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OIP5 Interacts with NCK2 to Mediate Human Spermatogonial Stem Cell Self-Renewal and Apoptosis through Cell Cyclins and Cycle Progression and Its Abnormality Is Correlated with Male Infertility

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research 2024年第1期2023卷 455-469页

作者： Yinghong Cui Wei Chen Li Du Zuping He The Key Laboratory of Model Animals and Stem Cell biology in Hunan Province The Research Center of Reproduction and Translational Medicine of Hunan ProvinceHunan Normal University School of MedicineChangsha 410013HunanChina

Spermatogonial stem cells(SSCs)have important applications in both reproduction and regenerative ***,specific genes and signaling transduction pathways in mediating fate decisions of human SSCs remain ***,we have demonstrated for the first time that OIP5(Opa interacting protein 5)controlled the self-renewal and apoptosis of human *** sequencing identified that NCK2 was a target for OIP5 in human SSCs,and interestingly,OIP5 could interact with NCK2 as shown by Co-IP(co-immunoprecipitation),IP-MS(mass spectrometry),and GST pulldown ***2 silencing decreased human SSC proliferation and DNA synthesis but enhanced their ***,NCK2 knockdown reversed the influence of OIP5 overexpression on human ***,OIP5 inhibition decreased the numbers of human SSCs at S and G2/M phases,while the levels of numerous cell cycle proteins,including cyclins A2,B1,D1,E1 and H,especially cyclin D1,were remarkably ***,whole-exome sequencing of 777 patients with nonobstructive azoospermia(NOA)revealed 54 singlenucleotide polymorphism mutations of the OIP5 gene(6.95%),while the level of OIP5 protein was obviously lower in testes of NOA patients compared to fertile ***,these results implicate that OIP5 interacts with NCK2 to modulate human SSC self-renewal and apoptosis via cell cyclins and cell cycle progression and that its mutation and/or lower expression is correlated with *** such,this study offers novel insights into molecular mechanisms underlying the fate determinations of human SSCs and the pathogenesis of NOA,and it provides new targets for treating male infertility.

关键词： OIP5 Apoptosis reversed

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Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma

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Cancer Innovation 2024年第2期3卷 80-95页

作者： Satoru Sasagawa Jun Kumai Toru Wakamatsu Yoshihiro Yui molecular biology Laboratory Research InstituteNozaki Tokushukai HospitalDaitoOsakaJapan Sarcoma Treatment Laboratory Research InstituteNozaki Tokushukai HospitalDaitoOsakaJapan Department of Musculoskeletal Oncology Service Osaka International Cancer InstituteOsakaJapan

Background:Synovial sarcoma(SS)is an SS18-SSX fusion gene-driven soft tissue sarcoma with mesenchymal characteristics,associated with a poor prognosis due to frequent metastasis to a distant organ,such as the *** deacetylase(HDAC)inhibitors(HDACis)are arising as potent molecular targeted drugs,as HDACi treatment disrupts the SS oncoprotein complex,which includes HDACs,in addition to general HDACi *** provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells,we examined cellular responses to HDACi treatment in combination with two-dimensional(2D)and 3D culture ***:Using several SS cell lines,biochemical and cell biological assays were performed with romidepsin,an HDAC1/2 selective ***38 was concomitantly used as an ameliorant drug with romidepsin ***,apoptosis induction,and MHC class I polypeptide-related sequence A/B(MICA/B)induction were monitored to evaluate the drug *** addition to the conventional 2D culture condition,spheroid culture was adopted to evaluate the influence of cell-mass microenvironment on ***:By monitoring the cellular behavior with romidepsin and/or SN38 in SS cells,we observed that responsiveness is diverse in each cell *** the apoptotic inducible cells,co-treatment with SN38 enhanced cell *** nonapoptotic inducible cells,cytostasis and MICA/B induction were observed,and SN38 improved MICA/B induction *** a novel efficacy of SN38,we revealed TWIST1 suppression in SS *** the spheroid(3D)condition,romidepsin efficacy was severely restricted in TWIST1-positive *** demonstrated that TWIST1 downregulation restored romidepsin efficacy even in spheroid form,and concomitant SN38 treatment along with romidepsin reproduced the ***:The current study demonstrated the benefits and concerns of using HDACi for SS treatment in 2D and

关键词： HDAC inhibitor MICA/B SN38 spheroid synovial sarcoma TWIST1

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Glucagon-like peptide (GLP)-1 regulation of lipid and lipoprotein metabolism

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Medical Review 2024年第4期4卷 301-311页

作者： Simon Hoffman Khosrow Adeli molecular medicine Research InstituteThe Hospital for Sick ChildrenUniversity of TorontoTorontoONCanada Cardiovascular&Metabolic Disease Merck Research LaboratoriesSouth San FranciscoCAUSA molecular medicine Research InstituteThe Hospital for Sick ChildrenUniversity of Toronto555 University Avenue M5G 1X8TorontoONCanada

Metabolic health is highly dependent on intestinal and hepatic handling of dietary and endogenous lipids and *** of lipid and lipoprotein metabolism are commonly observed in patients with insulin resistant states such as obesity,metabolic syndrome,and type 2 ***-idence from both animal models and human studies indicates that a major underlying factor in metabolic or diabetic dysli-pidemia is the overproduction of hepatic and intestinal apoli-poprotein(apo)B-containing lipoprotein *** particles are catabolized down into highly proatherogenic remnants,which can be taken up into the arterial intima and promote plaque *** gut-derived peptides have been identiﬁed as key regulators of energy metabolism;one such peptide is the incretin hormone glucagon-like peptide(GLP)-*** laboratory has previously demonstrated that GLP-1 can signal both centrally and peripherally to reduce postprandial and fasting lipoprotein ***,we have demonstrated that GLP-1 receptor(GLP-1R)agonists can ameliorate diet-induced ***,we published evidence for a novel vagal neuroendocrine signalling pathway by which native GLP-1 may exert its anti-lipemic eﬀ***,we demonstrated a novel role for other gut-derived peptides in regulating intestinal lipoprotein ***,ample evidence supports a key role for GLP-1R on the portal vein aﬀerent neurons and nodose ganglion in modulating intestinal fat absorption and lipoprotein produc-tion and identiﬁes other gut-derived peptides as novel regula-tors of postprandial *** from these data may support identiﬁcation of potential drug targets and the development of new therapeutics targeting treatment of dia-betic dyslipidemia.

关键词： glucagon-like peptide-1 lipid lipoprotein intes-tine neuroendocrine

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Suspended particulate matter promotes epithelial-to-mesenchymal transition in alveolar epithelial cells via TGF-β1-mediated ROS/IL-8/SMAD3 axis

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Journal of Environmental Sciences 2024年第7期141卷 139-150页

作者： Shahrzad Molavinia Dian Dayer Mohammad Javad Khodayar Gholamreza Goudarzi Maryam Salehcheh Cellular and molecular research Center Medical Basic Sciences Research InstituteAhvaz Jundishapur University of Medical SciencesAhvazIran Department of Toxicology School of PharmacyAhvaz Jundishapur University of Medical SciencesAhvazIran Student research Committee Ahvaz Jundishapur University of Medical SciencesAhvazIran Toxicology research Center Medical Basic Sciences Research InstituteAhvaz Jundishapur University of Medical SciencesAhvazIran Air Pollution and Respiratory Diseases research Center Ahvaz Jundishapur University of Medical SciencesAhvazIran Iranian scientific Association of Clean Air TehranIran

Epidemiological evidence presents that dust storms are related to respiratory diseases,such as pulmonary fibrosis(PF).However,the precise underlying mechanisms of SPM-elicited adverse effects still need to be ***-mesenchymal transition(EMT)process is a characteristic of *** discussed whether suspended particulate matter(SPM)is involved in EMT induction via transforming growth factor-β1(TGF-β1).In this study,a detailed elemental analysis(55 elements),particle size,and morphology were *** investigate the toxicity of SPM,an MTT test was performed to detect cell ***,A549cells were exposed to selected concentrations of SPM(20 and 40μg/mL)for single and repeated *** DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species(ROS).The ELISA assay demonstrated increased levels of interleukin-8(IL-8)and TGF-β1 in the *** blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent *** of western blot demonstrated that E-cadherin was reduced,whereas p-SMAD3,vimentin,andα-smooth muscle actin were *** findings indicated that SPM triggered EMT by induction of oxidative stress,inflammation,and the TGF-β1/SMAD3 pathway activation.

关键词： Particulate matter TGF-β1 Oxidative stress Epithelial-mesenchymal transition Pulmonary fibrosis Cells

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Targeting oral-gut microbial transmission in diabetic coronary heart disease:unveiling key pathogenic mechanisms

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Science China(Life Sciences) 2024年第10期67卷 2287-2288页

作者： Ismail Cimen Aab Cardiovascular research institute Department of MedicineUniversity of Rochester School of Medicine and DentistryRochester 14642USA

Diabetes significantly exacerbates the occurrence and adverse prognosis of coronary heart disease(CHD),emphasizing the importance of focusing on the prevention and management of diabetesrelated *** study identifies and verifies for the first time a distinctive oral-gut microbiota profile in patients with diabetic coronary heart disease(DCHD),marked by an increased abundance of oral Fusobacterium nucleatum and gut Lactobacillus.

关键词： coronary prevention diabetic

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Opto-fluidically multiplexed assembly and micro-robotics

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Light(Science & Applications) 2024年第3期13卷 544-554页

作者： Elena Erben Weida Liao Antonio Minopoli Nicola Maghelli Eric Lauga Moritz Kreysing Max Planck institute of molecular Cell biology and Genetics Dresden 01307Germany Center for Systems biology Dresden 01307Germany institute of Biological and Chemical Systems–Biological Information Processing.Karlsruhe institute of Technology(KIT) Eggenstein-Leopoldshafen 76344Germany Department of Applied Mathematics and Theoretical Physics University of CambridgeCambridge CB30WAUK

Techniques for high-definition micromanipulations,such as optical tweezers,hold substantial interest across a wide range of ***,their applicability remains constrained by material properties and laser *** while microfluidic manipulations have been suggested as an alternative,their inherent capabilities are limited and further hindered by practical challenges of implementation and *** we show that the iterative application of laser-induced,localized flow fields can be used for the relative positioning of multiple micro-particles,irrespectively of their material *** to the standing theoretical proposal,our method keeps particles mobile,and we show that their precision manipulation is non-linearly accelerated via the multiplexing of temperature stimuli below the heat diffusion *** resulting flow fields are topologically rich and mathematically *** represent unprecedented microfluidic control capabilities that are illustrated by the actuation of humanoid micro-robots with up to 30 degrees of freedom,whose motions are sufficiently well-defined to reliably communicate personal characteristics such as gender,happiness and *** results constitute high-definition micro-fluidic manipulations with transformative potential for assembly,micro-manufacturing,the life sciences,robotics and optohydraulically actuated micro-factories.

关键词： manipulation fluid assembly

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Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

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National Science Review 2024年第6期11卷 119-128页

作者： Chunyu Zhao Jia Tu Chuchu Wang Wenbin Liu Jinge Gu Yandong Yin Shengnan Zhang Dan Li Jiajie Diao Zheng-Jiang Zhu Cong Liu Interdisciplinary research Center on biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences University of Chinese Academy of Sciences Bio-X institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education Shanghai Jiao Tong University Zhangjiang institute for Advanced Study Shanghai Jiao Tong University Department of Cancer biology University of Cincinnati College of Medicine

Accumulation of aggregated α-synuclein(α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease(PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids(LPLs),particularly targeting lysophosphatidylcholine(LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

关键词： α-synuclein Parkinson's disease lysophosphatidylcholine, aggregation

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AKT2^(S128)/CCTα^(S315/319/323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 782-796页

作者： Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key Laboratory of Carcinogenesis and Translational research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina Peking University International Cancer institute Peking University100191 BeijingChina research Unit of molecular Cancer research Chinese Academy of Medical SciencesBeijingChina Soochow University Cancer institute Suzhou 215000China institute of Cancer research Shenzhen Bay LaboratoryShenzhen 518107China

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic *** study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)***,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in ***,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC *** activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK *** of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient ***-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC *** conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关键词： CAFs metabolism resistance

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Toosendanin: upgrade of an old agent in cancer treatment

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Chinese Journal of Natural medicines 2024年第10期22卷 887-899页

作者： LI Shuwei XIONG Qingyi SHEN Yiwen LIN Jiayi ZHANG Lijun WU Ye JIN Jinmei LUAN Xin Shanghai Frontiers Science Center for Chinese medicine Chemical biology institute of Interdisciplinary Integrative medicine research and Shuguang Hospital Shanghai University of Traditional Chinese medicine

Toosendanin(TSN), a tetracyclic triterpenoid derived from Melia toosendan and M. azedarach, demonstrates broad application prospects in cancer treatment. Although previously employed as a pesticide, recent studies have revealed its potential therapeutic value in treating various types of cancer. TSN exerts an anticancer effect via mechanisms including proliferation inhibition, apoptosis induction, migration suppression, and angiogenesis inhibition. However, TSN's toxicity, particularly its hepatotoxicity, significantly limits its therapeutic application. This review explored the dual nature of TSN, evaluating both its anticancer potential and toxicological risks, emphasizing the importance of balancing these aspects in therapeutic applications. Furthermore, we investigated the incorporation of TSN into novel therapeutic strategies, such as Proteolysis-targeting chimeras(PROTAC) technology and nanotechnology-based drug delivery systems(DDS), which enhance treatment efficacy while mitigating toxicity in normal tissues.

关键词： Cancer therapy Hepatotoxicity Nano-delivery systems PROTAC Toosendanin

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Mitigating growth-stress tradeoffs via elevated TOR signaling in rice

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molecular Plant 2024年第2期17卷 240-257页

作者： Wei Li Jiaqi Liu Zeqi Li Ruiqiang Ye Wenzhen Chen Yuqing Huang Yue Yuan Yi Zhang Huayi Hu Peng Zheng Zhongming Fang Zeng Tao Shiyong Song Ronghui Pan Jian Zhang Jumim Tu Jen Sheen Hao Du State Key Laboratory of Rice biology College of Agriculture and BiotechnologyZhejiang UniversityYu-Hang-Tang Road No.866Hangzhou 310058China ZJU-Hangzhou Global scientific and Technological Innovation Center Zhejiang UniversityHangzhou 311215China Hainan institute of Zhejiang University Sanya 572025China National Key Laboratory of Plant molecular Genetics CASCenter for Excellence in Molecular Plant SciencesShanghai lnstitute of Plant Physiology and EcologyChineseAcademy of SciencesShanghai 200032China Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region(Ministry of Education) College of Agricultural SciencesGuizhouUniversityGuiyang 550025China State Key Laboratory of Rice biology and Breeding China National Rice Research InstituteHangzhou 311400China Department of molecular biology and Center for Computational and Integrative biology Massachusetts General Hospitaland Department of GeneticsHarvard Medical SchoolBostonMA02114USA

Rice production accounts for approximately half of the freshwater resources utilized in agriculture,result-ing in greenhouse gas emissions such as methane(CH4)from flooded paddy *** address this chal-lenge,environmentally friendly and cost-effective water-saving techniques have become widely adopted in rice ***,the implementation of water-saving treatments(WsTs)in paddy-field rice has been associated with a substantial yield loss of up to 50%as well as a reduction in nitrogen use efficiency(NUE).In this study,we discovered that the target of rapamycin(TOR)signaling pathway is compromised in rice under *** profiling-coupled transcriptome sequencing(polysome-seq)analysis unveiled a substantial reduction in global translation in response to WST associated with the downregulation of TOR ***,biochemical,and genetic analyses revealed new insights into the impact of the positive TOR-S6K-RPS6 and negative TOR-MAF1 modules on translation repression under ***,ammonium exhibited a greater ability to alleviate growth constraints under WsT by enhancing TOR signaling,which simultaneously promoted uptake and utilization of ammonium and nitrogen *** further demonstrated that TOR modulates the ammonium transporter AMT1;1 as well as the amino acid permease APP1 and dipeptide transporter NPF7.3 at the translational level through the 5'untranslated ***,these findings reveal that enhancing TOR signaling could mitigate rice yield penalty due to WST by regulating the processes involved in protein synthesis and *** study will contribute to the breeding of new rice varieties with increased water and fertilizer utilization efficiency.

关键词： target of rapamycin TOR water-saving rice low-carbon agriculture drought nitrogen use efficiency NUE

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