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Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

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Acta Pharmaceutica Sinica B 2024年第2期14卷 821-835页

作者： Liping Bai Jin Yang Siting Yu Zhongzheng Xiang Yuanyuan Zeng Meiling Shen Xiaorong Kou Qinjie Wu Changyang Gong Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Radiotherapy(RT) can potentially induce systemic immune responses by initiating immunogenic cell death(ICD) of tumor cells.However,RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases.Herein,we construct multifunctional self-sufficient nanoparticles(MARS) with dual-enzyme activity(GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse.In addition to limiting the Warburg effect to actualize starvation therapy,MARS catalyzes glucose to produce hydrogen peroxide(H_(2)O_(2)),which is then used in the Cu^(+)-mediated Fenton-like reaction and RT sensitization.RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms,which have a robust ICD impact on mobilizing the immune system.Thus,when MARS is combined with RT,potent systemic antitumor immunity can be generated by activating antigen-presenting cells,promoting dendritic cells maturation,increasing the infiltration of cytotoxic T lymphocytes,and reprogramming the immuno suppre ssive tumor microenvironment.Furthermore,the synergistic therapy of RT and MARS effectively suppresses local tumor growth,increases mouse longevity,and results in a 90% reduction in lung metastasis and postoperative recurrence.Overall,we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

关键词： Dual-enzyme activity Radiotherapy Chemodynamic therapy Fenton-likereaction Radical storms Immunogeniccell death Tumormicroenvironment Systemicimmunity

Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu Yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting Niu Department of Hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for MM.To further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome 1q21.Given the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and efficacy.Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression.Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering

Carcinoembryonic antigen in the diagnosis,treatment,and follow-up of focal liver lesions

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World Journal of Gastrointestinal Surgery 2024年第4期16卷 999-1007页

作者： Osman Nuri Dilek Dilaraİrem Arslan Kahraman Gökhan Kahraman Department of Surgery İzmir Katip Celebi UniversitySchool of Medicineİzmir 35150Turkey Department of Patology Merzifon KMP State HospitalAmasya 5300Turkey Department of Radiology Suluova State HospitalAmasya 5500Turkey

In this editorial review,we comment on the article published in the recent issue of the World Journal of Gastrointestinal Surgery.Carcinoembryonic antigen(CEA)is a fetal glycoprotein and can be secreted in very small amounts from healthy adults after birth.CEA is widely used not only for diagnostic tumor markers but also importantly for the management of some gastrointestinal tumors.The most common clinical use is surveillance for the monitoring of colorectal carcinoma.However,CEA can become elevated in several malign or benign characterized pathologies.Serum CEA level may vary depending on the location of the lesion,whether it metastasizes or not,and its histopathological characteristics.It has been determined that cases with high preoperative CEA have a more aggressive course and the risk of metastasis to the lymph tissue and liver increases.In this editorial review,we focused on evaluating the role of CEA in clinical practice with a holistic approach,including the diagnostic and prognostic significance of CEA in patients with focal liver lesions,the role of CEA in follow-up after definitive surgery,and also hepatic resection for metastasis,and the management of all patients with raised CEA.

关键词： Carcinoembriyonic antigen Liver Focal liver lesions Metastasis Surgery Prognosis Surveillance

General anesthetic agents induce neurotoxicity through astrocytes

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Neural Regeneration Research 2024年第6期19卷 1299-1307页

作者： Yanchang Yang Tiantian Liu Jun Li Dandan Yan Yuhan Hu Pin Wu Fuquan Fang Patrick M.McQuillan Wenxin Hang Jianhang Leng Zhiyong Hu Department of Anesthesiology The First Affiliated Hospital Zhejiang University School of Medicine Department of Anesthesiology Ningbo Women and Children's Hospital 3. Department of Anesthesiology Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College 4. Cell Biology Department Yale University 5. Department of Anesthesiology Penn State Hershey Medical Centre Penn State College of Medicine 6. Department of Central Laboratory Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine

Neuroscientists have recognized the importance of astrocytes in regulating neurological function and their influence on the release of glial transmitters. Few studies, however, have focused on the effects of general anesthetic agents on neuroglia or astrocytes. Astrocytes can also be an important target of general anesthetic agents as they exert not only sedative, analgesic, and amnesic effects but also mediate general anesthetic-induced neurotoxicity and postoperative cognitive dysfunction. Here, we analyzed recent advances in understanding the mechanism of general anesthetic agents on astrocytes, and found that exposure to general anesthetic agents will destroy the morphology and proliferation of astrocytes, in addition to acting on the receptors on their surface, which not only affect Ca2+signaling, inhibit the release of brain-derived neurotrophic factor and lactate from astrocytes, but are even involved in the regulation of the pro-and anti-inflammatory processes of astrocytes. These would obviously affect the communication between astrocytes as well as between astrocytes and neighboring neurons, other neuroglia, and vascular cells. In this review, we summarize how general anesthetic agents act on neurons via astrocytes, and explore potential mechanisms of action of general anesthetic agents on the nervous system. We hope that this review will provide a new direction for mitigating the neurotoxicity of general anesthetic agents.

关键词： astrocytes brain-derived neurotrophic factor general anesthetic agents N-methyl-D-aspartate receptor neuron neurotoxicity perioperative neurocognition Toll-like receptor γ-aminobutyric acid receptor

Tributyltin causes generational neurodevelopmental toxicity and the protective effect of folic acid in zebrafish

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Journal of Environmental Sciences 2024年第3期137卷 615-625页

作者： Haoxing Cai Naying Zheng Chen Tang Yuxuan Zhang Zhenghong Zuo Chengyong He state Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiang’an Hospital of Xiamen UniversityXiamen UniversityXiamen 361005China

Tributyltin(TBT),a common organotin environmental pollutant,may pose a threat to human development during critical early-life periods.We aimed to assess the neurodevelopmental intergenerational toxicity of early-life exposure to TBT and the protective effect of DNA methyl donor folic acid(FA).Specifically,after early-life exposure(1–21 days postfertilization,dpf)to TBT(0,1,10 and 100 ng/L),zebrafish(Danio rerio)were cultured in clean medium until sexual maturity.The exposed females were mated with unexposed males to produce embryos(F1).The F1 generation were cultured(4–120 hours post-fertilization,hpf)with and without 1 mmol/L FA.The neurotoxic effects of early-life TBT exposure for zebrafish and their offspring(F1)were significantly enhanced anxiety and reduced aggression,decreased gene expression of DNA methyltransferase in the brain and increased serotonin levels in the body.Moreover,the intergenerational neurodevelopmental toxicity,as manifested in the F1 generation,was attenuated by FA supplementation.In summary,early-life TBT exposure led to intergenerational neurodevelopmental deficits in zebrafish,and DNA methyl donors had a protective effect on F1 neurodevelopment,which can inform the prevention and treatment of intergenerational neurotoxicity due to organotin pollutants.

关键词： Tributyltin Neurodevelopment Intergeneration DNA methylation Folic acid Zebrafish

Increased N6-methyladenosine is related to the promotion of the methyltransferase METTL14 in ovarian aging

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Genes & Diseases 2024年第3期11卷 151-154页

作者： Chunfeng Qian Zhenxing Liu Yonghong Qian Jie Ding Rulei Chen Han Su Minghong Shen Hong Li Boxian Huang state Key Laboratory of Reproductive Medicine and Offspring Health Suzhou Affliated Hospital of Nanjing Medicine and Offspring HealthSuzhou Affiliated Hospital of Nanjing Medical UniversitySuzhouMunicipal HospitalGusu SchoolNanjing Medical UniversitySuzhouJiangsu 215002China Department of Gynecology Affliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu School of Nanjing Medical UniversitySuzhouJiangsu 215002China Department of Pathology Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu School of Nanjing Medical UniversitySuzhouJiangsu 215002China

The ovary is a vital female reproductive organ that functions to produce oocyte gametes and cyclically expressed sex hormones to maintain reproductive capacity and hormone homeostasis.Ovarian aging,characterized by declines in follicle quantity and oocyte quality,leads to premature ovarian failure,premature ovarian insufficiency,or diminished ovarian reserve,thus contributing to female infertility.Distinct gene-expression signatures from RNA transcriptional level and post-transcriptional regulation are relative to oocyte quality and reproductive age.

关键词： promotion signature maintain

RNF187 governs the maintenance of mouseGC-2 cell development by facilitating histone H3ubiquitination at K57/80

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Asian Journal of Andrology 2024年第3期26卷 272-281页

作者： Bing-Ya Xu Xiang-Ling Yu Wen-Xin Gao Ting-Ting Gao Hao-Yue Hu Tian-Tian Wu Cong Shen Xiao-Yan Huang Bo Zheng Yi-Bo Wu Human Reproductive and Genetic Center Affiliated Hospital of Jiangnan UniversityWuxi 214122China state Key Laboratory of Reproductive Medicine Department ofHistology and EmbryologySchool of Basic Medical SciencesNanjing Medical UniversityNanjing 211166China Changzhou Maternal and Child Health Care hospital Changzhou Medical CenterNanjing Medical UniversityChangzhou 213000China state Key Laboratory of Reproductive Medicine Center for Reproduction andGeneticsSuzhou Municipal HospitalThe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversitySuzhou 215002China.

RING finger 187(RNF187),a ubiquitin-ligating(E3)enzyme,plays a crucial role in the proliferation of cancer cells.However,it remains unclear whether RNF187 exhibits comparable functionality in the development of germline cells.To investigate thepotential involvement of RNF187 in germ cell development,we conducted interference and overexpression assays using GC-2 cells,a mouse spermatocyte-derived cell line.Our findings reveal that the interaction between RNF187 and histone H3 increases theviability,proliferation,and migratory capacity of GC-2 cells.Moreover,we provide evidence demonstrating that RNF187 interactswith H3 and mediates the ubiquitination of H3 at lysine 57(K57)or lysine 80(K80),directly or indirectly resulting in increasedcellular transcription.This is a study to report the role of RNF187 in maintaining the development of GC-2 cells by mediatinghistone H3 ubiquitination,thus highlighting the involvement of the K57 and K80 residues of H3 in the epistatic regulation of genetranscription.These discoveries provide a new theoretical foundation for further comprehensive investigations into the functionof RNF187 in the reproductive system.

关键词： GC-2 cell histone H3 RNF187 ubiquitination

Targeted drug approvals in 2023:breakthroughs by the FDA and NMPA

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Signal Transduction and Targeted Therapy 2024年第3期9卷 813-821页

作者： Lang Zheng Wenjing Wang Qiu Sun Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China Medical Publishers West China HospitalSichuan UniversityChengdu 610041China

According to the official website of China’s National Medicines and Pharmaceutical Administration(NMPA),a total of 87 novel drugs were approved in China in 2023,with targeted drugs accounting for 67.8%of the total,amounting to 59 drugs(Fig.1a;Table 1)[https://***/yaopin/ypjgdt/index.html].Notably,domestic innovation is flourishing,with five first-in-class drugs,including Glumetinib,a c-Met inhibitor from Haihe Biopharma;Leritrelvir,a 3CL protease inhibitor from Raynovent;Anaprazole,a proton pump inhibitor from Xuanzhu Biopharm;Pegol-Sihematide,an EPO drug from Hansoh Pharma;and Zuberitamab from BioRay Biopharmaceutical Co.,Ltd.Additionally,the world’s first allosteric inhibitor targeting TYK2,Sotyktu(deucravacitinib),has been approved for the treatment of psoriasis and Selumetinib,a MEK inhibitor co-developed by AstraZeneca and Merck Sharp&Dohme(MSD),became the first approved drug in China for the treatment of neurofibromatosis type I(NF1).Beyond these drugs,the approval of novel drug types such as CAR-T cell products,siRNA,monoclonal antibodies,dual antibodies,and ADCs in China is a significant development in the country’s pharmaceutical industry(Fig.1a).

关键词： drugs Merck approval

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy

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Chinese Journal of Natural Medicines 2024年第2期22卷 127-136页

作者： WANG Wei LIU Lijuan YANG Zhuo LU Chuanjian TU Pengfei ZHAO Ruizhi ZENG Kewu state Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China state Key Laboratory of Dampness Syndrome of Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510006China

Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.

关键词： Psoriasis Optimized Yinxieling Formula(OYF) FUS protein Molecular targets Affinity-purified strategy