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Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice

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Acta Pharmaceutica Sinica B 2023年第2期13卷 542-558页

作者： Nazi Song Hongjiao Xu Shuohan Wu Suijia Luo Jingyao xu Qian Zhao Rui Wang Xianxing Jiang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 511400China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China School of Life Sciences Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical Sciences&Research Unit of Peptide ScienceLanzhou UniversityLanzhou 730000China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China

Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

关键词： NASH Liver fibrosis Combination therapy Mitochondrial function Mitophagy Mitochondrial biogenesis AMPK EDPs AdipoR1/2 agonist

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Suspected malignant hyperthermia in a young Chinese patient undergoing a micro varicocelectomy surgery

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Chinese Medical Journal 2023年第17期136卷 2116-2118页

作者： Hongjiao Xu Zhaomin Wang Zhongmei Peng Jianhai Zhang Xiang Li Di Liu Jie Qi Jinbao Li Department of Anesthesiology Shanghai Jiaotong University First People’s Hospital(Shanghai General Hospital)Shanghai 200080China

To the Editor:Malignant hyperthermia(MH)is a pharmacogenetic disorder of skeletal muscles that presents as an acute hypermetabolic state triggered by depolarizing muscle relaxants and volatile anesthetics in susceptible individuals.[1]The reported incidence of MH reaction ranged from 1:250,000 to 1:10,000.[1]However,the exact incidence in the Asian population remains unknown.A recent report suggested that the incidence of MH in Japan was 1 to 2 per 100,000 anesthetics,[2]which was similar to that in Western countries.In China,there are only a few reported cases,which may be attributed to incomplete records,and the actual incidence might be higher.[3,4]In China,between January 1978 and March 2004,only 34 cases of MH were recorded.[5]Due to the lack of the effective drug dantrolene,the mortality rate at that time was 73.5%.[5]Here,we reported the onset and treatment of a patient with suspected MH.

关键词： hyperthermia patient mortality

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Small molecule targeting of oncogenic FTO demethylation in acute myeloid leukemia

Small molecule targeting of oncogenic FTO demethylation in a...

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第十届全国化学生物学学术会议

作者： Yue Huang Hongjiao Xu Cai-Guang Yang Shanghai Institue of Materia Medica Chinese Academy of Sciences

FTO.the first mRNA demethytase,promotes leukemogenesis and Inhibits ATRA-mediated differentiation.Here,we report the discovery of a novel Inhibitor for FTO demethylatlon that enables treatment of acute myeloid leukemia （AMD） with FTO-overexpresston.A number of assays were performed In order to understand the Inhibitor mode of action,and all the data point,towards direct Inhibition of FTO demethylatlon in vitro and in AML cells.Furthermore.FTO Inhibitor efficiently suppresses the development of leukemogenesis in mice.Taken together,our newfound inhibitors could servo as chemical probes to attenuate FTO activity and provide proot-of-concept that mRNA demethylase would be viewed as a druggable target against AML.

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Small molecule targeting of oncogenic FTO demethylation in acute myeloid leukemia

Small molecule targeting of oncogenic FTO demethylation in a...

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第十届全国化学生物学学术会议

作者： Y Yue Huang Hongjiao Xu Cai-Guang Yang Shanghai Institue of Materia Medica Chinese Academy of Sciences

N6-methyladenosine(m A) is a prevalent modification in mRNA that significantly impacts biological regulation and human diseases. Recently, we demonstrated the critical functional importance of FTO, the first RNA demethylase, in leukemogensis and drug response. Achieving a chemical method to specific manipulate FTO demethylation would shed lights on RNA epigenetics, remaining a big challenge, however. Here, we have identified a new inhibitor derived from meclofenamic acid(MA) for FTO demethylation that enables treatment of acute myeloid leukemia(AML). A number of assays were performed in order to understand the inhibitor mode of action, and all the data point towards direct inhibitions of FTO demethylation in vitro and in AML cells. In addition, FTO inhibitor exhibits favorable pharmacokinetics and efficiently supresses the development of leukemogensis in mice. Taken together, these data reveal that our newfound inhibitor of FTO could serve as a chemical probe to attenuate FTO activity and provide proof-of-concept that mRNA demethylase would be viewed as a druggable target against AML..

关键词： AML FTO inhibitor demethylation chemical probe

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主题粒度的潜在国际科技合作识别方法研究——以中俄为例

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情报科学 2023年第5期41卷 138-143页

作者：徐红姣何彦青中国科学技术信息研究所北京100038

【目的/意义】在国际政治经济环境和全球创新格局不断变化的背景下,拓展全球科技创新合作伙伴、建立更为广泛和紧密的全球科技创新合作网络,成为亟待解决的问题。【方法/过程】本文基于科技论文构建主题词共现矩阵,筛选二阶共现主题词... 详细信息

【目的/意义】在国际政治经济环境和全球创新格局不断变化的背景下,拓展全球科技创新合作伙伴、建立更为广泛和紧密的全球科技创新合作网络,成为亟待解决的问题。【方法/过程】本文基于科技论文构建主题词共现矩阵,筛选二阶共现主题词对作为潜在国际科技合作主题对,通过定义主题对的国际合作潜力指数以及主题路径的国际科技合作路径强度指数,判定主题对的国际合作潜力并寻找有效的主题合作路径。【结果/结论】以中俄人工智能领域的SCI论文和CPCI-S论文为分析对象,通过对该领域潜在国际科技合作主题的识别和分析,证实本文所提方法的有效性。【创新/局限】本文提出一种识别潜在国际科技合作主题的方法,并利用中俄两国论文进行实证研究,但未考虑不同国家研究产出规模差异,未对关键词进行语义分析,需在后续研究中进一步探讨。

关键词：潜在合作主题识别国际科技合作知识发现合作机会发现科研合作主题识别

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A Rhein-Based Rh(Ⅲ) Arene Complex with Anti-tumor Cell Proliferative Activity Inhibits RNA Demethylase FTO

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Chinese Journal of Chemistry 2022年第10期40卷 1156-1164页

作者： Lu Liu Yaqiong Kong Liang He Xiuxiu Wang Meng-Meng Wang Hongjiao Xu Cai-Guang Yang Zhi Su Jing Zhao Zong-Wan Mao Yue Huang Hong-Ke Liu School of Chemistry and Materials Science Nanjing Normal UniversityNanjingJiangsu 210023China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Schoolof Chemistry Sun Yat-Sen UniversityGuangzhouGuangdong 510275China School of Chemistry and Chemial Enginering Nanjing UniversityNanjingJingsu 210023China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouZhejiang 310024China

Metallodrugs with fine-tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design.However,it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression regulation.This report describes a rhein-based Rh(l)-arene complex,Rh1,that exhibited promising antiproliferative ffects in several tumor cellines.Rh1 induced cell death through the autophagy,cell cycle arrest,and accumulation of intracllular reactive oxygen species(ROs),In addition,Rh1 upregulated the global N^(6)-methyladenosine(m^(6)A)levels in A549 cells in the fat mass-and obesity-associated protein(FTO)-dependent manner.Collectively,the metal-based FTO inhibitor Rh1 effectively suppressed tumor cell proliferation and modulated the abundance of cellular m^(6)A,highlighting the potential of metal-based agents to target and regulate epitranscriptomics for tumor suppression.

关键词： Rhodium mRNA Antiproliferation FTO m^(6)A

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Effect of Ca Addition and Heat Treatment on the A390(S)/AM60(L) Interface Microstructure

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Journal of Wuhan University of Technology(Materials Science) 2016年第5期31卷 1117-1122页

作者：马立坤陈翌庆 LIU Lihua SU Yong xu Guangchen FANG hongjiao School of Materials Science and Engineering Hefei University of Technology

Overcasting is a new kind of dissimilar joining technique used to produce the aluminum（solid）/magnesium（liquid） bonding bi-metallic material in this study. For the Al/Mg（A390/AM60） bi-metallic samples, the interface microstructures are the research points, which directly influence the mechanical properties. It is, therefore, of vital importance to find a method to improve the interface microstructures. This research focused on the effect of the calcium（Ca） addition in the liquid Mg alloys and the heat treatment on the A390/AM60 interface microstructures of the bi-metallic samples. The testing results showed that, with Ca addition in AM60, owing to two possible reasons, the interface microstructure and the shear strength of the A390/AM60 bi-metallic samples could be improved. The heat treatment could further improve the interface microstructure and the mechanical properties by dissolving β-Mg_（17）Al_（12） into α-Mg and destroying the Mg_2Si layer structure.

关键词： overcasting A390/AM60 bi-metallic material Ca addition heat treatment

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Small Molecule Dac51 Targeting FTO

Small Molecule Dac51 Targeting FTO

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第十一届全国化学生物学学术会议

作者： Hongjiao Xu Ze Dong Lu Liu Yue Huang Cai-Guang Yang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences

FTO, the first m6 A demethylases, has been reported to regulate tumorigenesis of glioblastoma stem cells [1] and melanoma [2]. Given the antitumor effect of Fto gene depletion, we are interested in the exploration of small-molecule FTO inhibitors for the therapeutic potential. We have identified small molecule FB23-2 that suppressed AML proliferation by targeting FTO. [3] Herein, we designed and developed a more potent FTO inhibitor Dac51, which inhibited FTO demethylation with an enzymatic activity of 0.4 ± 0.1 μM in terms of IC50. The structural complex of FTO bound with inhibitor Dac51 was determined, which provided structural element for the understanding of the mode of action of Dac51. Furthermore, Dac51 could be used as a tool compound in order to verify the druggability of FTO enzyme, since the target engagement was investigated through the cell-based assay using photo-probe.

关键词： FTO inhibitor tumorigenesis druggability

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The antimicrobial peptide YD attenuates inflammation via miR-155 targeting CASP12 during liver fibrosis

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Acta Pharmaceutica Sinica B 2021年第1期11卷 100-111页

作者： Zhibin Yan Dan Wang Chunmei An Hongjiao Xu Qian Zhao Ying Shi Nazi Song Bochuan Deng Xiaomin Guo Jing Rao Lu Cheng Bangzhi Zhang Lingyun Mou Wenle Yang Xianxing Jiang Junqiu Xie Key Laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical Sciences2019RU066Lanzhou UniversityLanzhou 730000China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

The antimicrobial peptide APKGVQGPNG(named YD),a natural peptide originating from Bacillus amyloliquefaciens CBSYD1,exhibited excellent antibacterial and antioxidant properties in vitro.These characteristics are closely related to inflammatory responses which is the central trigger for liverfibrosis.However,the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely studied.In this study,we show that YD improved liver function and inhibited the progression of liver fibrosis by measuring the serum transaminase activity and the expression of a-smooth muscle actin and collagen I in carbon tetrachloride-induced mice.Then we found that YD inhibited the level of miR-155,which plays an important role in inflammation and liver fibrosis.Bioinformatics analysis and luciferase reporter assay indicate that Casp12 is a new target of miR-155.We demonstrate that YD signifi-cantly decreases the contents of inflammatory cytokines and suppresses the NF-k B signaling pathway.Further studies show that transfection of the miR-155 mimic in RAW264.7 cells partially reversed the YD-mediated CASP12 upregulation,the downregulated levels of inflammatory cytokines,and the inactivation of the NF-k B pathways.Collectively,our study indicates that YD reduces inflammation throughthe mi R-155 e Casp12 e NF-k B axis during liver fibrosis and provides a promising therapeutic candidate for hepatic fibrosis.

关键词： Liver fibrosis Inflammation Antimicrobial peptide MiR-155 CASP12

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新发展格局下我国文化旅游产业链优化升级研究

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企业经济 2022年第11期41卷 123-133页

作者：陈瑾陶虹佼徐蒙江西省社会科学院江西南昌330077

近年来,基于文化旅游融合所构建的文化旅游产业链,既得益于我国旅游市场规模的驱动,也得益于长期以来政府政策体系支持。因此,开展我国文化旅游产业链优化升级研究意义重大。在新发展格局背景下,基于产业组织及产业链理论,分析多元融合... 详细信息

近年来,基于文化旅游融合所构建的文化旅游产业链,既得益于我国旅游市场规模的驱动,也得益于长期以来政府政策体系支持。因此,开展我国文化旅游产业链优化升级研究意义重大。在新发展格局背景下,基于产业组织及产业链理论,分析多元融合、“五链”协同、要素提升、“三新”加速在文化旅游产业链优化升级中的逻辑关系;并以陕西省西安市为例,总结传统文化旅游产业链优化升级经验:深掘文化内涵激活全产业链、塑造文旅头部集成商构筑竞争力、“三新”撬动文旅商深度融合、跨界整合与布局优化空间链;提出我国文化旅游产业链优化升级重要路径:以政府引领、头部企业为主体构建企业链生态、以文旅商多元融合为目标促进价值链攀升、以要素整合满足顾客需求为方略推进供需链优化、以体制机制创新为突破打造空间链布局新优势、以区块链赋能文旅产业为契机助力技术链升级。

关键词：新发展格局文化旅游产业链优化升级

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