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METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2176-2192页

作者： Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University200438 ShanghaiChina The Department of Medical Genetics Naval Medical University200433 ShanghaiChina translational Medicine research Center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital100048 BeijingChina The Department of Pharmaceutical Analysis School of PharmacyNaval Medical University200433 ShanghaiChina Key laboratory of Biosafety Defense Ministry of Education200433 ShanghaiChina Shanghai Key laboratory of Medical Biodefense 200433 ShanghaiChina

Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular ***,the molecular mechanisms that control progressive MAFLD have yet to be fully ***,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and ***,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver *** experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)*** of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and *** together,these findings indicate potential therapies for the treatment of MAFLD progression.

关键词： S100A4 MyD88 metabolism

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translation machinery: the basis of translational control

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Journal of Genetics and Genomics 2024年第4期51卷 367-378页

作者： Shu Yuan Guilong Zhou Guoyong Xu State Key laboratory of Hybrid Rice Institute for Advanced Studies(IAS)Wuhan UniversityWuhanHubei 430072China Hubei Hongshan laboratory WuhanHubei 430070China

Messenger RNA(mRNA)translation consists of initiation,elongation,termination,and ribosome recycling,carried out by the translation machinery,primarily including tRNAs,ribosomes,and translation factors(TrFs).translational regulators transduce signals of growth and development,as well as biotic and abiotic stresses,to the translation machinery,where global or selective translational control occurs to modulate mRNA translation efficiency(TrE).As the basis of translational control,the translation machinery directly determines the quality and quantity of newly synthesized peptides and,ultimately,the cellular ***,regulating the availability of diverse machinery components is reviewed as the central strategy of translational *** provide classical signaling pathways(e.g.,integrated stress responses)and cellular behaviors(e.g.,liquideliquid phase separation)to exemplify this strategy within different physiological contexts,particularly during hostemicrobe *** new technologies developed,further understanding this strategy will speed up translational medicine and translational agriculture.

关键词： translational control Ribosome tRNA translation machinery uORF Phase separation Immune response

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RNAirport:a deep neural network-based database characterizing representative gene models inplants

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Journal of Genetics and Genomics 2024年第6期51卷 652-664页

作者： Sitao Zhu Shu Yuan Ruixia Niu Yulu Zhou Zhao Wang Guoyong Xu State Key laboratory of Hybrid Rice Institute for Advanced Studies(IAS)Wuhan UniversityWuhanHubei 430072China Hubei Hongshan laboratory WuhanHubei 430070China

A 5'-leader,known initially as the 5'-untranslated region,contains multiple isoforms due to alternative splicing(aS)and alternative transcription start site(aTSS).Therefore,a representative 5'-leader is demanded to examine the embedded RNA regulatory elements in controlling translation ***,we develop a ranking algorithm and a deep-learning model to annotate representative 5'-leaders for five plant *** rank the intra-sample and inter-sample frequency of aS-mediated transcript isoforms using the Kruskal-Wallis test-based algorithm and identify the representative aS-5'-*** further assign a representative 5'-end,we train the deep-learning model 5'leaderP to learn aTsS-mediated 5'-end distribution patterns from cap-analysis gene expression *** model accurately predicts the 5'-end,confirmed experimentally in Arabidopsis and *** representative 5'-leader-contained gene models and 5'leaderP can be accessed at RNAirport(http:/***/leader5P/).The Stage 1 annotation of 5'-leader records 5'-leader diversity and will pave the way to Ribo-Seq open-reading frame annotation,identical to the project recently initiated by human GENCODE.

关键词： 5'-leader Transcript isoforms RNA regulatory elements UORF Deep learning Synthetic biology translational control

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Mitochondria-targeted carrier-free nanoparticles based on dihydroartemisinin against hepatocellular carcinoma

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Chinese Chemical Letters 2024年第10期35卷 329-333页

作者： Zhiyu Yu Xiang Luo Cheng Zhang Xin Lu Xiaohui Li Pan Liao Zhongqiu Liu Rong Zhang Shengtao Wang Zhiqiang Yu Guochao Liao Joint laboratory for translational Cancer research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China Guangzhou Yuemei Pharmaceutical Technology Co. Ltd.Guangzhou 510535China Afiliated Foshan Maternity&Child Healthcare Hospital Southern Medical UniversityFoshan 528000China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhou 510515China Department of laboratory Medicine Dongguan Institute of Clinical Cancer ResearchDongguan Key Laboratory of Precision Diagnosis and Treatment for TumorsThe Tenth Afiliated Hospital of Southern Medical University(Dongguan People's Hospital)Dongguan 523058China

Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic ***(DHA),a derivative of artemisinin,has been shown to exert anti-tumor effects through the production of reactive oxygen species(ROS)and resultant mitochondrial ***,clinical translation is limited by several drawbacks,such as insolubility,instability and low ***,based on a nanomedicine-based delivery strategy,we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium(TPP),aiming to improve bioavailability and mitochondrial ***-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then *** cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS,which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway,leading to *** vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular *** findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.

关键词： Hepatocellular carcinoma Carrier-freenanoparticles Dihydroartemisinin Mitochondria targeting Apoptosis

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Plant-derived nanovesicles as an emerging platform for cancer therapy

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Acta Pharmaceutica Sinica B 2024年第1期14卷 133-154页

作者： Hanzhe Liu Guo-Feng Luo Zhengjun Shang The State Key laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key laboratory of Oral Biomedicine Ministry of Education School and Hospital of StomatologyWuhan UniversityWuhan 430079China

Plant-derived nanovesicles(PDNVs)derived from natural green products have emerged as an attractive nanoplatform in biomedical *** are usually characterized by unique structural and biological functions,such as the bioactive lipids/proteins/nucleic acids as therapeutics and targeting groups,immune-modulation,and long-term *** the rapid development of nanotechnology,materials,and synthetic chemistry,PDNVs can be engineered with multiple functions for efficient drug delivery and specific killing of diseased cells,which represent an innovative biomaterial with high biocompatibility for fighting against *** this review,we provide an overview of the state-of-theart studies concerning the development of PDNVs for cancer *** original sources,methods for obtaining PDNVs,composition and structure are introduced *** an emphasis on the featured application,the inherent anticancer properties of PDNVs as well as the strategies in constructing multifunctional PDNVs-based nanomaterials will be discussed in ***,some scientific issues and technical challenges of PDNVs as promising options in improving anticancer therapy will be discussed,which are expected to promote the further development of PDNVs in clinical translation.

关键词： Naturally occurring nanovesicles Plant Nanotechnology Drug delivery Cancer therapy

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Mesenchymal stem cell-derived exosomes: Versatile nanomaterials for skin wound treatment

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Nano research 2024年第4期17卷 2836-2856页

作者： Yuzhen Xiao Hexi Li Junhui Zhang Songyun Yang Chunsen Zhang Yizhou Huang Xin Tang Huiqi Xie Department of Orthopedic Surgery and Orthopedic research Institute Laboratory of Stem Cell and Tissue EngineeringState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China School of Basic Medical Sciences and Forensic Medicine Sichuan UniversityChengdu 610041China West China School of Public Health and West China Fourth Hospital Sichuan UniversityChengdu 610041China Sports Medicine Center West China HospitalSichuan UniversityChengdu 610041China

Accumulating studies reveal that mesenchymal stem cells(MSCs)promote skin wound healing mainly through the paracrine ***,one of the crucial paracrine mediators in wound healing,are cell-derived nanosized membranous vesicles containing diverse bioactive *** the potent ability of modulating skin cell behaviors,MSC-derived exosomes(MSC-Exos)are regarded as a promising nanomaterial for regenerative wound *** hostile conditions,MSC-Exos are efficient in protecting skin cells from severe damage and restoring their *** to recent studies,MSC-Exos possess remarkable pro-healing effects in a variety of skin wounds,typically resulting in increased wound closure,inhibited scar tissue formation,and better restoration of skin *** further enhance the therapeutic potential of MSC-Exos,the development of applicable pretreatment strategies and the optimization of exosome delivery are under intensive ***,we summarize current research progress of MSC-Exos for skin wound treatment,with an emphasis on the biological effects of these nanovesicles,the repair mechanisms,and future challenges in clinical translation.

关键词： exosomes mesenchymal stem cells diabetic wounds burn wounds scar wound healing

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Biomaterials and emerging technologies for tissue engineering and in vitro models

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Bio-Design and Manufacturing 2024年第3期7卷 237-239页

作者： J.Miguel Oliveira Rui L.Reis 3B’s research Group I3Bs-Research Institute on BiomaterialsBiodegradables and BiomimeticsHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineUniversity of MinhoAveParkZona Industrial da Gandra4805-017 BarcoGuimarãesPortugal ICVS/3B’s-PT Government Associate laboratory 4806-909 Braga/GuimarãesPortugal

The latest advances in the field of biomaterials have opened new avenues for scientific breakthroughs in tissue engineer-ing which greatly contributed for the successful translation of tissue engineering products into the market/***-materials are easily processed to become similar to natural extracellular matrix,making them ideal temporary supports for mimicking the three-dimensional(3D)microenvironment required for maintaining the adequate cell/tissue functions both in vitro and in vivo^([1]).

关键词： breakthrough biomaterials engineer

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Genetic regulation of m^(6)A RNA methylation and its contribution in human complex diseases

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Science China(Life Sciences) 2024年第8期67卷 1591-1600页

作者： Kexuan Chen Jiuhong Nan Xushen Xiong The Second Affiliated Hospital&Liangzhu laboratory Zhejiang University School of MedicineHangzhou 311121China State Key laboratory of Transvascular Implantation Devices The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 311121China

N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA *** of m^(6)A has been revealed to lead to abnormal physiological conditions and cause various types of human *** studies have delineated the genetic regulatory maps for m^(6)A methylation by mapping the quantitative trait loci of m^(6)A(m^(6)A-QTLs),thereby building up the regulatory circuits linking genetic variants,m^(6)A,and human complex ***,we review the recent discoveries concerning the genetic regulatory maps of m^(6)A,describing the methodological and technical details of m^(6)A-QTL identification,and introducing the key findings of the cis-and trans-acting drivers of m^(6)*** further delve into the tissue-and ethnicity-specificity of m^(6)A-QTL,the association with other molecular phenotypes in light of genetic regulation,the regulators underlying m^(6)A genetics,and importantly,the functional roles of m^(6)A in mediating human complex ***,we discuss potential research avenues that can accelerate the translation of m^(6)A genetics studies toward the development of therapies for human genetic diseases.

关键词： m^(6)A disease genetics m^(6)A-QTL GWAS

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ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2–BECN1 interaction

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2026-2038页

作者： Shiqiang Xu Qilian Ma Junwen Shen Ningning Li Shan Sun Nana Wang Yang Chen Chunsheng Dong Kin Yip Tam Jochen H.M.Prehn Hongfeng Wang Zheng Ying Jiangsu Key laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China MOE Key laboratory of Geriatric Diseases and Immunology College of Pharmaceutical SciencesSuzhou Medical College of Soochow UniversitySuzhou 215123China Jiangsu Province Engineering research Center of Precision Diagnostics and Therapeutics Development Soochow UniversitySuzhou 215123China Dept.of Physiology&Medical Physics and FUTURE-NEURO research Centre Royal College of Surgeons in IrelandDublin D02 YN77Ireland Faculty of Health Sciences University of MacaoTaipaMacao 999078China Insititutes of Biology and Medical Science Soochow UniversitySuzhou 215123China

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative *** GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and *** to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)*** there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains *** the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced ***,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in ***,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.

关键词： Amyotrophic lateral sclerosis Frontotemporal dementia C9orf72 Autophagy BCL2 BECN1/Beclin 1 Dipeptide repeat Neurodegeneration

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A piezoelectric-driven microneedle platform for skin disease therapy

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The Innovation 2024年第3期5卷 110-121页

作者： Ziyan Chen Xin Liu Zixi Jiang Huayi Wu Tao Yang Lanyuan Peng Lisha Wu Zhongling Luo Mi Zhang Juan Su Yan Tang Jinmao Li Yang Xie Han Shan Qibo Lin Xiuli Wang Xiang Chen Hanmin Peng Shuang Zhao Zeyu Chen Department of Dermatology Xiangya HospitalCentral South UniversityChangsha 410008China Furong laboratory(Precision Medicine) Changsha 410008China National Engineering research Center of Personalized Diagnostic and Therapeutic Technology Xiangya HospitalCentral South UniversityChangsha 410008China Hunan Engineering research Center of Skin Health and Disease Xiangya HospitalCentral South UniversityChangsha 410008China Hunan Key laboratory of Skin Cancer and Psoriasis Xiangya HospitalCentral South UniversityChangsha 410008China National Clinical research Center of Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China School of Mechanical and Electrical Engineering Central South UniversityChangsha 410083China Department of Dermatology Xijing HospitalThe Fourth Military Medical UniversityXi’anShaanxi 710000China State Key laboratory of Mechanics and Control for Aerospace Structures Nanjing University of Aeronautics&AstronauticsNanjing 210016China Institute of Photomedicine Shanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghai 200443China

With over a million cases detected each year,skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate,propensity for recurrence,and potential for post-treatment *** therapy(PDT)is a treatment with minimal invasiveness or scarring and few side effects,making it well tolerated by ***,this treatment requires further research and development to improve its effective clinical ***,a piezoelectric-driven microneedle(PDMN)platform that achieves high efficiency,safety,and non-invasiveness for enhanced PDT is *** platform induces deep tissue cavitation,increasing the level of protoporphyrin IX and significantly enhancing drug penetration.A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT(PDMN-PDT).Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25%and 50%,respectively,without any anesthesia compared to traditional *** findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment,which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.

关键词： needle anesthesia clinical

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