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m^(6)A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

Frontiers of Medicine 2024年第3期18卷 499-515页

作者： Han Wu Weitao Jiang Ping Pang Wei Si Xue Kong Xinyue Zhang Yuting Xiong Chunlei Wang Feng Zhang Jinglun Song Yang Yang Linghua Zeng Kuiwu Liu Yingqiong Jia Zhuo Wang Jiaming Ju Hongtao Diao Yu Bian Baofeng Yang department of pharmacology(National key Laboratory of Frigid Zone Cardiovascular Diseases the State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction(MI)can lead to heart failure.RNA N6-methyladenosine(m^(6)A)methylation has been shown to play a pivotal role in the occurrence and development of many illnesses.In investigating the biological function of the m^(6)A reader YTHDF1 in cardiac fibrosis,adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts,and MI surgery in vivo and transforming growth factor-β(TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models.Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis,whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development.Mechanistically,zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter.YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway,thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis.Consistently,our data indicated that YTHDF1 was involved in activation,proliferation,and migration to participate in cardiac fibrosis in vitro.Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

关键词： cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

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Single-base editing in IGF2 improves meat production and intramuscular fat deposition in Liang Guang Small Spotted pigs

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Journal of Animal Science and Biotechnology 2024年第1期15卷 108-126页

作者： Tianqi Duo Xiaohong Liu Delin Mo Yu Bian Shufang Cai Min Wang Ruiqiang Li Qi Zhu Xian Tong Ziyun Liang Weilun Jiang Shiyi Chen Yaosheng Chen Zuyong He state key Laboratory of Biocontrol School of Life SciencesSun Yat-Sen UniversityGuangzhou 510275GuangdongChina department of pharmacology(the state‑province key laboratories of Biomedicine‑Pharmaceutics of china Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin 150081China Hunan Provincial key Laboratory for Genetic Improvement of Domestic Animal College of Animal Science and TechnologyHunan Agricultural UniversityChangsha 410128China

Background Chinese indigenous pigs are popular with consumers for their juiciness,flavour and meat quality,but they have lower meat production.Insulin-like growth factor 2(IGF2) is a maternally imprinted growth factor that promotes skeletal muscle growth by regulating cell proliferation and differentiation.A single nucleotide polymorphism(SNP) within intron 3 of porcine IGF2 disrupts a binding site for the repressor,zinc finger BED-type containing 6(ZBED6),leading to up-regulation of IGF2 and causing major effects on muscle growth,heart size,and backfat thickness.This favorable mutation is common in Western commercial pig populations,but absent in most Chinese indigenous pig breeds.To improve meat production of Chinese indigenous pigs,we used cytosine base editor 3(CBE3)to introduce IGF2 intron3-C3071T mutation into porcine embryonic fibroblasts(PEFs) isolated from a male Liang Guang Small Spotted pig(LGSS),and single-cell clones harboring the desired mutation were selected for somatic cell nuclear transfer(SCNT) to generate the founder line of IGF2^(T/T) pigs.Results We found the heterozygous progeny IGF2^(C/T) pigs exhibited enhanced expression of IGF2,increased lean meat by 18%-36%,enlarged loin muscle area by 3%-17%,improved intramuscular fat(IMF) content by 18%-39%,marbling score by 0.75-1,meat color score by 0.53-1.25,and reduced backfat thickness by 5%-16%.The enhanced accumulation of intramuscular fat in IGF2^(C/T) pigs was identified to be regulated by the PI3K-AKT/AMPK pathway,which activated SREBP1 to promote adipogenesis.Conclusions We demonstrated the introduction of IGF2-intron3-C3071T in Chinese LGSS can improve both meat production and quality,and first identified the regulation of IMF deposition by IGF2 through SREBP1 via the PI3KAKT/AMPK signaling pathways.Our study provides a further understanding of the biological functions of IGF2and an example for improving porcine economic traits through precise base editing.

关键词： CBE3 IGF2 Intramuscular fat Meat production PI3K-AKT/AMPK ZBED6

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Cancer organoids:A platform in basic and translational research

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Genes & Diseases 2024年第2期11卷 614-632页

作者： Xin Ma Qin Wang Guozheng Li Hui Li Shouping Xu Da Pang department of Breast Surgery Harbin Medical University Cancer HospitalHarbinHeilongjiang 150081China Sino-Russian Medical Research Center Harbin Medical University Cancer HospitalHarbinHeilongjiang 150081China Heilongjiang Academy of Medical Sciences HarbinHeilongjiang 150086China department of pharmacology (The state-province key laboratories of Biomedicine-Pharmaceutics of china) College of Pharmacy of Harbin Medical UniversityHarbinHeilongjiang 150086China

An accumulation of previous work has established organoids as good preclinical models of human tumors,facilitating translation from basic research to clinical practice.They are changing the paradigm of preclinical cancer research because they can recapitulate the heterogeneity and pathophysiology of human cancers and more closely approximate the complex tissue environment and structure found in clinical tumors than in vitro cell lines and animal models.However,the potential applications of cancer organoids remain to be comprehensively summarized.In the review,we firstly describe what is currently known about cancer organoid culture and then discuss in depth the basic mechanisms,including tumorigenesis and tumor metastasis,and describe recent advances in patient-derived tumor organoids(PDOs)for drug screening and immunological studies.Finally,the present challenges faced by organoid technology in clinical practice and its prospects are discussed.This review highlights that organoids may offer a novel therapeutic strategy for cancer research.

关键词： Drug assays Immunotherapy Mechanism research Organoids Precision medicine

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LncRNA CCRR maintains Ca2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway

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Science china Life Sciences 2024年第8期 1601-1619页

作者： Hua Yang Lina Xuan Shengjie Wang Huishan Luo Xiaomeng Duan Jianjun Guo Shijia Cui Jieru Xin Junwei Hao Xiufang Li Jun Chen Feihan Sun Xiaolin Hu Siyun Li Ying Zhang Lei Jiao Baofeng Yang Lihua Sun department of pharmacology Harbin Medical University (State Key Laboratory of Frigid Zone Cardiovascular Diseasethe State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of EducationJoint International Research Laboratory of Cardiovascular Medicine ResearchMinistry of EducationChina)College of PharmacyHarbin Medical University

Cardiac conduction regulatory RNA（CCRR） has been documented as an antiarrhythmic lnc RNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca2+homeostasis in myocardial infarction（MI）.Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca2+homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca2+overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation（RIP） analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lnc RNA that acts by maintaining the function of FTO,thereby reducing the m6A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

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YBX1 inhibits mitochondrial-mediated apoptosis in ischemic heart through the PI3K/AKT signaling pathway

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Frigid Zone Medicine 2024年第1期4卷 51-64页

作者： Fangfang Bi Miao Cao Yuquan Wang Qingming Pan Zehong Jing Danyang Bing Lifang Lyu Tong Yu Tianyu Li Xuelian Li Haihai Liang Hongli Shan Yuhong Zhou department of pharmacology(state-province key laboratories of Biomedicine-Pharmaceutics of china Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin 150081China Shanghai Frontiers Science Research Center for Druggability of Cardiovascular noncoding RNA Institute for Frontier Medical TechnologyShanghai University of Engineering ScienceShanghai 201620China department of Basic Medicine Xiamen Medical CollegeXiamen 361023China

Background:Myocardial infarction(MI)is associated with higher morbidity and mortality in the world,especially in cold weather.YBX1 is an RNA-binding protein that is required for pathological growth of cardiomyocyte by regulating cell growth and protein synthesis.But YBX1,as an individual RNA-binding protein,regulates cardiomyocytes through signaling cascades during myocardial infarction remain largely unexplored.Methods:In vivo,the mouse MI model was induced by ligating the left anterior descending coronary artery(LAD),and randomly divided into sham operation group,MI group,MI+YBX1 knockdown/overexpression group and MI+negative control(NC)group.The protective effect of YBX1 was verified by echocardiography and triphenyltetrazolium chloride staining.In vitro,mitochondrial-dependent apoptosis was investigated by using CCK8,TUNEL staining,reactive oxygen species(ROS)staining and JC-1 staining in hypoxic neonatal mouse cardiomyocytes(NMCMs).Results:YBX1 expression of cardiomyocytes was downregulated in a mouse model and a cellular model on the ischemic condition.Compared to mice induced by MI,YBX1 overexpression mediated by adeno-associated virus serotype 9(AAV9)vector reduced the infarcted size and improved cardiac function.Knockdown of endogenous YBX1 by shRNA partially aggravated ischemia-induced cardiac dysfunction.In hypoxic cardiomyocytes,YBX1 overexpression decreased lactic dehydrogenase(LDH)release,increased cell viability,and inhibited apoptosis by affecting the expression of apoptosis related proteins,while knockdown of endogenous YBX1 by siRNA had the opposite effect.Overexpression of YBX1 restored mitochondrial dysfunction in hypoxic NMCMs by increasing mitochondrial membrane potential and ATP content and decreasing ROS.In hypoxic NMCMs,YBX1 overexpression increased the expression of phosphorylated phosphatidylinositol 3 kinase(PI3K)/AKT,and the anti-apoptosis effect of YBX1 was eliminated t by LY294002,PI3K/AKT inhibitor.Conclusion:YBX1 protected the heart from ischemic damage by inhibiting the mitochond

关键词： YBX1 PI3K/AKT apoptosis mitochondrial function myocardial infarction

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Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis

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Frigid Zone Medicine 2024年第1期4卷 41-50页

作者： Tongzhu Jin Zhen Ye Ruonan Fang Yue Li Wei Su Qianqian Wang Tianyu Li Hongli Shan Yanjie Lu Haihai Liang Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD) Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin 150081China department of Pharmacy Suqian First HospitalSuqian 223800China Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070) Chinese Academy of Medical SciencesHarbin 150081China

Background and Objective:Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance.The Wnt signaling pathway is closely implicated in organ fibrosis,and Notum,a highly conserved secreted inhibitor,modulates Wnt signaling.The objective of this study was to explore the role and mechanism of Notum in cardiac fibrosis.Methods:A mouse model of cardiac remodeling was established through left coronary artery ligation surgery,with the addition of Notum injection following myocardial infarction surgery.The protective effect of Notum on myocardial infarction was assessed by evaluating cardiac function,including survival rate,echocardiographic assessment,and cardiac contraction analyses.Inflammatory cell necrosis and infiltration were confirmed through H&E and Masson staining.The expression of fibrosis-related genes andβ-catenin pathway markers was detected using Western blot quantificational RT-PCR(qRT-PCR).Additionally,EdU,wound healing,and immunofluorescence staining analyses were performed to detect the effect of Notum's in transforming growth factor beta-1(TGF-β1)induced myofibroblast transformation.Results:The administration of Notum treatment resulted in enhanced survival rates,improved cardiac function,and decreased necrosis and infiltration of inflammatory cells in mice subjected to left coronary artery ligation.Furthermore,Notum effectively impeded the senescence of cardiac fibroblasts and hindered their pathological transformation into cardiac fibroblasts.Additionally,it significantly reduced collagen production and attenuated the activation of the Wnt/β-catenin pathway.Our preliminary investigations successfully demonstrated the therapeutic potential of Notum in both fibroblasts in vitro and in a mouse model of myocardial infarction-induced cardiac fibrosis in vivo.Conclusion:Notum inhibition of the Wnt/β-catenin signaling pathway and cardiac fibroblast senescence ultimately hampers the onset of cardi

关键词： cardiac fibrosis Notum Wnt/β-catenin senescence myocardial infarction

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Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1322-1338页

作者： Fengfeng Li Man Jiang Minghui Ma Xuyang Chen Yidan Zhang Yixin Zhang Yuanyuan Yu Yunfeng Cui Jiahui Chen Hui Zhao Zhijie Sun Deli Dong department of pharmacology(the state-province key laboratories of Biomedicine-Pharmaceutics of china Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin 150086China Translational Medicine Research and Cooperation Center of Northern china Heilongjiang Academy of Medical SciencesHarbin Medical UniversityHarbin 150086China department of pharmacology China Pharmaceutical UniversityNanjing 211198China

Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis.It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis.Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile.We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in Hep G2 cells.Gavage administration of nitazoxanide inhibited high-fat diet(HFD)-induced increases of liver weight,blood and liver lipids,and ameliorated HFD-induced renal lipid accumulation in hamsters.Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers.In the hamsters with pre-existing hyperlipidemia and hepatic steatosis,nitazoxanide also showed therapeutic effect.Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet(WD)-induced hepatic steatosis in Apoe-/-mice.The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.

关键词： Nitazoxanide Tizoxanide Hyperlipidemia Hepatic steatosis AMPK Autophagy SQSTM1/P62 Mitochondrial uncoupling

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The Entropy Perspective on Human Illness and Aging

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Engineering 2022年第2期8卷 22-26页

作者： Zhiguo Wang department of pharmacology&state–province key laboratories of Biomedicine-Pharmaceutics of china&key Laboratory of Cardiovascular Medicine Research Ministry of EducationCollege of PharmacologyHarbin Medical UniversityHarbin 150001China

1.Entropy and its implications in human disease and aging Entropy,which is a thermodynamic property or an interpreta-tion of the second law of thermodynamics,was first defined in 1865 by the German physicist Rudolph Clausius[1].It eventually evolved into a general scientific concept that is of universal and paramount importance in three aspects.First,entropy is a measur-able physical property that is commonly associated with a state of chaos,disorderliness,randomness,or uncertainty of any systems[2].Second,entropy is a measure of the amount of energy that is unavailable to do work[2].Third,the universe or an isolated sys-tem always obeys“the principle of entropy increase”that irre-versible or spontaneous processes can occur only in the direction of entropy increase—that is,the direction of increasing chaos,dis-order,randomness,or uncertainty[2].

关键词： entropy Entropy chaos

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Preliminary evidence for the presence of multiple forms of cell death in diabetes cardiomyopathy

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Acta Pharmaceutica Sinica B 2022年第1期12卷 1-17页

作者： Jinjing Wei Yongting Zhao Haihai Liang Weijie Du Lihong Wang department of Endocrinology the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China department of Endocrinology the Second Affiliated Hospital of Harbin Medical UniversityHarbin 150081China department of pharmacology(state-province key laboratories of Biomedicine-Pharmaceutics of china Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin 150081China

Diabetic mellitus(DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications(DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy(DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure.Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis,necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease.Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly,published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies.

关键词： Diabetes mellitus Diabetic cardiomyopathy Cell death Apoptosis Autophagic cell death Aautosis Pyroptosis Necroptosis Ferroptosis

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lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy,leading to atherogenesis

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Frontiers of Medicine 2023年第2期17卷 317-329页

作者： Yuhua Fan Yue Zhang Hongrui Zhao Wenfeng Liu Wanqing Xu Lintong Jiang Ranchen Xu Yue Zheng Xueqing Tang Xiaohan Li Limin Zhao Xin Liu Yang Hong Yuan Lin Hui Chen Yong Zhang department of pharmacology State–Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular Medicine ResearchMinistry of EducationCollege of PharmacyHarbin Medical UniversityHarbin 150081China department of Pathology and Pathophysiology College of Basic Medical SciencesHarbin Medical University-DaqingDaqing 163319China Center for Drug Research and Development Guangdong Pharmaceutical UniversityGuangzhou 510006China

Long noncoding RNAs(lncRNAs)play a critical role in the regulation of atherosclerosis.Here,we investigated the role of the lncRNA growth arrest-specific 5(lncR-GAS5)in atherogenesis.We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis,which presented as increased plaque size and reduced collagen content.Moreover,impaired autophagy was observed,as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells.By contrast,lncR-GAS5 knockdown promoted autophagy.Moreover,serine/arginine-rich splicing factor 10(SRSF10)knockdown increased the LC3II/LC3I ratio and decreased the P62 level,thus enhancing the formation of autophagic vacuoles,autolysosomes,and autophagosomes.Mechanistically,lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium,which was reversed by the knockdown of SRSF10.Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene,SRSF10.Notably,miR-193-5p overexpression decreased plaque size and increased collagen content.Altogether,these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy.In conclusion,lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway.Thus,miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

关键词： lncR-GAS5 miR-193-5p splicing factor SRSF10 autophagy atherogenesis

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