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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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Salidroside Ameliorates Lung Injury Induced by PM_(2.5) by Regulating SIRT1-PGC-1αin Mice

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Biomedical and Environmental Sciences 2024年第4期37卷 367-376页

作者： LI Xiao Hong LIU yu Mei SHAN Hui TAN Jin Feng ZHOU Jian song yuan Jin LI Si Qi LIU Chen xu Dong Qun yu Li LI Wan Wei School of Public Health Shandong Second Medical UniversityWeifang 261053ShandongChina Key Laboratory of Health Inspection and Quarantine Weifang 261053ShandongChina Weifang Environmental Monitoring Station Weifang 261042ShandongChina Department of Orthopedics The 80th Army Hospital of PLAWeifang 261000ShandongChina Environment and Health Related Product Safety Institute of Chinese Center for Disease Control and Prevention Beijing 100021China School of Basic Medicine Shandong Second Medical UniversityWeifang 261053ShandongChina

Objective This study aimed to clarify the intervention effect of salidroside(SAL)on lung injury caused by PM_(2.5) in mice and illuminate the function of SIRT1-PGC-1ɑ*** Specific pathogen-free(SPF)grade male C57BL/6 mice were randomly assigned to the following groups:control group,SAL group,PM_(2.5) group,SAL+PM_(2.5) *** the first day,SAL was given by gavage,and on the second day,PM_(2.5) suspension was given by intratracheal *** whole experiment consist of a total of 10 cycles,lasting 20 *** the end of treatment,blood samples and lung tissues were collected and *** of pathological changes in lung tissue using inverted microscopy and transmission electron *** expression of inflammatory,antioxidants,apoptosis,and SIRT1-PGC-1ɑproteins were detected by Western *** Exposure to PM_(2.5) leads to obvious morphological and pathologica changes in the lung of ***_(2.5) caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1,Nrf2,SOD2,SIRT1 and PGC-1ɑ,and an increase in the protein expressions of IL-6,IL-1β,Bax,caspase-9 and cleaved ***,SAL reversed the aforementioned changes caused by PM_(2.5) by activating the SIRT1-PGC-1α *** SAL can activate SIRT1-PGC-1ɑ to ameliorate PM2.5-induced lung injury.

关键词： PM_(2.5) Salidroside Oxidative stress Inflammation Apoptosis SIRT1-PGC-1α

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Temporal and Spectral Characteristics of Persistent Emission and Special Bursts of Magnetar SGR J1935+2154 Based on Insight-HXMT

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Research in Astronomy and Astrophysics 2024年第6期24卷 225-233页

作者： xue-Feng Lu Li-Ming song Ming-yu Ge Shuang-Nan Zhang Jin-Lu Qu Ce Cai Cong-Zhan Liu Cheng-Kui Li yu-Cong Fu Ying-Chen xu Key Laboratory of Particle Astrophysics Institute of High Energy PhysicsBeijing 100049China University of Chinese Academy of Sciences Chinese Academy of SciencesBeijing 100049China College of Physics and Hebei Key Laboratory of Photophysics Research and Application Hebei Normal UniversityShijiazhuang 050024China Department of Astronomy Beijing Normal UniversityBeijing 100875China

In October 2022,the magnetar SGR J1935+2154 entered the active outburst *** the episode,the InsightHXMT satellite carried out a long observation that lasted for 20 *** than 300 bursts were detected,and a certain amount of persistent radiation signals were also *** paper mainly introduces the results of persistent radiation profile folding and period search based on Insight-HXMT *** the same time,the burst phase distribution characteristics,spectral lag results of burst,the spectral characteristics of zero-lag bursts and the time-resolved spectral evolution characteristics of high-flux bursts are *** found that there is no significant delay feature during different energy bands for the bursts of SGR J1935+*** observed zero-lag burst does not have a unique *** time-resolved spectrum of the individual burst has consistent spectral types and spectral parameters at different time periods of the *** also find that the burst number phase distribution and the burst photon phase distribution have the same tendency to concentrate in specific regions of the persistent emission profile.

关键词： radiation mechanisms:general dense matter magnetic fields

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Tuning electronic properties of cobalt phthalocyanines for oxygen reduction and evolution reactions

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Science China Chemistry 2024年第1期67卷 398-407页

作者： Jianlin Jiang Zhen Liu Shuaijun Pan Xinnian Xia bing Qin Yang Hu xuxu Wang Jiamin Lan yu Gu Encai Ou Weijian xu Joseph J.Richardson Rui Guo SINOPEC Research Institute of Petroleum Processing Co. Ltd.Beijing 100083China College of Chemistry and Chemical Engineering Hunan UniversityChangsha 410082China College of Chemistry and Materials Science Hunan Agricultural UniversityChangsha 410128China Department of Chemical Engineering The University of MelbourneParkville 3010Australia College of Environmental Science and Engineering Hunan UniversityChangsha 410082China School of Engineering RMIT UniversityMelbourneVictoria 3001Australia

Metal–phthalocyanines are a class of catalytically active materials promising in energy conversion and storage fields(e.g.,electrocatalysis).However,understanding and controlling the electrochemical properties in metal-phthalocyanine systems is ***,we elucidate the electrocatalytic origins of a series of cobalt-phthalocyanine molecular catalysts and finetune their electronic properties at the atomic level,both experimentally and *** interactions between the cobalt center and the local coordination environment are regulated by introducing either electron-donating or electron-withdrawing groups on the phthalocyanine ligand,and the spin-orbit splitting of cobalt is increased by~0.15 eV compared with the nonsubstituted ***,the aminated cobalt phthalocyanine-based electrocatalysts exhibit low free energies in the ratedetermining steps of the oxygen reduction(-1.68 eV)and oxygen evolution reactions(0.37 eV).This contributes to the high electrocatalytic activity(e.g.,a halfwave potential of 0.84 V and an overpotential of 0.30 V at 10 mAcm^(-2)),featuring a high selectivity of a four-electron pathway(i.e.,a negligible by-product of hydrogen peroxide).These catalysts also exhibit exceptional kinetic current density(Tafel slope of 100 mV dec^(-1))in oxygen reduction reactions,in addition to a superior power density(158 mWcm^(-2))and a high cycling stability(>1,300 cycles)in Zn-air batteries,outperforming the commercial Pt/C and/or RuO2counterparts.

关键词： interfacial wettability molecular catalysts carbon nanotubes density functional theory electrochemistry

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Triceps skinfold thickness trajectories and the risk of all-cause mortality:A prospective cohort study

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World Journal of Clinical Cases 2024年第15期12卷 2568-2577页

作者： Na Yang Li-yun He Zi-Yi Li yu-Cheng Yang Fan Ping ling-ling xu Wei Li Hua-bing Zhang yu-Xiu Li Department of Endocrinology Key Laboratory of Endocrinology of National Health CommissionPeking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

BACKGROUND The measurement of triceps skinfold(TSF)thickness serves as a noninvasive metric for evaluating subcutaneous fat *** its clinical utility,the TSF thickness trajectories and their correlation with overall mortality have not been thoroughly *** To explore TSF thickness trajectories of Chinese adults and to examine their associations with all-cause *** This study encompassed a cohort of 14747 adults sourced from the China Health and Nutrition *** class trajectory modeling was employed to identify distinct trajectories of TSF *** were classified into subgroups reflective of their respective TSF thickness *** utilized multivariate Cox regression analyses and mediation examinations to explore the link between TSF thickness trajectory and overall mortality,including contributory *** Upon adjustment for multiple confounding factors,we discerned that males in the‘Class 2:Thin-stable’and‘Class 3:Thin-moderate’TSF thickness trajectories exhibited a markedly reduced risk of mortality from all causes in comparison to the‘Class 1:Extremely thin’*** the mediation analyses,the Geriatric Nutritional Risk Index was found to be a partial intermediary in the relationship between TSF thickness trajectories and *** females,a lower TSF thickness pattern was significantly predictive of elevated all-cause mortality risk exclusively within the non-elderly *** In males and non-elderly females,lower TSF thickness trajectories are significantly predictive of heightened mortality risk,independent of single-point TSF thickness,body mass index,and waist circumference.

关键词： Triceps skinfold thickness Trajectory All-cause mortality Body mass index Geriatric Nutritional Risk Index

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Mesenchymal stem cell therapy for liver fibrosis need“partner”:Results based on a meta-analysis of preclinical studies

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World Journal of Gastroenterology 2024年第32期30卷 3766-3782页

作者： Yan xu xue-song Wang Xiao-Lei Zhou Wen-Ming Lu Xing-Kun Tang yu Jin Jun-song Ye Subcenter for Stem Cell Clinical Translation First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina School of Rehabilitation Medicine Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Department of Medical Genetics School of MedicineTongji UniversityShanghai 200092China Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases Ministry of EducationGannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina

BACKGROUND The efficacy of mesenchymal stem cells(MSCs)in treating liver fibrosis has been demonstrated in several clinical ***,their low survival and liver implantation rates remain *** recent years,a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver *** has inspired new ways of thinking about treating liver *** To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver *** Data sources included four electronic databases and were constructed until January *** subjects,interventions,comparators,outcomes,and study design principle were used to screen the literature,and the quality of the literature was evaluated to assess the risk of *** randomised controlled trials were selected,and the final 13 studies were included in the final *** A total of 13 studies were included after *** analysis showed that MSCs combined with drug therapy significantly improved liver function,promoted the repair of damaged liver tissues,reduced the level of liver fibrosis-related indexes,and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment,promoting the homing of MSCs,and regulating the relevant signaling pathways,and the treatment efficacy was superior to MSCs ***,the combined treatment statistics showed no amelioration in serum albumin levels(standardized mean difference=0.77,95%confidence interval:-0.13 to 1.68,P=0.09).CONCLUSION In conclusion,MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic ***,due to the different drugs,the treatment mechanism and effect also ***,more randomized controlled trials are needed to compare the therapeutic effic

关键词： drugs alone partner

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Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer

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National Science Review 2024年第4期11卷 216-227页

作者： Da-Yong Hou Ni-yuan Zhang Lu Wang Mei-yu Lv Xiang-Peng Li Peng Zhang yue-Ze Wang Lei Shen Xiu-Hai Wu Bo Fu Peng-yu Guo Zi-Qi Wang Dong-bing Cheng Hao Wang Wanhai xu NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics Heilongjiang Key Laboratory of Scientific Research in Urology Harbin Medical University Department of Urology Harbin Medical University Cancer Hospital CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology(NCNST) School of Chemistry Chemical Engineering & Life Science Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases Wuhan University of Technology

Mitochondriopathy inspired adenosine triphosphate(ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration(IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites,leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like ***, the reported transformable nucleopeptide(NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei,which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines(T24,EJ and RT-112) revealed that the half-maximal inhibitory concentration(IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

关键词： self-assembly nucleopeptide nanomaterial bladder cancer mitochondriopathy

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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

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Genes & Diseases 2024年第1期11卷 397-412页

作者： Zhe Chen Qian Guo Shichen Huang Lei Li Feng Wu Zhilong Liu Zhigang Li Tao Chen Guanbin song Shuangnian xu Jieping Chen yu Hou Department of Hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Institute of Life Sciences Chongqing Medical UniversityChongqing 400016China Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400044China Chongqing Foreign Language School Chongqing 400039China

Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML ***,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive *** metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of ***,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of *** a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA *** synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft *** results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.

关键词： AML Combinatorial inhibition FOXO3A GNG7 mTOR

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Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

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Journal of Pharmaceutical Analysis 2024年第3期14卷 389-400页

作者： Xiangye Yin Yingjie Zhuang Haiqin song yujian xu Fan Zhang Jianxin Cui Lei Zhao Yingjie yu Qixu Zhang Jun Ye Youbai Chen Yan Han Department of Plastic and Reconstructive Surgery The First Medical CenterChinese PLA General HospitalBeijing100853China Department of General Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai200023China State Key Laboratory of Organic-Inorganic Composites Beijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing100029China Department of Plastic Surgery University of Texas MD Anderson Cancer CenterHoustonTX77030USA State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology ***(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single ***(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major *** this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and *** so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in ***,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and ***,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

关键词： Antibody drug conjugate Cutaneous squamous cell carcinoma DNA damage Platinum drug Targeted therapy

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Dipeptidyl peptidase-4 inhibitors and the risk of infection: A systematic review and meta-analysis of cardiovascular outcome trials

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World Journal of Diabetes 2024年第5期15卷 1011-1020页

作者： Na Yang Li-yun He Peng Liu Zi-Yi Li yu-Cheng Yang Fan Ping ling-ling xu Wei Li Hua-bing Zhang yu-Xiu Li Department of Endocrinology Key Laboratory of Endocrinology of National Health CommissionPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Endocrinology The First Affiliated Hospitaland College of Clinical Medicine of Henan University of Science and TechnologyLuoyang 471000Henan ProvinceChina

BACKGROUND Since adverse events during treatment affect adherence and subsequent glycemic control,understanding the safety profile of oral anti-diabetic drugs is imperative for type 2 diabetes mellitus(T2DM)*** To evaluate the risk of infection in patients with T2DM treated with dipeptidyl-peptidase 4(DPP-4)*** Electronic databases were *** selection criteria included randomized controlled trials focused on cardiovascular *** these studies,the effects of DPP-4 inhibitors were directly compared to those of either other active anti-diabetic treatments or *** trials involving 53616 patients were deemed *** calculated aggregate relative risks employing both random-effects and fixed-effects approaches,contingent upon the *** The application of DPP-4 inhibitors showed no significant link to the overall infection risk[0.98(0.95,1.02)]or the risk of serious infections[0.96(0.85,1.08)],additionally,no significant associations were found with opportunistic infections[0.69(0.46,1.04)],site-specific infections[respiratory infection 0.99(0.96,1.03),urinary tract infections 1.02(0.95,1.10),abdominal and gastrointestinal infections 1.02(0.83,1.25),skin structure and soft tissue infections 0.81(0.60,1.09),bone infections 0.96(0.68,1.36),and bloodstream infections 0.97(0.80,1.18)].CONCLUSION This meta-analysis of data from cardiovascular outcome trials revealed no heightened infection risk in patients undergoing DPP-4 inhibitor therapy compared to control cohorts.

关键词： T2DM drugs treatment

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