic candidate LMT503, a substrate that modulates NADH quinone oxidoreductase (NQO1), which induces anti-inflammatory macrophage polarization by NAD⁺ enhancement. To determine the anti-inflammatory effect of LMT503, a dextran sulfate sodium (DSS)-induced colitis mouse model was used in this study. Treatment of bone marrow-derived macrophages (BMDMs) with LMT503 increased IL-10 and Arg1 levels but decreased levels of TNF-α, iNOS, and IL-6. LMT503 also increased levels of SIRT1, SIRT3, and SIRT6, suggesting that macrophages were driven to an anti-inflammatory character. In a murine DSS-induced colitis model, oral treatment with LMT503 ameliorated colonic inflammation and decreased infiltrating monocytes and neutrophils. Although NAD⁺ enhancement did not alter CX₃CR1^intCD206^- or CX₃CR1^hiCD206⁺ colon macrophage population, it decreased levels of TNF-α and iNOS and increased IL-10 level, with colonic macrophages showing an anti-inflammatory character shift. Depletion of CX₃CR1 expressing gut resident macrophages abrogated the immune regulatory effect of LMT503 in the colon. These data suggest that LMT503 is a therapeutic candidate that can target macrophages to drive polarization with an immunosuppressive character and ameliorate IBD. © 2025

关键词： Colon Gut macrophage Inflammatory bowel disease Macrophage polarization NAD+ modulation

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Biomedical data and AI

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science China Life sciences 2025年第5期68卷 1536-1540页

作者： Hao Xu Shibo Zhou Zefeng Zhu Vincenzo Vitelli Liangyi Chen Ziwei Dai Ning Yang Luhua Lai Shengyong Yang Sergey Ovchinnikov Zhuoran Qiao Sirui Liu Chen Song Jianfeng Pei Han Wen Jianfeng Feng Yaoyao Zhang Zhengwei Xie Yang-Yu Liu Zhiyuan Li Fulai Jin Hao Li Mohammad Lotfollahi Xuegong Zhang Ge Yang Shihua Zhang Ge Gao Pulin Li Qi Liu Jing-Dong Jackie Han Peking-Tsinghua Center for Life Sciences (CLS) Academy for Advanced Interdisciplinary StudiesPeking University Center for Quantitative Biology (CQB) Academy for Advanced Interdisciplinary StudiesPeking University Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program Academy for Advanced Interdisciplinary StudiesPeking University Department of Physics University of Chicago School of Life Sciences Southern University of Science and Technology Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies College of Chemistry and Molecular Engineering Peking University Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan University Department of Biology Massachusetts Institute of Technology Lambic Therapeutics Inc. Changping Laboratory Al for Science Institute Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence Fudan University Department of Obstetrics and Gynecology West China Second University HospitalSichuan University Peking University International Cancer Institute and Peking University-Yunnan Baiyao International Medical Institute and State Key Laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking University Health Science CenterPeking University Channing Division of Network Medicine Department of MedicineBrigham and Women's Hospital and Harvard Medical School Center for Artificial Intelligence and Modeling the Carl R.Woese Institute for Genomic BiologyUniversity of Illinois Urbana-Champaign Department of Genetics and Genome Sciences School of Medicine and Department of Computer and Data Sciences and Department of Population and Quantitative Health SciencesCase Western Reserve University Department of Biochemistry and Biophysics University of California Sanger Institute Department of Automation Tsinghua University State Key Laboratory of Multimodal Artificial Intelligence Systems I

The development of artificial intelligence(AI) and the mining of biomedical data complement each other. From the direct use of computer vision results to analyze medical images for disease screening, to now integrating biological knowledge into models and even accelerating the development of new AI based on biological discoveries, the boundaries of both are constantly expanding, and their connections are becoming closer.

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Bioactivity, Efficacy, and Safety of a Wound Healing Ointment With Medicinal Plant Bioactives: In Vitro and In Vivo Preclinical Evaluations

Scientific World Journal

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Scientific World Journal 2025年第1期2025卷 9466270页

作者： Floriano, Juliana Ferreira Rodrigues, Daniel Ohara, Rie Almeida, Nara Lígia Martins Lara, Vanessa Soares Sartorelli, Patricia Graeff, Carlos Frederico de Oliveira Grecco, Simone dos Santos González, Alejandra Hortencia Miranda D’Alpino, Paulo Henrique Perlatti Imperial College London National Heart and Lung Institute imperial.ac.uk GBR London United Kingdom Botucatu Medical School São Paulo State University (UNESP) São Paulo unesp.br BRA Botucatu Brazil Bioengineering and Biomaterials Group School of Pharmaceutical Sciences São Paulo State University (UNESP) unesp.br BRA Araraquara São Paulo Brazil Biotechnology and Innovation in Health Program Universidade Anhanguera de São Paulo (UNIAN) São Paulo BRA Brazil Brazil Department of Health Management Fundação Nacional de Gestão de Saúde São Paulo Brazil Undergraduate Program Medical School Universidade Nove de Julho Bauru São Paulo Brazil Department of Surgery Stomatology Pathology and Radiology Bauru School of Dentistry University of São Paulo (USP) São Paulo usp.br BRA Bauru Brazil Department of Chemistry Institute of Environmental Chemical and Pharmaceutical Sciences Federal University of São Paulo São Paulo unifesp.br BRA Diadema Brazil Department of Physics School of Sciences POSMAT-Post-Graduate Program in Materials Science and Technology São Paulo State University (UNESP) São Paulo Bauru Brazil Department of Research and Development (RD) and Innovation Center Triplet Biotechnology Solutions Inc Bauru São Paulo Brazil Post-Graduate Program in Dentistry Uniderp Anhanguera University Mato Grosso do Sul Campo Grande Brazil Post-Graduate Program in Integrated Dental Sciences University of Cuiabá (UNIC) Mato Grosso do Sul Cuiabá Brazil Department of Physics School of Sciences São Paulo State University (UNESP) São Paulo unesp.br BRA Bauru Brazil

Chronic wounds have a significant impact on patients’ quality of life, necessitating the management of pain, infection, bleeding, and emotional challenges. Debridement, which involves the removal of nonviable tissue, is crucial for promoting wound healing. In addition to surgical methods, cost-effective alternatives such as local solutions and ointments with biological properties have been explored. The use of natural compounds with anti-inflammatory, antibacterial, and collagen-synthesizing abilities holds promise for wound healing. This in vitro and in vivo preclinical study aimed to assess the safety and effectiveness of a wound healing ointment containing bioactive ingredients derived from medicinal plants (extracts, essential oils, and vegetable oils). The chemical composition of the ointment was characterized using Fourier transform infrared (FTIR) spectroscopy to gain insights into its synergistic action. Preclinical tests were conducted following standardized protocols. FTIR analysis revealed similarities between the product’s spectrum and that of bioactive compounds. The in vitro tests demonstrated that all formulations of the ointment induced no cell death, DNA damage, or acute toxicity in cell cultures (p < 0.05). No lethal dose was observed, indicating the safety of the ointment at all concentrations. The ointment also stimulated a notably more organized, significantly higher collagen production compared to control groups (p < 0.05). In vivo preclinical analyses also demonstrated no adverse responses being effective in the healing process compared to the control group (silver sulfadiazine) in terms of wound contraction and ulcer re-epithelization (p < 0.05). Significantly higher means of wound contraction were observed in the groups treated with the bioactive-containing ointment when compared to both the positive control group (sulfadiazine) and the control untreated groups (p < 0.05). The regenerative ointment exhibited excellent biocompatibility and bi

关键词： biocompatibility chronic wounds natural compounds preclinical tests wound care

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HOS15 represses flowering by promoting GIGANTEA degradation in response to low temperature in Arabidopsis

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Plant Communications 2023年第4期4卷 225-239页

作者： Gyeongik Ahn Hee Jin Park Song Yi Jeong Gyeong-Im Shin Myung Geun Ji Joon-Yung Cha Jeongsik Kim Min Gab Kim Dae-Jin Yun Woe-Yeon Kim Research Institute of Life Science Institute of Agricultural and Life ScienceGyeongsang National UniversityJinju 52828Republic of Korea Division of Applied Life Science(BK21 Four) Plant Biological Rhythm Research CenterPlant Molecular Biology and Biotechnology Research CenterGraduate School of Gyeongsang National UniversityJinju 52828Republic of Korea Department of Biological Sciences College of Natural SciencesChonnam National UniversityGwangju 61186Republic of Korea Faculty of Science Education and Interdisciplinary Graduate Program in Advanced Convergence Technology and Science Jeju National UniversityJeju 63243Republic of Korea College of Pharmacy and Research Institute of Pharmaceutical Science PMBBRCGyeongsang National UniversityJinju 52828Republic of Korea Institute of Glocal Disease Control Konkuk UniversitySeoul 05029Republic of Korea Key Laboratory of Molecular Epigenetics of the Ministry of Education(MOE) Northeast Normal UniversityChangchun 130024China

Flowering is the primary stage of the plant developmental transition and is tightly regulated by environmental factors such as light and ***,the mechanisms by which temperature signals are integrated into the photoperiodic flowering pathway are still poorly ***,we demonstrate that HOS15,which is known as a GI transcriptional repressor in the photoperiodic flowering pathway,controls flowering time in response to low ambient *** 16℃,the hos15 mutant exhibits an early flowering phenotype,and HOS15 acts upstream of photoperiodic flowering genes(GI,CO,and FT).GI protein abundance is increased in the hos15 mutant and is insensitive to the proteasome inhibitor ***,the hos15 mutant has a defect in low ambient temperature-mediated GI degradation,and HOS15 interacts with COP1,an E3 ubiquitin ligase for GI *** analyses of the hos15 cop1 double mutant revealed that repression of flowering by HOS15 is dependent on COP1 at 16℃.However,the HOS15-COP1 interaction was attenuated at 16℃,and GI protein abundance was additively increased in the hos15 cop1 double mutant,indicating that HOS15 acts independently of COP1 in GI turnover at low ambient *** study proposes that HOS15 controls GI abundance through multiple modes as an E3 ubiquitin ligase and transcriptional repressor to coordinate appropriate flowering time in response to ambient environmental conditions such as temperature and day length.

关键词： Arabidopsis flowering response low ambient temperature HOS15 GIGANTEA

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Red onion skin extract rich in flavonoids encapsulated in ultrafine fibers of sweet potato starch by electrospinning

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Food Chemistry 2023年 406卷 134954页

作者： Cruz, Elder Pacheco da Jansen, Estefani Tavares Fonseca, Laura Martins Hackbart, Helen Cristina dos Santos Siebeneichler, Tatiane Jéssica Pires, Juliani Buchveitz Gandra, Eliezer Avila Rombaldi, Cesar Valmor Zavareze, Elessandra da Rosa Dias, Alvaro Renato Guerra Graduate Program in Food Science and Technology Department of Agroindustrial Science and Technology Federal University of Pelotas RS Pelotas96010-900 Brazil Center for Chemical Pharmaceutical and Food Sciences Federal University of Pelotas RS Pelotas96010-900 Brazil

Electrospinning encapsulation is a highly viable method to protect bioactive compounds and prevent their degradation. Hence, this study produced ultrafine fibers based on yellow and white sweet potato starches and a red onion skin extract (ROSE;0, 3, 6, and 9 %, w/w) using electrospinning. The fibers were evaluated for morphology, thermogravimetric properties, antioxidant, in vitro release simulation, thermal resistance (100 and 180 °C), and wettability. The fibers with ROSE presented 251–611 nm diameters, 67–78 % loading capacity, and 51.6–95.4 and 13.4–99.4 % thermal resistance (100 and 180 °C, respectively);apigenin presented the highest thermal protection. The phenolic compounds showed low release using 10 % ethanol and greater release with 50 % ethanol. The fibers with 9 % ROSE showed 2,2′-azino-bis(3-ethylbenzothiazoline) 6-sulfonic acid radical inhibition above 92 %. The ultrafine fibers and the unencapsulated ROSE showed inhibitory action against Escherichia coli and Staphylococcus aureus;only unencapsulated ROSE showed bactericidal activity. © 2022 Elsevier Ltd

关键词： Contact angle

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Dynamic change of gene-to-gene regulatory networks in response to SARS-CoV-2 infection

arXiv

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arXiv 2020年

作者： Tanaka, Yoshihisa Higashihara, Kako Nakazawa, Mai Adachi Yamashita, Fumiyoshi Tamada, Yoshinori Okuno, Yasushi Graduate School of Pharmaceutical Sciences Kyoto University Japan RIKEN Cluster for Science Technology and Innovation Hub Medical Sciences Innovation Hub Program Japan Graduate School of Medicine Kyoto University Japan

The current pandemic of SARS-CoV-2 has caused extensive damage to society. The characterization of SARS-CoV-2 prpfiles has been addressed by researchers globally with the aim of resolving this disruptive crisis. This investigation process is indispensable for an understanding of how SARS-CoV-2 behaves in human host cells. However, little is known about the systematic molecular mechanisms involved in the effect of SARS-CoV-2 infection on human host cells. Here, we have presented gene-to-gene regulatory networks in response to SARS-CoV-2 using a Bayesian network model. We examined the dynamic changes of the SARS-CoV-2-purturbated networks established by our proposed framework for gene network analysis, revealing that interferon signaling gradually switches to the subsequent inflammatory-cytokine signaling cascades. Furthermore, we have succeeded in capturing a COVID-19 patient-specific network in which transduction of these signalings is coincidently induced. This enabled us to explore local regulatory systems influenced by SARS-CoV-2 in host cells more precisely at an individual level. Our panel of network analyses has provided new insight into SARS-CoV-2 research from the perspective of cellular systems. Copyright © 2020, The Authors. All rights reserved.

关键词： SARS

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Revisiting some overlooked registered Thai traditional medicine preparations: an alert to a regulatory affair

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Bulletin of the National Research Centre 2022年第1期46卷 1-9页

作者： Vimolmangkang, Sornkanok Rani, Dolly Prestwong, Naruemon Sutcharitchan, Chayanis Pakdeesattayapong, Duangkamol Department of Pharmacognosy and Pharmaceutical Botany Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok Thailand Center of Excellence in Plant Produced Pharmaceuticals Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok Thailand Graduate Program in Pharmaceutical Science and Technology Faculty of Pharmaceutical Sciences Chulalongkorn University Bangkok Thailand Herbal Products Division Food and Drug Administration Thailand Ministry of Public Health Nonthaburi Thailand

This study evaluated the heavy metal identity and content of registered Thai Traditional medicine (TTM) preparations in Thailand to ensure consumer safety. Both qualitative and quantitative information about the elemental composition of the heavy metal content in each TTM crude drug and the heavy metal content in some registered TTM preparations in Thailand was performed. Seven kinds of mineral-based TTM crude drugs, namely realgar, orpiment, Chinese powder, Sen, vermilion, natural vermilion, and cinnabar, were analyzed with X-ray diffraction and scanning electron microscopy and energy-dispersive spectroscopy techniques to determine the type of metal and elemental composition to confirm their chemical formulas. Furthermore, the number of heavy metals, such as arsenic (As), lead (Pb), and mercury (Hg), was in three samples of realgar-containing preparations; one sample of Sen-containing preparation, and eight samples of cinnabar-containing preparations. Heavy metals were determined with inductively coupled plasma-optical emission spectrometry. It was observed that realgar and orpiment consisted of arsenic sulfide (AsS) and arsenic trisulfide (As2S3), respectively. Both crude drugs contained approximately 50% of As. Vermilion, natural vermilion, and cinnabar consisted of mercuric sulfide (HgS), with Hg accounting for approximately 66%. Sen consisted of Pb (II, IV) oxide (Pb3O4) with an approximate Pb percentage of 80%. However, Pb was absent in Chinese powder and consisted mainly of calcium carbonate (CaCO3). A traditional detoxification procedure can reduce the amount of As and Hg in processed crude drugs by at least 20%. Pb was higher in some TTM preparations, and no CaCO3 was detected in Chinese powder. Our results raise concerns on both safety and efficacy to consumers and alert public health policymakers that they should implement regulations so that the quality (authenticity) and quantity of elemental medicine used in traditional medicine are correctly labeled a

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Actinidia deliciosa as a complemental therapy against nephropathy and oxidative stress in diabetic rats

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Food science and Human Wellness 2023年第6期12卷 1981-1990页

作者： Ali Y.Naoom Wenyi Kang Nora F.Ghanem Mohamed M.Abdel-Daim Fatma M.El-Demerdash Department of Medical Laboratory Techniques Imam Ja'afar Al-Sadiq UniversityAl-Muthanna 66002Iraq National R&D Center for Edible Fungus Processing Technology Henan UniversityKaifeng 475004China Department of Zoology Faculty of ScienceKafr ElSheikh UniversityKafr El Sheikh 33516Egypt Department of Pharmaceutical Sciences Pharmacy ProgramBatterjee Medical CollegeJeddah 21442Saudi Arabia Pharmacology Department Faculty of Veterinary MedicineSuez Canal UniversityIsmailia 41522Egypt Department of Environmental Studies Institute of Graduate Studies and ResearchAlexandria UniversityAlexandria 21526Egypt

This study aimed to evaluate the anti-hyperglycemic and antioxidant role of Actinidia deliciosa(kiwifruits)aqueous extract in streptozotocin-treated *** were distributed into;control,*** aqueous extract(ADAE;1 g/kg orally),streptozotocin(STZ;50 mg/kg,i.p,single dose),and STZ plus ADAE,*** showed that ADAE had high antioxidant and radical scavenging *** in blood sugar level,lipid peroxidation(LPO),kidney function biomarkers,and perturbations in hematological parameters were observed in diabetic ***,enzymatic and non-enzymatic antioxidants,protein content,and alkaline phosphatase(ALP)activity ***,histological,immunohistochemical alpha-smooth muscle actin immunoreactivity(α-SMA-ir)and histochemical(collagen,total protein,DNA,and RNA)alterations were observed in rat ***,STZ produced upregulation of inflammatory associated genes(tumor necrosis factor-alpha;TNF-αand transforming growth factorβ1;TGF-β1)and triggered apoptosis by upregulating apoptotic related gene[Bcl2-associated X protein(Bax)]and downregulating anti-apoptotic related gene B-cell lymphoma-2(Bcl-2)based on real-time PCR ***,diabetic rats administered with ADAE showed significant restoration in LPO,antioxidant status,and biochemical indices besides tissue architecture,and genes improvement regarding STZ ***,*** has a valuable ameliorative infl uence and can restore glucose levels and improve kidney dysfunction in diabetic rats.

关键词： Diabetes mellitus Actinidia deliciosa Inflammation Apoptosis Oxidative stress Nephropathy

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Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites

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Cancer Communications 2024年第1期44卷 47-75页

作者： Ji Eon Kim So-Young Park Chulhwan Kwak Yoonji Lee Dae-Geun Song Jae Woo Jung Haesong Lee Eun-Ae Shin Yangie Pinanga Kyung-hee Pyo Eun Hae Lee Wonsik Kim Soyeon Kim Chang-Duck Jun Jeanho Yun Sun Choi Hyun-Woo Rhee Kwang-Hyeon Liu Jung Weon Lee Department of Pharmacy College of PharmacySeoul National UniversitySeoulRepublic of Korea Research Institute of Pharmaceutical Sciences College of PharmacySeoul National UniversitySeoulRepublic of Korea BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit College of Pharmacy and Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea Department of Chemistry Seoul National UniversitySeoulRepublic of Korea College of Pharmacy Chung-Ang UniversitySeoulRepublic of Korea Natural Product Informatics Research Center Korea Institute of Science and Technology(KIST)Gangneung-siGangwon-doRepublic of Korea School of Life Sciences Gwangju Institute of Science and Technology(GIST)GwangjuRepublic of Korea Department of Biochemistry College of MedicineDong-A UniversityBusanRepublic of Korea Global AI Drug Discovery Center College of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea Interdisciplinary Program in Genetic Engineering Seoul National UniversitySeoulRepublic of Korea

Background:Transmembrane 4 L six family member 5(TM4SF5)translocates subcellularly and functions metabolically,although it is unclear how intracellu-lar TM4SF5 translocation is linked to metabolic *** is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of ***:Here,we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites(MLCSs),using in vitro cells and in vivo animal systems,via approaches by immunofluorescence,proximity labelling based proteomics analysis,organelle reconstitution ***:Upon extracellular glucose repletion following depletion,TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8(FKBP8)and lysosomal *** labeling showed molecular clustering of phospho-dynamic-related protein I(DRP1)and certain mitophagy receptors at TM4SF5-enriched MLCSs,leading to mitochondrial fis-sion and ***4SF5 bound NPC intracellular cholesterol transporter 1(NPC1)and free cholesterol,and mediated export of lysosomal cholesterol to mitochondria,leading to impaired oxidative phosphorylation but intact tri-carboxylic acid(TCA)cycle andβ-*** mouse models,hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria,both with positive relations to liver ***:Our findings suggested that TM4SF5-enriched MLCSs regu-late glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming,presumably while hepatocellular carcinogenesis,recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial repro-gramming to support biomolecule synthesis in addition to glycolytic energetics.

关键词： cholesterol fluorescent imaging glucose catabolism hepatocellular carcinogenesis mem-brane contact sites mitochondria function mitophagy oxidative phosphorylation protein-protein interaction tetraspanin

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Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase(NAMPT)and their preclinical neuroprotective activity

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细胞研究（英文版） 2022年第6期32卷 570-584页

作者： Hong Yao Minghui Liu Leibo Wang Yumeng Zu Chou Wu Chenyu Li Ruoxi Zhang Haigen Lu Feifei Li Shuang Xi Shuangquan Chen Xuanyu Gu Tianya Liu Jie Cai Shirong Wang Maojun Yang Guo-Gang Xing Wei Xiong Lan Hua Yefeng Tang Gelin Wang School of Pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyMinistry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijingChina Joint Graduate Program of Peking-Tsinghua-NIBS School of Life SciencesPeking UniversityBeijingChina School of Pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyMinistry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijingChina School of Pharmaceutical Sciences Beijing Advanced Innovation Center for Structural BiologyMinistry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyTsinghua UniversityBeijingChina Joint Graduate Program of Peking-Tsinghua-NIBS School of Life SciencesTsinghua UniversityBeijingChina Tsinghua-Peking Joint Center for Life Sciences Tsinghua UniversityBeijingChina Ministry of Education Key Laboratory of Protein Science Tsinghua-Peking Joint Center for Life SciencesBeijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijingChina Neuroscience Research Institute Peking UniversityBeijingChina Beijing Advanced Innovation Center for Intelligent Robots and System Beijing Institute of TechnologyBeijingChina School of Life Sciences Tsinghua UniversityBeijingChina GHDDI BeijingChina

The decline of nicotinamide adenine dinucleotide(NAD)occurs in a variety of human pathologies including ***-boosting agents can provide neuroprotective ***,we report the discovery and development of a class of potent activators(NATs)of nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD salvage *** obtained the crystal structure of NAMPT in complex with the NAT,which defined the allosteric action of NAT near the enzyme active *** optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT *** effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional ***,NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy(CIPN)without any overt *** findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.

关键词： Neural stem cells X-ray crystallography

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