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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

science China Life sciences 2025年第1期68卷 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou Fudan University shanghai Cancer Center and institutes of Biomedical sciences Fudan University Department of Oncology Shanghai Medical CollegeFudan University Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University Department of Oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer Key Laboratory of Breast Cancer in shanghai Fudan University Shanghai Cancer CenterFudan University shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

关键词： p53 NRF2 SLC7A11 WEE1 AZD1775 ferroptosis nucleolar stress

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A new horizon for neuroscience:terahertz biotechnology in brain research

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Neural Regeneration Research 2025年第2期20卷 309-325页

作者： Zhengping Pu Yu Wu Zhongjie Zhu Hongwei Zhao Donghong Cui shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina Department of Psychiatry Kangci Hospital of JiaxingTongxiangZhejiang ProvinceChina shanghai Synchrotron Radiation Facility Shanghai Advanced Research InstituteChinese Academy of SciencesShanghaiChina Key Laboratory of Interfacial Physics and Technology Shanghai Institute of Applied PhysicsChinese Academy of ScienceShanghaiChina National Facility for Protein science in shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghaiChina

Terahertz biotechnology has been increasingly applied in various biomedical fields and has especially shown great potential for application in brain *** this article,we review the development of terahertz biotechnology and its applications in the field of *** evidence indicates promising prospects for the use of terahertz spectroscopy and terahertz imaging techniques in the diagnosis of amyloid disease,cerebrovascular disease,glioma,psychiatric disease,traumatic brain injury,and myelin *** vitro and animal experiments have also demonstrated the potential therapeutic value of terahertz technology in some neuropsychiatric *** the precise underlying mechanism of the interactions between terahertz electromagnetic waves and the biosystem is not yet fully understood,the research progress in this field shows great potential for biomedical noninvasive diagnostic and therapeutic ***,the biosafety of terahertz radiation requires further exploration regarding its two-sided efficacy in practical *** review demonstrates that terahertz biotechnology has the potential to be a promising method in the field of neuropsychiatry based on its unique advantages.

关键词： biological effect brain neuron neuropsychiatry neuroscience non-thermal effect terahertz imaging terahertz radiation terahertz spectroscopy terahertz technology

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Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

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Neural Regeneration Research 2025年第1期20卷 93-106页

作者： Yujie Yang Xinyi Li Jiaying Lu Jingjie Ge Mingjia Chen Ruixin Yao Mei Tian Jian Wang Fengtao Liu Chuantao Zuo Key Laboratory of Arrhythmias Ministry of EducationDepartment of Medical GeneticsShanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina Department of Neurology National Research Center for Aging and MedicineNational Center for Neurological Disordersand State Key Laboratory of Medical NeurobiologyHuashan HospitalFudan UniversityShanghaiChina Department of Nuclear Medicine&PET Center National Center for Neurological Disordersand National Clinical Research Center for Aging and MedicineHuashan HospitalFudan UniversityShanghaiChina International Human Phenome institutes(shanghai) ShanghaiChina Human Phenome Institute Fudan UniversityShanghaiChina

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of *** review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest *** conducted a thorough literature search using reputable databases such as PubMed and Web of *** criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical *** findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting ***,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo *** validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic *** summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

关键词： aromatic amino acid decarboxylase brain imaging dopamine transporter Parkinson’s disease parkinsonism positron emission tomography presynaptic dopaminergic function vesicle monoamine transporter type 2

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Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage

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Neural Regeneration Research 2025年第4期20卷 1015-1030页

作者： Ruoyu Huang Qiuyu Pang Lexin Zheng Jiaxi Lin Hanxi Li Lingbo Wan Tao Wang Department of Forensic science School of Basic Medicine and Biological SciencesSuzhou Medicine College of Soochow UniversitySuzhouJiangsu ProvinceChina

Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and *** plays a key role in the establishment and maintenance of the central nervous *** brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and *** brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental ***,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system *** hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and *** cholesterol levels are associated with the risk of intracerebral ***,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell *** cholesterol accumulation in the brain has been found after intracerebral *** this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell *** also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

关键词： cell death cholesterol metabolism intracerebral hemorrhage myelination therapeutic target

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Protein arginine methyltransferase-6 regulates heterogeneous nuclear ribonucleoprotein-F expression and is a potential target for the treatment of neuropathic pain

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Neural Regeneration Research 2025年第9期20卷 2682-2696页

作者： Xiaoyu Zhang Yuqi Liu Fangxia Xu Chengcheng Zhou Kaimei Lu Bin Fang Lijuan Wang Lina Huang Zifeng Xu Department of Anesthesiology International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Anesthesiology Shanghai General HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina shanghai Key Laboratory of Embryo Original Diseases ShanghaiChina

Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal ***,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this *** this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic *** results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer *** addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain ***,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 ***,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was ***,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ***,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 *** findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.

关键词： dorsal root ganglion heterogeneous nuclear ribonucleoprotein F neuropathic pain protein arginine methyltransferase-6 sensory neurons

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ImSpiRE: image feature-aided spatial resolution enhancement method

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science China Life sciences 2025年第1期68卷 272-283页

作者： Yuwei Hua Yizhi Zhang Zhenming Guo Shan Bian Yong Zhang State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center Institute for Regenerative MedicineDepartment of NeurosurgeryShanghai East HospitalShanghai Key Laboratory of Signaling and Disease ResearchFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji University

The resolution of most spatially resolved transcriptomic technologies usually cannot attain the single-cell level, limiting their applications in biological discoveries. Here, we introduce ImSpiRE, an image feature-aided spatial resolution enhancement method for in situ capturing spatial transcriptome. Taking the information stored in histological images, ImSpiRE solves an optimal transport problem to redistribute the expression profiles of spots to construct new transcriptional profiles with enhanced resolution, together with extending the gene expression profiles into unmeasured regions. Applications to multiple datasets confirm that ImSpiRE can enhance spatial resolution to the subspot level while contributing to the discovery of tissue domains, signaling communication patterns, and spatiotemporal characterization.

关键词： spatial transcriptome histological images spatial resolution enhancement

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Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder

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Neural Regeneration Research 2025年第6期20卷 1541-1554页

作者： Jinmei Ye Cong Duan Jiaxin Han Jinrong Chen Ning Sun Yuan Li Tifei Yuan Daihui Peng Division of Mood Disorder Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina Department of Psychiatry First Hospital of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina shanghai Key Laboratory of Psychotic Disorders Brain Health InstituteNational Center for Mental DisordersShanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina Co-Innovation Center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

关键词： biomarker cytokine exosomes inflammasome major depressive disorder microglia mitochondrial DNA mitochondrial dysfunction neuroinflammation Toll-like receptor

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Celebrating the 2-Year-Birthday of science Bulletin

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science Bulletin 2017年第1期62卷 1-2页

作者： Xiao-Ya Chen science Bulletin shanghai institutes for biological sciences Chinese Academy of Sciences

2017 is definitely a remarkable year for science Bulletin(Sci Bull).Since being re-launched as Sci Bull in January 2015,the journal has had an excellent first two years and has already started to establish itself as a leading comprehensive journal for the natural *** year,Journal Citation Report will publish Sci Bull’s first official Impact *** issue of Sci Bull marks its 3rd year of *** journal deserves celebration because it has made significant

关键词：《科学》杂志通报自然科学影响因素公牛期刊

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GABA transporter 1 transcriptional starting site exhibiting tissue specific difference

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Cell Research 2001年第2期11卷 161-163页

作者： JIN XIAO PING, FANG HUANG, NA YANG, BU FENG LU, JIAN FEI, LI HE GUO Institute of Biochemistry and Cell Biology, shanghai institutes for biological science, Chinese Academy of sciences, 320 Yueyang Road, shanghai 200031, China Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Science Chinese Academy of Sciences Shanghai China

GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address the question, first, 5’ Rapid amplification of cDNA end (RACE) was used to determine GAT1 transcriptional starting sites in neonatal mouse cerebral cortex and intestine, adult mouse brain and adult rat testis. The products of 5’RACE were confirmed by DNA sequencing. We found that the transcript of GAT1 in neonatal mouse cerebral cortex and adult mouse brain starts at the same site (inside of exon 1), while in mouse intestine, GAT1 starts transcription in intron 1, and in rat testis, the transcript of GAT1 has an additional untranslation exon to the 5’ direction.

关键词： GABA transporter 1(GAT1) transcriptional starting site 5’ RACE tissue spedcific difference DNA sequencing.

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Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury

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Acta Pharmacologica Sinica 2005年第3期26卷 315-322页

作者： Hai-lei DING~2 Hai-feng ZHU~2 Jian-wen DONG~2 Wei-zhong ZHU~2 Wei-wei YANG~3 Huang-tian YANG~3 Zhao-nian ZHOU~(2,4)2 Physiological Laboratory of Hypoxia,shanghai institutes for biological sciences,Chinese Academy of sciences,shanghai 200031,China 3 Laboratory of Molecular Cardiology,Health science Center,shanghai institutes for biological sciences,Chinese Academy of sciences and shanghai Second Medical University,shanghai 200025,China Physiological Laboratory of Hypoxia Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China Laboratory of Molecular Cardiology Health Science Center Shanghai Institutes for Biological Sciences Chinese Academy of Sciences and Shanghai Second Medical University Shanghai China

Aim:To investigate the role of inducible nitric oxide synthase (iNOS)-derivednitric oxide (NO) in the cardioprotection of intermittent hypoxia (IH) against is-chemia/reperfusion (I/R) ***:Langendorff-perfused isolated rathearts were used to measure variables of left ventricular function during baselineperfusion,ischemia,and reperfusion *** plus nitrite (NOx) content inmyocardium was measured using a biochemical method,iNOS mRNA and pro-tein expression in rat left ventricles were detected using reverse transcription poly-merase chain reaction (RT-PCR) and Western blot,***:Myo-cardial function recovered better in IH rat hearts than in normoxic control *** iNOS-selective inhibitor aminoguanidine (AG) (100μmol/L) significantlyinhibited the protective effects of IH,but had no influence on normoxic rat *** baseline content of NOx in IH hearts was higher than that in normoxic *** 30 min ischemia,the NOx level in normoxic hearts increased compared tothe corresponding baseline level,whereas there was no significant change in ***,the NOx level in IH hearts was still higher than that of normoxichearts during ischemia and reperfusion *** 100μmol/L significantly di-minished the NOx content in IH and normoxic hearts during ischemia and *** baseline levels of iNOS mRNA and protein in IH hearts were higherthan those of normoxic *** to the corresponding baseline level,iNOS mRNA and protein levels in normoxic rat hearts increased and those in IH rathearts decreased after *** addition of AG 100μmol/L significantlydecreased iNOS mRNA and protein expression in IH rat hearts after I/***:IH upregulated the baseline level of iNOS mRNA and protein expres-sion leading to an increase in NO production,which may play an important role inthe cardiac protection of IH against I/R injury.

关键词： intermittent hypoxia ischemia/reperfusion inducible nitric oxide synthase aminoguanidine: rats

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