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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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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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Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2443-2461页

作者： Nazi Song Hongjiao Xu Jiahua Liu Qian Zhao Hui Chen Zhibin Yan Runling Yang Zhiteng Luo Qi Liu Jianmei Ouyang Shuohan Wu Suijia Luo Shuyin Ye Runfeng Lin Xi Sun Junqiu Xie Tian Lan Zhongdao Wu Rui Wang Xianxing Jiang School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of Chiral Molecule and Drug DiscoverySun Yat-sen UniversityGuangzhou 510006China Department of Parasitology of Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510006China Key Laboratory of Tropical Disease Control Ministry of EducationSun Yat-sen UniversityGuangzhou 510006China Provincial Engineering Technology Research Center for Biological Vector Control Sun Yat-sen UniversityGuangzhou 510006China Research Unit of Peptide Science Chinese Academy of Medical SciencesLanzhou 730000China Key Laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China Guangdong Pharmaceutical University Guangzhou 510006China

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

关键词： GLP-1R GCGR Liver fibrosis Inflammation Apoptosis Candidate peptides

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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 unclear.Herein 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 severity.Interestingly,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 GCGR.The 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 mice.Various 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 signaling.These 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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“文化抵抗”:二战时期捷克斯洛伐克人民的“有声”斗争

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历史教学问题 2023年第5期 97-105,204页

作者：宋海群赣南师范大学新加坡研究中心 341000

二战时期,为了快速推进对外扩张计划,纳粹德国在捷克斯洛伐克推行了恢复德语剧院优势地位、疯狂摧残捷克民族文化和加强捷克斯洛伐克人民对纳粹德国文化认同等核心内容的“文化帝国主义”政策。这种残酷的文化政策很大程度上摧毁了捷克... 详细信息

二战时期,为了快速推进对外扩张计划,纳粹德国在捷克斯洛伐克推行了恢复德语剧院优势地位、疯狂摧残捷克民族文化和加强捷克斯洛伐克人民对纳粹德国文化认同等核心内容的“文化帝国主义”政策。这种残酷的文化政策很大程度上摧毁了捷克斯洛伐克的传统文化,引起捷克斯洛伐克人民不满和愤怒。他们以讲捷克语笑话的方式进行隐形反击,尽管这种反抗方式无法动摇纳粹德国的殖民统治,不过在一定程度上取笑、戏弄了纳粹法西斯,继承和发扬了本国历史传统文化,强化了民族认同,改善了群体的社会关系。捷克民族的“文化抵抗”反映了捷克斯洛伐克抵抗运动的民族坚定性、文化柔韧性和斗争持久性,有助于窥探二战时期法西斯统治下被占领国家人民特殊的生活和心理状态,一定程度上可为深化捷克斯洛伐克史、欧洲抵抗运动史和二战史研究提供新视角。

关键词：文化抵抗捷克斯洛伐克讲笑话抵抗运动 “文化帝国主义”

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从编纂到禁毁:苏联犹太人《黑皮书》历史考察

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陕西师范大学学报（哲学社会科学版） 2019年第2期48卷 57-68页

作者：宋永成陕西师范大学历史文化学院陕西西安710119

在二战期间,苏联政府为了唤起盟国特别是美国犹太人支持卫国战争,批准苏联犹太人反法西斯委员会和国外犹太组织联袂编纂《黑皮书》,旨在揭露纳粹德国及其帮凶在欧洲特别是在苏联被占领土上迫害和屠杀犹太人罪行。在编纂过程中,虽然犹委... 详细信息

在二战期间,苏联政府为了唤起盟国特别是美国犹太人支持卫国战争,批准苏联犹太人反法西斯委员会和国外犹太组织联袂编纂《黑皮书》,旨在揭露纳粹德国及其帮凶在欧洲特别是在苏联被占领土上迫害和屠杀犹太人罪行。在编纂过程中,虽然犹委会内部以及它与美国犹太人组织之间在该书的版本、内容等方面产生了诸多矛盾和冲突,但战后《黑皮书》在国外仍得以顺利出版,并在纽伦堡审判中发挥了重要作用。由于美苏冷战爆发、内容不合苏联当局胃口、苏联国家反犹主义复活等原因,俄文版《黑皮书》最终被苏联当局查禁并销毁,随后又被当作清洗犹委会的主要罪证之一。《黑皮书》的历史正好见证了从二战到冷战苏联对犹太人政策的蜕变过程。

关键词：《黑皮书》苏联犹太人反法西斯委员会所罗门·米霍埃尔斯反犹主义伊利亚·爱伦堡

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论英国对捷克斯洛伐克反法西斯抵抗运动的立场演变

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长春师范大学学报 2023年第5期42卷 76-81页

作者：宋海群赣南师范大学新加坡研究中心江西赣州341000

二战时期,捷克斯洛伐克出现了形式多样、规模不同的反法西斯抵抗运动。英国对捷克斯洛伐克反法西斯抵抗运动的立场呈现出阶段性变化:第一阶段为纳粹德国建立之初到丘吉尔上台,英国持相对漠视的立场;第二阶段从丘吉尔上台后至苏德战争爆... 详细信息

二战时期,捷克斯洛伐克出现了形式多样、规模不同的反法西斯抵抗运动。英国对捷克斯洛伐克反法西斯抵抗运动的立场呈现出阶段性变化:第一阶段为纳粹德国建立之初到丘吉尔上台,英国持相对漠视的立场;第二阶段从丘吉尔上台后至苏德战争爆发前,英国的立场变为积极支持;第三阶段自苏德战争爆发至二战结束,英国的立场保守性日益严重。之所以会有不同的立场,直接原因在于二战形势出现转折性变化,根本原因是英国希望尽可能维护、巩固和扩大自身利益,甚至不惜牺牲他国利益。

关键词：捷克斯洛伐克反法西斯抵抗运动英国爱德华·贝奈斯

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未来的陨灭——从海因里希·伯尔短篇小说解读战火中孩童的命运

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西安文理学院学报（社会科学版） 2017年第6期20卷 25-29,44页

作者：宋佳樾西安外国语大学德语学院西安710062

海因里希·伯尔作为二战后德国"废墟文学"的代表作家之一,直面战争带给人民的苦难与创伤,通过一系列脍炙人口的作品,深刻揭露了纳粹恐怖主义与战争的罪恶。其作品主要取材于第二次世界大战,以小人物为主人公,通过小人物的不幸,展现出了... 详细信息

海因里希·伯尔作为二战后德国"废墟文学"的代表作家之一,直面战争带给人民的苦难与创伤,通过一系列脍炙人口的作品,深刻揭露了纳粹恐怖主义与战争的罪恶。其作品主要取材于第二次世界大战,以小人物为主人公,通过小人物的不幸,展现出了德国民众的苦难与绝望。从伯尔早期短篇入手,通过对作品中孩童形象、行为及生存状况的解读,展现战火中孩童的悲惨命运。

关键词：短篇小说孩童命运反战

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