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Activation of NRF2 by celastrol increases antioxidant functions and prevents the progression of osteoarthritis in mice

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Chinese Journal of Natural Medicines 2024年第2期22卷 137-145页

作者： LIU Mingming GUO Jiatian ZHAO Jing LI Hongye FENG Xiaoxiao LIU Haojun ZHANG Hao JIA Xuejun WEI Rushuai LI Fang CHEN Chong HOU Mingzhuang LV Nanning XU Haiyan Department of human anatomy Xuzhou Medical UniversityXuzhou 221004China Department of Orthopedic Surgery The Affiliated Lianyungang Clinical College of Xuzhou Medical University(The Second People’s Hospital of Lianyungang)Lianyungang 222003China Department of Orthopaedics The First Afliated Hospital of Soochow UniversitySoochow UniversitySuzhou 215006China institute of Hematology Xuzhou Medical UniversityXuzhou 221004China

Excessive oxidative stress impairs cartilage matrix metabolism balance,significantly contributing to osteoarthritis(OA)development.Celastrol(CSL),a drug derived from Tripterygium wilfordii,has recognized applications in the treatment of cancer and immune system disorders,yet its antioxidative stress mechanisms in OA remain underexplored.This study aimed to substantiate CSL’s chondroprotective effects and unravel its underlying mechanisms.We investigated CSL’s impact on chondrocytes under both normal and inflammatory conditions.In vitro,CSL mitigated interleukin(IL)-1β-induced activation of proteinases and promoted cartilage extracellular matrix(ECM)synthesis.In vivo,intra-articular injection of CSL ameliorated cartilage degeneration and mitigated subchondral bone lesions in OA mice.Mechanistically,it was found that inhibiting nuclear factor erythroid 2-related factor 2(NRF2)abrogated CSL-mediated antioxidative functions and exacerbated the progression of OA.This study is the first to elucidate the role of CSL in the treatment of OA through the activation of NRF2,offering a novel therapeutic avenue for arthritis therapy.

关键词： Osteoarthritis Celastrol Articular cartilage Extracellular matrix NRF2

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Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance

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Science China(Life Sciences) 2024年第7期67卷 1413-1426页

作者： Xueyan Chen Weilin Wu Ji-Hak Jeong Matjaz Rokavec Rui Wei Shaolong Feng Werner Schroth Hiltrud Brauch Shangwei Zhong Jun-Li Luo Department of Oncology Xiangya HospitalCentral South UniversityChangsha 410008China Department of Molecular Medicine The Scripps Research InstituteJupiter 33458USA Dr.Margarete Fischer-Bosch-institute of Clinical Pharmacology Stuttgart 70376Germany iFIT Cluster of Excellence University of TübingenTübingen 72074Germany The Cancer Research institute and the second Affiliated Hospital Henyang Medical SchoolUniversity of South ChinaHengyang 421001China National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care HospitalChangsha 410008China

Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive(ER+)breast cancer.However,the efficacy of agents such as tamoxifen(Tam)is often compromised by the development of resistance.Here we report that cytokines-activated nuclear IKKαconfers Tam resistance to ER+breast cancer by inducing the expression of FAT10,and that the expression of FAT10 and nuclear IKKαin primary ER+human breast cancer was correlated with lymphotoxinβ(LTB)expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam.IKKαactivation or enforced FAT10 expression promotes Tam-resistance while loss of IKKαor FAT10 augments Tam sensitivity.The induction of FAT10 by IKKαis mediated by the transcription factor Pax5,and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKαattenuates p53-directed repression of FAT10.Thus,our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+breast cancer.

关键词： nuclear IKKα breast cancer Tam-resistance FAT10 Pax5 lymphotoxin nuclear IKKα-FAT0 pathway

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Crustal and uppermost mantle structure of the northeastern Qinghai-Xizang Plateau from joint inversion of surface wave dispersions and receiver functions with P velocity constraints

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Earthquake Science 2024年第2期37卷 93-106页

作者： Pei Zhang Xiaodong Song Jiangtao Li Xingchen Wang Xuezhen Zhang institute of Geophysics China Earthquake AdministrationBeijing 100081China The second Monitoring and Application Center China Earthquake AdministrationXi'an 710054China institute of Theoretical and Applied Geophysics School of Earth and Space SciencesPeking UniversityBeijing 100871China Department of Geophysics School of Geodesy and GeomaticsWuhan UniversityWuhan 430079China

Lithospheric structure beneath the northeastern Qinghai-Xizang Plateau is of vital significance for studying the geodynamic processes of crustal thickening and expansion of the Qinghai-Xizang Plateau. We conducted a joint inversion of receiver functions and surface wave dispersions with P-wave velocity constraints using data from the Chin Array Ⅱ temporary stations deployed across the Qinghai-Xizang Plateau. Prior to joint inversion, we applied the H-κ-c method(Li JT et al., 2019) to the receiver function data in order to correct for the back-azimuthal variations in the arrival times of Ps phases and crustal multiples caused by crustal anisotropy and dipping interfaces. High-resolution images of vS, crustal thickness, and vP/vSstructures in the Qinghai-Xizang Plateau were simultaneously derived from the joint inversion. The seismic images reveal that crustal thickness decreases outward from the Qinghai-Xizang Plateau. The stable interiors of the Ordos and Alxa blocks exhibited higher velocities and lower crustal vP/vSratios. While, lower velocities and higher vP/vSratios were observed beneath the Qilian Orogen and Songpan-Ganzi terrane(SPGZ), which are geologically active and mechanically weak, especially in the mid-lower crust.Delamination or thermal erosion of the lithosphere triggered by hot asthenospheric flow contributes to the observed uppermost mantle low-velocity zones(LVZs) in the SPGZ. The crustal thickness, vS, and vP/vSratios suggest that whole lithospheric shortening is a plausible mechanism for crustal thickening in the Qinghai-Xizang Plateau, supporting the idea of coupled lithospheric-scale deformation in this region.

关键词： joint inversion receiver functions surface waves crustal thickness vP/vS ratio NE Qinghai-Xizang Plateau

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Immunoglobulin G-mediated food intolerance and metabolic syndrome influence the occurrence of reflux esophagitis in Helicobacter pylori-infected patients

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World Journal of Gastroenterology 2024年第8期30卷 855-862页

作者： Li-Hui Wang Bin-Bin Su Sheng-Shu Wang Guan-Chao Sun Kun-Ming Lv Yi Li Hui Shi Qian-Qian Chen College Chinese PLA General HospitalBeijing 100853China Department of Gastroenterology Second Medical Center of Chinese PLA General HospitalBeijing 100853China institute of Geriatrics The 2nd Medical CenterBeijing Key Laboratory of Aging and GeriatricsNational Clinical Research Center for Geriatrics DiseasesSecond Medical Center of Chinese PLA General HospitalBeijing 100853China Department of Gastroenterology First Medical Center of Chinese PLA General HospitalBeijing 100853China

BACKGROUND Reflux esophagitis has an increasing prevalence and complex and diverse symptoms.Identifying its risk factors is crucial to understanding the etiology,prevention,and management of the disease.The occurrence of reflux esophagitis may be associated with food reactions,Helicobacter pylori(H.pylori)infection,and metabolic syndromes.AIM To investigate the risk factors for reflux esophagitis and analyze the effects of immunoglobulin(Ig)G-mediated food intolerance,H.pylori infection,and metabolic syndrome on reflux esophagitis.METHODS Outpatients attending the second Medical Center of the PLA General Hospital between 2017 and 2021 were retrospectively enrolled.The patients’basic information,test results,gastroscopy results,H.pylori test results,and IgG-mediated food intolerance results were collected.Multivariate logistic regression analysis was used to analyze risk factors for reflux esophagitis.Statistical mediation analysis was used to evaluate the effects of IgG-mediated food intolerance and metabolic syndrome on H.pylori infection affecting reflux esophagitis.RESULTS A total of 7954 outpatients were included;the prevalence of reflux esophagitis,IgG-mediated food intolerance,H.pylori infection,and metabolic syndrome were 20.84%,61.77%,35.91%,and 60.15%,respectively.Multivariate analysis showed that the independent risk factors for reflux esophagitis included IgG-mediated food intolerance(OR=1.688,95%CI:1.497-1.903,P<0.00001)and metabolic syndrome(OR=1.165,95%CI:1.030-1.317,P=0.01484),and the independent protective factor for reflux esophagitis was H.pylori infection(OR=0.400,95%CI:0.351-0.456,P<0.00001).IgG-mediated food intolerance had a partially positive mediating effect on H.pylori infection as it was associated with reduced occurrence of reflux esophagitis(P=0.0200).Metabolic syndrome had a partially negative mediating effect on H.pylori infection and reduced the occurrence of reflux esophagitis(P=0.0220).CONCLUSION Patients with IgG-mediated food intolerance and metabolic syndrome were at higher ris

关键词： Gastroesophageal reflux Esophagitis Food intolerance Metabolic syndrome Helicobacter pylori Chemokines

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Protein neddylation and its role in health and diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1869-1904页

作者： Shizhen Zhang Qing Yu Zhijian Li Yongchao Zhao Yi Sun Department of Breast Surgery the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Cancer institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China institute of Translational Medicine Zhejiang University School of MedicineHangzhou 310029China Department of Thyroid Surgery Zhejiang Cancer HospitalInstitute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou 310022China Key Laboratory of Head&Neck Cancer Translational Research of Zhejiang Province Hangzhou 310022China Department of Hepatobiliary and Pancreatic Surgery Zhejiang University School of MedicineHangzhou 310029China Zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China Zhejiang University Cancer Center Hangzhou 310029China Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang Hangzhou 310024China Research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin proteins.Neddylation of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular localization.Significantly,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among others.Thus,targeting neddylation becomes an attractive strategy for the treatment of these diseases.In this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates.We further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach.Finally,few perspectives were proposed for extensive future investigations.

关键词： NEDD8 attached attractive

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Cardiovascular disease burden in patients with urological cancers:The new discipline of uro-cardio-oncology

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Cancer Innovation 2024年第2期3卷 28-44页

作者： Yi Zheng Ying Liu Ziliang Chen Yunpeng Zhang Zuo Qi Ning Wu Zhiqiang Zhao Gary Tse Yong Wang Hailong Hu Yuanjie Niu Tong Liu Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease Department of CardiologyTianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinChina School of Nursing and Health Studies Hong Kong Metropolitan UniversityHong KongChina

Cancer remains a major cause of mortality worldwide,and urological cancers are the most common cancers among men.Several therapeutic agents have been used to treat urological cancer,leading to improved survival for patients.However,this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications.Here,we propose the novel discipline of uro-cardio-oncology,an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer.In this comprehensive review,we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers,including androgen deprivation therapy,vascular endothelial growth factor receptor tyrosine kinase inhibitors,immune checkpoint inhibitors,and chemotherapeutics.In addition,we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance,diagnosis,and effective management of cardiovascular complications.Finally,we provide an analysis of future perspectives in this emerging specialty,identifying areas in need of further research.

关键词： anticancer therapy cardiovascular toxicity mechanism multidisciplinary management urological cancer

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Influencing Factors of Healthy Aging Risk Assessed Using Biomarkers:A Life Course Perspective

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China CDC weekly 2024年第11期6卷 219-224,I0014-I0017页

作者： Cedric Zhang Bo Lua Yajie Gao Jinming Li Xingqi Cao Xinwei Lyu Yinuo Tu Shuyi Jin Zuyun Liu Center for Clinical Big Data and Analytics of the second Affiliated Hospital and Department of Big Data in Health Science School of Public Healththe Key Laboratory of Intelligent Preventive Medicine of Zhejiang ProvinceZhejiang University School of MedicineHangzhou CityZhejiang ProvinceChina institute of Epidemiology and Health Care University College LondonLondonUK College of Chemical and Biological Engineering Zhejiang UniversityHangzhou CityZhejiang ProvinceChina

Assessing individual risks of healthy aging using biomarkers and identifying associated factors have become important areas of research.In this study,we conducted a literature review of relevant publications between 2018 and 2023 in both Chinese and English databases.Previous studies have predominantly used single biomarkers,such as C-reactive protein,or focused on specific life course stages and factors such as socioeconomic status,mental health,educational levels,and unhealthy lifestyles.By summarizing the progress in this field,our study provides valuable insights and future directions for promoting healthy aging from a life course perspective.

关键词： such insight directions

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Nucleus-targeting orange-emissive carbon dots delivery adriamycin for enhanced anti-liver cancer therapy

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Chinese Chemical Letters 2024年第6期35卷 421-426页

作者： Qiang Li Jiangbo Fan Hongkai Mu Lin Chen Yongzhen Yang Shiping Yu The second Hospital of Shanxi Medical University Taiyuan 030001China Shanxi Medical University Taiyuan 030001China Key Laboratory of Interface Science and Engineering in Advanced Materials Ministry of EducationTaiyuan University of TechnologyTaiyuan 030024China Shanxi-Zheda institute of Advanced Materials and Chemical Engineering Taiyuan 030032China

Carbon dots(CDs)with precise targeting function show great potential in the field of drug delivery therapeutics.In this study,the functionalized nucleus-targeting orange-emissive CDs with nuclear localization sequence(NLS)were loaded with adriamycin(DOX)to obtain a nucleus-targeting orange-emissive CDs drug delivery system(CDs-NLS-DOX),which delivered DOX to tumor cell nuclei to enhance its anti-tumor activity.The drug carrier orange-emissive CDs showed excitation-independent behavior,stable and enhanced imaging capability and good biocompatibility in vitro and in vivo.Meanwhile,the CDs-NLS could target the nuclei efficiently,and the CDs-NLS-DOX complexes had a high drug loading rate(59.4%)after loading DOX,exhibiting p H-dependent DOX release behavior through breaking acylhydrazone bond in a weak acidic environment.In addition,the CDs-NLS-DOX complexes exhibited an enhanced killing activity against human hepatoma cells(HepG2).The in vivo therapeutic effects on HepG2 nude mice transplanted tumors indicated the CDs-NLS-DOX had a stronger ability to inhibit tumor growth compared to free DOX.In short,CDs-NLS-DOX is expected to be a precise and efficient nucleus-targeting nano-drug delivery system for tumor treatment.

关键词： Carbon dots Nucleus-targeting Adriamycin Drug delivery system Liver cancer therapy

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3'-Deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome

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Neural Regeneration Research 2024年第10期19卷 2270-2280页

作者： Yize Qi Yao Zhou Jiyang Li Fangyuan Zhu Gengni Guo Can Wang Man Yu Yijie Wang Tengfei Ma Shanwu Feng Li Zhou institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular&Cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjingJiangsu ProvinceChina Department of Anesthesiology The Second People’s Hospital of LianyungangLianyungangJiangsu ProvinceChina Department of Anesthesiology Women’s Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health Care HospitalNanjingJiangsu ProvinceChina

Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3(NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.

关键词： 3′-deoxyadenosin hippocampus long-term potentiation methamphetamine NOD-like receptor family pyrin domain containing-3(NLRP3)inflammasome synaptic plasticity

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Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

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Signal Transduction and Targeted Therapy 2024年第1期9卷 259-270页

作者： Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-Zhu Lyu Bing Zhang Kai-Wen Liu Na Li Jia-Chen Cui Guang-Xiang Huang Cheng-Lin Liu Jie Xu Jian-Qing Mi Zhu Chen Xiao-Hu Fan Sai-Juan Chen Shuo Chen Shanghai institute of Hematology National Research Center for Translational MedicineState Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Hematology Second Hospital of Dalian Medical UniversityDalian 116023China National Facility for Protein Science Shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Legend Biotech China Nanjing 211112China Shanghai Immune Therapy institute Shanghai Cancer InstituteState Key Laboratory of Oncogenes and Related GenesRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Wondercel Biotechnology Shenzhen 518052China

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关键词： cytotoxicity Antigen elevated

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