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DEMETHYLATION REGULATOR 1 regulates DNA demethylation of the nuclear and mitochondrial genomes

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Journal of Integrative Plant Biology 2022年第12期64卷 2344-2360页

作者： Zhen Wang Hao zheng Jinguang Huang Guodong Yang Kang Yan shizhong Zhang Changai Wu Chengchao zheng State Key Laboratory of Crop Biology College of Lite SciencesShandong Agricultural UniversityTai'an 271018China National Institute of Biological Sciences(NIBS) Beijing 102206China

Active DNA demethylation effectively modulates gene expression during plant development and in response to stress.However,little is known about the upstream regulatory factors that regulate DNA demethylation.We determined that the demethylation regulator 1(demr1)mutant exhibits a distinct DNA methylation profile at selected loci queried by methylation-sensitive polymerase chain reaction and globally based on whole-genome bisulfite sequencing.Notably,the transcript levels of the DNA demethylase gene REPRESSOR OF SILENCING 1(ROS1)were lower in the demr1 mutant.We established that DEMR1 directly binds to the ROS1 promoter in vivo and in vitro,and the methylation level in the DNA methylation monitoring sequence of ROS1 promoter decreased by 60%in the demr1 mutant.About 40%of the hyper-differentially methylated regions(DMRs)in the demr1 mutant were shared with the ros1-4 mutant.Genetic analysis indicated that DEMR1 acts upstream of ROS1 to positively regulate abscisic acid(ABA)signaling during seed germination and seedling establishment stages.Surprisingly,the loss of DEMR1 function also caused a rise in methylation levels of the mitochondrial genome,impaired mitochondrial structure and an early flowering phenotype.Together,our results show that DEMR1 is a novel regulator of DNA demethylation of both the nuclear and mitochondrial genomes in response to ABA and plant development in Arabidopsis.

关键词： DEMR1 DNA demethylation mitochondria plant development ROS1

Tyrosylprotein sulfotransferase suppresses ABA signaling via sulfation of SnRK2.2/2.3/2.6

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Journal of Integrative Plant Biology 2023年第8期65卷 1846-1851页

作者： Jun Wang Chunyan Wang Tianrun Wang shizhong Zhang Kang Yan Guodong Yang Changai Wu Chengchao zheng Jinguang Huang State Key Laboratory of Crop Biology College of Life SciencesShandong Agricultural UniversityTaian 271018China Department of Food Science and Engineering Shandong Agriculture and Engineering UniversityJinan 250100China

Phytohormone abscisic acid(ABA)plays vital roles in stress tolerance,while long-term overactivation of ABA signaling suppresses plant growth and development.However,the braking mechanism of ABA responses is not clear.Protein tyrosine sulfation catalyzed by tyrosylprotein sulfotransferase(TPST)is a critical post-translational modification.Through genetic screening,we identified a tpst mutant in Arabidopsis that was hypersensitive to ABA.In-depth analysis revealed that TPST could interact with and sulfate SnRK2.2/2.3/2.6,which accelerated their degradation and weakened the ABA signaling.Taken together,these findings uncovered a novel mechanism of desensitizing ABA responses via protein sulfation.

关键词： Arabidopsis ABA signaling tyrosylprotein sulfotransferase sulfation SnRK2.2/2.3/2.6

Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3618-3638页

作者： Feixia Wang Zhanghao Li Li Chen Ting Yang Baoyu Liang Zili Zhang Jiangjuan Shao Xuefen Xu Guoping Yin Shijun Wang Hai Ding Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjing 210023China Department of General Surgery Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China Department of Anesthesiology Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China College of Traditional Chinese Medicine Shandong University of Traditional Chinese MedicineJinan 250035China

Senescence of activated hepatic stellate cells(aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression.Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype(SASP).But little is known about how alanine-serine-cysteine transporter type-2(ASCT2),a high affinity glutamine transporter,affects HSC senescence and SASP during liver fibrosis.Here,we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers.We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo.The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration.Mechanically,ASCT2 was a direct target of glutaminolysisdependent proinflammatory SASP,interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82.From a translational perspective,atractylenolide Ⅲ is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2.The presence of -OH group in atractylenolide Ⅲ is suggested to be favorable for the inhibition of ASCT2.Importantly,atractylenolide Ⅲ could be utilized to treat liver fibrosis mice.Taken together,ASCT2 controlled HSC senescence while modifying the proinflammatory SASP.Targeting ASCT2 by atractylenolide Ⅲ could be a therapeutic candidate for liver fibrosis.

关键词： Hepatic stellate cells Senescence SASP ASCT2 Precursor IL-1α NF-κB Atractylenolide III Liver fibrosis

Methionine metabolism in chronic liver diseases:an update on molecular mechanism and therapeutic implication

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Signal Transduction and Targeted Therapy 2021年第1期6卷 17-25页

作者： Zhanghao Li Feixia Wang Baoyu Liang Ying Su Sumin Sun Siwei Xia Jiangjuan Shao Zili Zhang Min Hong Feng Zhang Shizhong Zheng Department of Pharmacology Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaNanjing University of Chinese MedicineNanjing 210023China Department of Pharmacology Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineNanjing University of Chinese MedicineNanjing 210023China Department of Pharmacology State Key Laboratory Cultivation Base for TCM Quality and EfficacyNanjing University of Chinese MedicineNanjing 210023China

As one of the bicyclic metabolic pathways of one-carbon metabolism,methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway.In addition to being a precursor for glutathione synthesis,and the principal methyl donor for nucleic acid,phospholipid,histone,biogenic amine,and protein methylation,methionine metabolites can participate in polyamine synthesis.Methionine metabolism disorder can aggravate the damage in the pathological state of a disease.In the occurrence and development of chronic liver diseases(CLDs),changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms.A methionine-deficient diet is commonly used for building CLD models.The conversion of key enzymes of methionine metabolism methionine adenosyltransferase(MAT)1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma.In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism,the liver injuries could be reduced.Recently,methionine supplementation has gradually attracted the attention of many clinical researchers.Most researchers agree that adequate methionine supplementation can help reduce liver damage.Retrospective analysis of recently conducted relevant studies is of profound significance.This paper reviews the latest achievements related to methionine metabolism and CLD,from molecular mechanisms to clinical research,and provides some insights into the future direction of basic and clinical research.

关键词： synthesis. linking donor

提升工程2.0培训:PEPR评价监测指标及模型的构建——以吉林省提升工程2.0培训评价为例

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吉林省教育学院学报 2022年第8期38卷 13-16页

作者：郑世忠吉林省教育学院

培训评价是教师培训的重要环节,对于培训具有很强的导向作用。当前,培训模型的构建和培训指标的确定多针对教师个体学习效果的评估,而对学校承担某一项目效果开展评估的研究成果较少,但对于提升工程2.0培训来说,“整校推进”是其培训的... 详细信息

培训评价是教师培训的重要环节,对于培训具有很强的导向作用。当前,培训模型的构建和培训指标的确定多针对教师个体学习效果的评估,而对学校承担某一项目效果开展评估的研究成果较少,但对于提升工程2.0培训来说,“整校推进”是其培训的重要特征,因此构建“整校考核”的模型就显得尤为重要。本文结合吉林省提升工程2.0培训实践,阐述了PEPR培训指标体系确定的基本原则、指标体系的结构及其内涵,以及评价指标体系在提升工程2.0培训监测中的应用,为提升工程2.0培训监管模型的构建提供参考。

关键词：提升工程2.0 培训评价模型建构

CTB induces mitochondrial apoptosis in hepatoma cells by p53 mitochondrial translocation dependent on Drp1-mediated mitochondrial fission

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CTB induces mitochondrial apoptosis in hepatoma cells by p53...

Regulation of the stability and ABA import activity of NRT1.2/NPF4.6 by CEPR2-mediated phosphorylation in Arabidopsis

中国化学会第十四届全国生物无机化学学术会议

作者： Jiangjuan Shao Zijian Guo Feng Zhang Shizhong Zheng Xiaoyong Wang College of Pharmacy Nanjing University of Chinese Medicine State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical Engineering Nanjing University State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University

Copper complexes are potential anticancer drugs by virtue of their available redox properties, low toxicity and physiological distribution. A copper(Ⅱ) complex, [Cu(ttpy-tpp)Br]Br(simplified as CTB), is a newly synthesized mitochondrion-targeting copper complex that triphenylphosphine(TPP) is introduced into it for its mitochondrion-targeting ability and lipophilic character. CTB can cross the cytoplasmic and mitochondrial membranes of tumor cells and influence the mitochondrial membrane potential more profoundly than the anticancer drug cisplatin. Nevertheless, the mechanism by which CTB targets mitochondria to exert a stronger anti-tumor effect is not fully understood, and further exploration is needed. The aim of this study is to investigate the relevance of mitochondrial dysfunction and apoptosis for the antitumor activity of CTB in hepatocellular carcinoma cells. Our results indicated that CTB suppressed the proliferation of hepatoma cells and induced apoptosis. In addition, mitochondrial damage, the loss of mitochondrial membrane potential, and the disturbance of energy metabolism were observed in the cells treated with CTB, while the activation of Bax and caspase-3/9, and inhibition of Bcl-2 were detected. This finding indicates that CTB-induced apoptosis is associated with mitochondrial pathway and occurs through a caspase-dependent way. Simultaneously, we also detected that the mitochondrial translocation of p53, mitochondrial division and elevated Drp1 protein levels in CTB-treated cells. In conclusion, our results demonstrate that CTB promotes mitochondrial apoptosis in hepatocellular carcinoma cells by inducing p53 mitochondrial translocation, and that this process relies on mitochondrial division controlled by Drp1. Our findings suggest that CTB merits further evaluation as a chemotherapeutic agent for human liver cancer.

关键词： Copper complex p53 mitochondrial translocation mitochondrial apoptosis Drp1 hepatoma cell

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Molecular Plant 2021年第4期14卷 633-646页

作者： Lei Zhang Zipeng Yu Yang Xu Miao Yu Yue Ren shizhong Zhang Guodong Yang Jinguang Huang Kang Yan Chengchao zheng Changai Wu State Key Laboratory of Crop Biology Shandong Engineering Research Center of Plant Microbial Restoration for Saline.Alkali LandCollege of Lifte SciencesShandong Agricultural UniversityTai'an 271018China State Key Laboratory of Plant Physioloy and Biochermistry Cllege of Biological SciencesChina Agricutural UniversityBeijing 100193 China These authors contributed equally to this article

Abscisic acid(ABA)transport plays an important role in systemic plant responses to environmental factors.However,it remains largely unclear about the precise regulation of ABA transporters in plants.In this study,we show that the C-terminally encoded peptide receptor 2(CEPR2)directly interacts with the ABA transporter NRT1.2/NPF4.6.Genetic and phenotypic analyses revealed that NRT1.2/NPF4.6 positively regulates ABA response and that NRT1.2/NPF4.6 is epistatically and negatively regulated by CEPR2.Further biochemical assays demonstrated that CEPR2 phosphorylates NRT1.2/NPF4.6 at serine 292 to promote its degradation under normal conditions.However,ABA treatment and non-phosphorylation at serine 292 prevented the degradation of NRT1.2/NPF4.6,indicating that ABA inhibits the phosphorylation of this residue.Transport assays in yeast and Xenopus oocytes revealed that non-phosphorylated NRT1.2/NPF4.6 had high levels of ABA import activity,whereas phosphorylated NRT1.2/NPF4.6 did not import ABA.Analyses of complemented nrt1.2 mutants that mimicked non-phosphorylated and phosphorylated NRT1.2/NPF4.6 confirmed that non-phosphorylated NRT1.2S292A had high stability and ABA import activity in planta.Additional experiments showed that NRT1.2/NPF4.6 was degraded via the 26S proteasome and vacuolar degradation pathways.Furthermore,we found that three E2 ubiquitin-conjugating enzymes,UBC32,UBC33,and UBC34,interact with NRT1.2/NPF4.6 in the endoplasmic reticulum and mediate its ubiquitination.NRT1.2/NPF4.6 is epistatically and negatively regulated by UBC32,UBC33,and UBC34 inplanta.Taken together,these results suggest that the stability and ABA import activity of NRT1.2/NPF4.6 are precisely regulated by its phosphorylation and degradation in response to environmental stress.

关键词： CEPR2 NRT1.2/NPF4.6 phosphorylation UBC32 UBC33 and UBC34 degradation import activity

Ligustrazine-induced apoptosis is involved in its regulation of expression of Bcl-2 and Bax by caspase-dependent mechanism in rat hepatic stellate cells

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Ligustrazine-induced apoptosis is involved in its regulation...

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

中华医学会第三次全国肝纤维化、肝硬化学术会议

作者： Feng Zhang Na Lei Yin Lu Shizhong Zheng Department of Clinical Pharmacy College of PharmacyNanjing University of Chinese Medicine

Aims ccumulating experimental and clinical studies provide clear evidence for reversibility of hepatic fibrosis.Apoptosis of activated hepatic stellate cells(HSCs)has proven critical to fibrosis re

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 26-37页

作者： Li Chen Siwei Xia Shuqi Wang Yuanyuan Zhou Feixia Wang Zhanghao Li Yang Li Desong Kong Zili Zhang Jiangjuan Shao Xuefen Xu Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina Chinese Medicine Modernization and Big Data Research Center Nanjing University of Chinese MedicineNanjingJiangsuChina

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

关键词： Liver fibrosis cGAS Naringenin Inflammation Hepatic stellate cells