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Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1283-1301页

作者： Qian Zhao Jiale Dong Han Liu Hui Chen Huan Yu Shuyin Ye Shuangjin Yu Yu Li Longhui Qiu Nazi Song hongjiao xu Qi Liu Zhiteng Luo Yuyi Li Rui Wang Guodong Chen Xianxing Jiang School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of Chiral Molecule and Drug DiscoverySun Yat-sen UniversityGuangzhou 510006China Organ Transplant Center the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510006China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China School of Life Sciences Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China

The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains *** we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease ***,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and *** data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO *** lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon *** findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

关键词： GLP-1 receptor Glucagon receptor Chronic kidney disease Diabetic nephropathy Kidney fibrosis Dual-agonism

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精神科治疗性关系评估量表-护士版的汉化及信效度检验

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中华护理教育 2024年第4期21卷 473-478页

作者：李岩周晶徐洪娇樊玉霞李娜刘美红蔺晶青岛市精神卫生中心心身医学科青岛市266034 青岛市精神卫生中心办公室青岛市266034 青岛市精神卫生中心护理部青岛市266034 青岛市精神卫生中心心理医院青岛市266034 青岛市精神卫生中心精神六科青岛市266034

目的引进精神科治疗性关系评估量表-护士版(Therapeutic Relationship Assessment Scale-Nurse,TRAS-N)并验证其信效度。方法按照Brislin翻译模型对葡萄牙语及英语版量表进行翻译和回译,通过预调查对中文版量表进行初步检验,邀请10名精... 详细信息

目的引进精神科治疗性关系评估量表-护士版(Therapeutic Relationship Assessment Scale-Nurse,TRAS-N)并验证其信效度。方法按照Brislin翻译模型对葡萄牙语及英语版量表进行翻译和回译,通过预调查对中文版量表进行初步检验,邀请10名精神科专家评价量表的内容效度,便利选取青岛市及日照市2所精神卫生中心的360名临床护士展开调查,并进行信效度分析。结果中文版TRAS-N的各条目CR值范围为6.313~17.359、与量表总分的相关系数范围0.429~0.766;I-CVI为0.800~1.000,S-CVI为0.942。验证性因子分析结果显示结构方程模型拟合指标:χ^(2)/df=2.297,RMSEA=0.074,IFI=0.914,TLI=0.903,CFI=0.913,RMR=0.041;中文版TRAS-N与护患关系量表-护士视角版的会聚效度为0.348;Cronbach'sα系数为0.940,2周后重测信度为0.884。结论中文版TRAS-N具有良好的信效度,可用于评估我国精神科临床护士治疗性关系。

关键词：精神科护士治疗性关系信度效度

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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 ***,there are no effective therapy to treat this devastating *** 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 *** recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver ***,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis ***,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 *** 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 *** effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK ***,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial *** 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 *** 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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围产期抑郁筛查实践的最佳证据总结

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循证护理 2024年第16期10卷 2887-2891页

作者：刘娜高改孔伶俐刘家骏杨明梁群英徐洪娇青岛市精神卫生中心山东266000 武汉大学中南医院广州中医药大学第一临床医学院广州中医药大学

目的:提取、评价和整合围产期抑郁筛查实践相关的证据,为医护人员实施围产期抑郁筛查工作提供循证依据。方法:计算机检索指南网、专业学会网和综合数据库中围产期抑郁筛查实践的相关文献,文献类型包括临床决策、最佳实践、指南、证据总... 详细信息

目的:提取、评价和整合围产期抑郁筛查实践相关的证据,为医护人员实施围产期抑郁筛查工作提供循证依据。方法:计算机检索指南网、专业学会网和综合数据库中围产期抑郁筛查实践的相关文献,文献类型包括临床决策、最佳实践、指南、证据总结、系统评价和专家共识,检索时限为2017年1月1日—2023年8月23日。结果:共纳入9篇文献,包括3篇指南、1篇证据总结、2篇系统评价和3篇专家共识;共提取围产期抑郁的筛查频率、筛查时机、筛查方法及筛查障碍4个主题,共13条证据。结论:本研究总结的围产期抑郁筛查实践的证据质量较高,可为临床医护人员提供循证依据,以更科学有效地实施围产期抑郁筛查工作。

关键词：围产期抑郁症筛查证据总结循证护理

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共情疲劳在精神科护士组织支持感与治疗性关系之间的中介效应

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中华现代护理杂志 2024年第23期30卷 3155-3160页

作者：李岩周晶徐洪娇樊玉霞刘美红李娜蔺晶青岛市精神卫生中心心身医学科青岛266034 青岛市精神卫生中心医院办公室青岛266034 青岛市精神卫生中心护理部青岛266034 青岛市精神卫生中心心理医院青岛266071 青岛市精神卫生中心精神六科青岛266034

目的调查精神科护士治疗性关系、组织支持感及共情疲劳现状,并分析三者之间的作用机制。方法本研究为横断面研究。于2023年8—9月便利抽取青岛市、济南市及临沂市3所三级甲等精神专科医院的310名精神科护士作为研究对象。采用一般资料... 详细信息

目的调查精神科护士治疗性关系、组织支持感及共情疲劳现状,并分析三者之间的作用机制。方法本研究为横断面研究。于2023年8—9月便利抽取青岛市、济南市及临沂市3所三级甲等精神专科医院的310名精神科护士作为研究对象。采用一般资料调查表、治疗性关系评估量表-护士版、组织支持感量表及共情疲劳量表进行调查,采用SPSS 22.0软件及Process宏插件进行数据分析。结果本研究共发放问卷310份,回收有效问卷282份,有效回收率为90.97%。282名精神科护士治疗性关系总分为(95.59±18.75)分,共情疲劳总分为45.50(24.75,68.25)分,组织支持感总分为(43.66±13.34)分;治疗性关系与组织支持感呈正相关,与共情疲劳呈负相关,组织支持感与共情疲劳呈负相关(均P<0.01)。组织支持感可直接正向作用于治疗性关系(β=0.291,P<0.01),也可通过共情疲劳的中介效应间接作用于治疗性关系(β=0.212,P<0.01),中介效应占比42.15%。结论共情疲劳在精神科护士组织支持感与治疗性关系之间起部分中介效应;护理管理者应增强对精神科护士的组织支持,以降低其共情疲劳水平,进而改善精神科治疗性关系。

关键词：横断面研究精神科护士治疗性关系组织支持感共情疲劳中介效应

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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 ***,it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression *** report describes a rhein-based Rh(l)-arene complex,Rh1,that exhibited promising antiproliferative ffects in several tumor ***1 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 ***,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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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 *** characteristics are closely related to inflammatory responses which is the central trigger for ***,the therapeutic effects of YD against hepatic fibrosis and the underlying mechanisms are rarely *** 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 *** we found that YD inhibited the level of miR-155,which plays an important role in inflammation and liver *** analysis and luciferase reporter assay indicate that Casp12 is a new target of *** demonstrate that YD signifi-cantly decreases the contents of inflammatory cytokines and suppresses the NF-k B signaling *** 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 ***,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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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

*** first mRNA demethytase,promotes leukemogenesis and Inhibits ATRA-mediated ***,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 *** Inhibitor efficiently suppresses the development of leukemogenesis in *** 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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