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Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural Medicines 2024年第1期22卷 31-46页

作者： QU Jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang school of life sciences Beijing University of Chinese MedicineBeijing 100029China school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China State Key Laboratory of Medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM).Si-Wu-Tang(SWT),a traditional Chinese medicine(TCM)formula,is known for treating gynecological diseases and liver fibrosis.Our previous studies demonstrated that long non-coding RNA H19(H19)was markedly upregulated in fibrotic livers while its deficiency markedly reversed fibrogenesis.However,the mechanisms by which SWT influences H19 remain unclear.Thus,we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the liver.Our results showed that SWT markedly improved ECM deposition and bile duct reactions in the liver.Notably,SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling,primarily in hepatic stellate cells(HSCs),and influencing cytoskeleton-related angiogenesis and hepatocellular injury.This modulation collectively led to reduced ECM deposition.Through extensive bioinformatics analyses,we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200,miR-211,and let7b,thereby regulating the above cellular regulatory pathways.Meanwhile,SWT reversed H19-related miRNAs and signaling pathways,diminishing ECM deposition and liver fibrosis.However,these protective effects of SWT were diminished with the overexpression of H19 in vivo.In conclusion,our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词： Liver fibrosis LncRNA H19 Si-Wu-Tang miRNAs Cytoskeleton ECM deposition

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Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping Liu Yajing Li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China school of life sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： Liver fibrosis Epigenetics regulation DNA methylation Histone acetylation Histone methylation mRNA methylation Non-coding RNA Drug development

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MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons

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Neural Regeneration Research 2024年第12期19卷 2698-2707页

作者： Bhupender Sharma Melissa MTorres Sheryl Rodriguez Laxman Gangwani Subodh Kumar Center of Emphasis in Neuroscience Department of Molecular and Translational MedicinePaul L.Foster School of MedicineTexas Tech University Health Sciences CenterEl PasoTXUSA Bond life sciences Center and Department of Veterinary Pathobiology University of MissouriColumbiaMOUSA L.Frederick Francis Graduate school of Biomedical sciences Texas Tech University Health Sciences CenterEl PasoTXUSA

Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic synapse f

关键词： Alzheimer's disease GABAergic synapse gamma-aminobutyric acid type A receptor subunitα-1(GABRα1) microRNA-502-3p(miR-502-3p) miRNA in situ hybridization Patch-clamp

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Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway

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Chinese Journal of Natural Medicines 2024年第4期22卷 318-328页

作者： YE Qiaobei ZHU Yu SHI Meng LV Linxi GONG Yuyan ZHANG Luyao YANG Lehe ZHAO Haiyang ZHAO Chengguang XU Huanhai Affiliated Yueqing Hospital Wenzhou Medical UniversityWenzhou 325600China The Institute of life sciences Biomedical Collaborative Innovation Center of Zhejiang ProvinceWenzhou UniversityWenzhou 325035China school of Pharmaceutical sciences Wenzhou Medical UniversityWenzhou 325035China

Double cortin-like kinase 1(DCLK1)exhibits high expression levels across various cancers,notably in human colorectal cancer(CRC).Diacerein,a clinically approved interleukin(IL)-1βinhibitor for osteoarthritis treatment,was evaluated for its impact on CRC proliferation and migration,alongside its underlying mechanisms,through both in vitro and in vivo analyses.The study employed MTT assay,colony formation,wound healing,transwell assays,flow cytometry,and Hoechst 33342 staining to assess cell proliferation,migration,and apoptosis.Additionally,proteome microarray assay and western blotting analyses were conducted to elucidate diacerein’s specific mechanism of action.Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo.Through high-throughput proteomics microarray and molecular docking studies,we identified that diacerein directly interacts with DCLK1.Mechanistically,the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed.Furthermore,diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets,including MCL-1,VEGF,and survivin,thereby inhibiting CRC progression in a mouse model,thereby inhibiting CRC progression in a mouse model.

关键词： DCLK1 Diacerein Rhein STAT3 Colorectal cancer

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Dietary oxidized cholesterol causes mucus barrier thinner via decreasing Muc2 expression in the proximal colon and increasing the abundance of mucus-degrading bacteria

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Food Science and Human Wellness 2024年

作者： Chi Yan Shou-He Huang Zi-Xing Chen Hua-Fang Ding Zhen-Yu Chen school of life sciences Faculty of Science The Chinese University of Hong Kong

Oxidized cholesterol (OXC) is a harmful dietary substance. Although the consumption of OXC has been associated with colonic inflammation， related underlying mechanisms are still limited. We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model. Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC. Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon， accompanied by an increase in the abundance of two mucus-degrading bacteria， namely A. muciniphila and B. acidifaciens. Consistently， oral exposure of OXC promoted mucus barrier erosion in DSS-induced colitis mice and facilitated bacteria infiltration in the colon. The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice， suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis. Finally， the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins. These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.

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Reducing Subspaces of Toeplitz Operators Induced by a Class of Non-analytic Monomials over the Unit Ball

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Acta Mathematica Sinica,English Series 2024年第7期40卷 1767-1777页

作者： Yan Yue SHI Bo ZHANG Xu TANG Yu Feng LU school of Mathematical sciences Ocean University of China school of Mathematics and Information sciences Yantai University school of Mathematical sciences Space Engineering University school of Mathematical sciences Dalian University of Technology

In this paper, we describe the minimal reducing subspaces of Toeplitz operators induced by non-analytic monomials on the weighted Bergman spaces and Dirichlet spaces over the unit ball B2. It is proved that each minimal reducing subspace M is finite dimensional, and if dim M ≥ 3,then M is induced by a monomial. Furthermore, the structure of commutant algebra ■ is determined by N and the two dimensional minimal reducing subspaces of ■. We also give some interesting examples.

关键词： Reducing subspace operator-weighted shifts Toeplitz operator von Neumann algebra 47B35 47B37

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The evolving views of hematopoiesis:from embryo to adulthood and from in vivo to in vitro

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Journal of Genetics and Genomics 2024年第1期51卷 3-15页

作者： Yifan Zhang Feng Liu Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology School of Life SciencesShandong UniversityQingdaoShandong 266237China State Key Laboratory of Membrane Biology Institute of ZoologyInstitute for Stem Cell and RegenerationUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China

The hematopoietic system composed of hematopoietic stem and progenitor cells(HSPCs)and their differentiated lineages serves as an ideal model to uncover generic principles of cell fate transitions.From gastrulation onwards,there successively emerge primitive hematopoiesis(that produces specialized he-matopoietic cells),pro-definitive hematopoiesis(that produces lineage-restricted progenitor cells),and definitive hematopoiesis(that produces multipotent HSPCs).These nascent lineages develop in several transient hematopoietic sites and finally colonize into lifelong hematopoietic sites.The development and maintenance of hematopoietic lineages are orchestrated by cell-intrinsic gene regulatory networks and cell-extrinsic microenvironmental cues.Owing to the progressive methodology(e.g.,high-throughput lineage tracing and single-cell functional and omics analyses),our understanding of the developmental origin of hematopoietic lineages and functional properties of certain hematopoietic organs has been updated;meanwhile,new paradigms to characterize rare cell types,cell heterogeneity and its causes,and comprehensive regulatory landscapes have been provided.Here,we review the evolving views of HSPC biology during developmental and postnatal hematopoiesis.Moreover,we discuss recent advances in the in vitro induction and expansion of HSPCs,with a focus on the implications for clinical applications.

关键词： Hematopoietic stem and progenitor cell Developmental hematopoiesis Postnatal hematopoiesis In vitro hematopoiesis

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The NAC Transcription Factor ANAC089 Modulates Seed Vigor through the ABI5-VTC2 Module in Arabidopsis thaliana

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Phyton-International Journal of Experimental Botany 2024年第6期93卷 1101-1116页

作者： Yuan Tian Lulu Zhi Ping Li Xiangyang Hu Shanghai Key Laboratory of Bio-Energy Crops School of Life SciencesShanghai UniversityShanghai200444China

Seed viability is an essential feature for genetic resource conservation as well as sustainable crop production.Long-term storage induces seed viability deterioration or seed aging,accompanied by the accumulation of toxic reactive oxygen species(ROS)to suppress seed germination.Controlled deterioration treatment(CDT)is a gen-eral approach for mimicking seed aging.The transcription factor ANAC089 was previously reported to modulate seed primary germination.In this study,we evaluated the ability of ANAC089 to control seed viability during aging.Compared with that in the wild-type line,the mutation of ANAC089 signiﬁcantly increased H_(2)O_(2),thereby reducing seed viability after CDT,while the overexpression of ANAC089 reduced H_(2)O_(2) and improved seed long-evity,indicating a critical role for ANAC089 in maintaining seed viability through H_(2)O_(2) signaling.A series of stu-dies have shown that ANAC089 targets and negatively regulates the level of ABI5,an important transmitter of abscisic acid(ABA)signals,to affect seed viability after CDT.Furthermore,ABI5 negatively regulated the expres-sion of VTC2,which is involved in the biosynthesis of the antioxidant ascorbic acid and H_(2)O_(2) scavenging.As a result,ANAC089 attenuates the generation of H_(2)O_(2),thereby enhancing seed viability through the ABI5-VTC2 module during the seed aging process.Taken together,our results reveal a novel mechanism by which ANAC089 enhances seed viability by coordinating ABI5 and VTC2 expression,ultimately preventing the overac-cumulation of H_(2)O_(2),which would have led to reduced seed viability.

关键词： Arabidopsis seed aging ANAC089 ABI5 VTC2 H_(2)O_(2)

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Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10,MC38 and Hep1-6 Tumor Models

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Chinese Journal of Integrative Medicine 2024年第4期30卷 348-358页

作者： FU Yu-bing LIU Chen-feng WANG Jin-jia JI Xiao-lin TANG Rong-han LIAO Kun-yu CHEN Ling-yue HONG Ya-zhen FAN Bin-bin WANG Shi-cong LIU Wen-Hsien State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life ScienceXiamen UniversityXiamenFujian Province(361102)China Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development ZhangzhouFujian Province(363000)China

Objective To investigate the anti-tumor effects of Pien Tze Huang(PZH)in mouse models of B16–F10 melanoma,MC38 colorectal cancer,Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model.Methods Various tumor models,including B16–F10,MC38 and Hep1-6 tumor hypodermic inoculation models,B16–F10 and Hep1-6 pulmonary metastasis models,Hep1-6 orthotopic implantation model,and chemically induced hepatocellular carcinoma model,were utilized to evaluate the anti-tumor function of PZH.Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice.For cell proliferation and death of tumor cells in vitro,as well as T cell activation markers,cytokine production and immune checkpoints analysis,single-cell suspensions were prepared from mouse spleen,lymph nodes,and tumors after PZH treatment.Results PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth(Pliferation and survival of tumor cells(P>0.05).Nevertheless,PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma,tumor necrosis factor alpha,and interleukin 2 in CD4^(+)T cells in vitro(P<0.01 or P<0.05).Importantly,PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8^(+)T cells(P<0.01 or P<0.05).Conclusion This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity,indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.

关键词： Pien Tze Huang metastasis anti-tumor immunity T cell activation T cell exhaustion immune checkpoints Chinese medicine

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Revealing the role of CCoAOMT1: fine-tuning bHLH transcription factors for optimal anther development

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Science China(life sciences) 2024年第3期67卷 565-578页

作者： Zesen Lai Jianzheng Wang Ying Fu Menghan Wang Hong Ma Shiqing Peng Fang Chang State Key Laboratory of Genetic Engineering Ministry of Education Key Laboratory of Biodiversity Sciences and Ecological Engineering and Institute of Biodiversity SciencesInstitute of Plant BiologySchool of Life SciencesFudan UniversityShanghai 200438China school of Tropical Agriculture and Forestry Agriculture-Rural Affairs and Rural RevitalizationHainan UniversityHaikou 570228China Key Laboratory of Biology and Genetic Resources of Tropical Crops Ministry of AgricultureInstitute of Tropical Bioscience and BiotechnologyChinese Academy of Tropical Agricultural SciencesHaikou 571101China Department of Biology Huck Institutes of the Life SciencesPennsylvania State UniversityUniversity ParkPA 16802USA

The tapetum,a crucial innermost layer encompassing male reproductive cells within the anther wall,plays a pivotal role in normal pollen development.The transcription factors (TFs) bHLH010/089/091 redundantly facilitate the rapid nuclear accumulation of DYSFUNCTIONAL TAPETUM 1,a gatekeeper TF in the tapetum.Nevertheless,the regulatory mechanisms governing the activity of bHLH010/089/091 remain unknown.In this study,we reveal that caffeoyl coenzyme A O-methyltransferase 1 (CCoAOMT1) is a negative regulator affecting the nuclear localization and function of bHLH010 and bHLH089,probably through their K259 site.Our findings underscore that CCoAOMT1 promotes the nuclear export and degradation of bHLH010 and bHLH089.Intriguingly,elevated CCoAOMT1 expression resulted in defective pollen development,mirroring the phenotype observed in bhlh010 bhlh089 mutants.Moreover,our investigation revealed that the K259A mutation in the bHLH089 protein disrupted its translocation from the nucleus to the cytosol and impeded its degradation induced by CCoAOMT1.Importantly,transgenic plants with the probHLH089::bHLH089^(K259A)construct failed to rescue proper pollen development or gene expression in bhlh010 bhlh089 mutants.Collectively,these findings emphasize the need to maintain balanced TF homeostasis for male fertility.They firmly establish CCoAOMT1 as a pivotal regulator that is instrumental in achieving equilibrium between the induction of the tapetum transcriptional network and ensuring appropriate anther development.

关键词： anther development nuclear localization bHLH O-methyltransferase transcription factor homeostasis

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