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ROS-responsive nanoparticles targeting inflamed colon for synergistic therapy of inflammatory bowel disease via barrier repair and anti-inflammation

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Nano Research 2024年第6期17卷 5409-5423页

作者： Ding Wang Qi Jiang Ruoyu Shen lijun peng Wentao Zhou Tingting Meng Fuqiang Hu Jianwei Wang Hong Yuan College of Pharmaceutical Science Zhejiang UniversityHangzhou 310058China Jinhua Institute of Zhejiang University Jinhua 321299China The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009China

The destruction of the intestinal barrier is likely to cause an increase in intestinal permeability and cause pathological damage.Numerous studies have demonstrated that intestinal barrier function plays an important role in the occurrence and development of inflammatory bowel disease(IBD).Oral administration is the most common route for intestinal diseases.In this study,a synergistic strategy is proposed for IBD management through active barrier repair combined with anti-inflammatory treatment,which can interrupt the pathological process of IBD,resulting in the significantly improved efficacy of existing treatments.Based on the specific pH values and high reactive oxygen species(ROS)levels in inflammatory sites of IBD,an orally administrated ROS-responsive drug delivery system targeting inflamed colon has been designed,and confirmed in vitro and in vivo.The anti-inflammatory drug dexamethasone acetate(Dex)and the barrier function regulator LY294002 are delivered by the synthesized nanocarrier to treat IBD synergistically by inhibiting inflammation and actively repairing the intestinal barrier through tight junctions(TJs).The accumulation of nanocarriers in the inflamed colon and synergistic efficacy has been validated in mice with colitis.In brief,a drug delivery system and a therapeutic strategy for IBD are successfully developed.

关键词： nanotechnology reactive oxygen species(ROS)-responsive targeted delivery inflammatory bowel disease(IBD) intestinal barrier combination treatment

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RNA ac^(4)C modification in cancer biology:from regulatory mechanisms to clinical applications

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Science China(Life Sciences) 2024年第4期67卷 832-835页

作者： lijun Tao Yunqing Lu Zhuojia Chen Lichen Ge Junming He Jianxin peng Hongsheng Wang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China Department of Hepatobiliary Surgery Guangdong Province Traditional Chinese Medical HospitalGuangzhou 510120China

关键词： clinical (4) modification

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N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA

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National Science Review 2024年第3期11卷 72-91页

作者： Jiawang Zhou Haisheng Zhang Ke Zhong lijun Tao Yu Lin Guoyou Xie Yonghuang Tan You Wu Yunqing Lu Zhuojia Chen Jiexin Li Xin Deng Qin peng Zigang Li Hongsheng Wang Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical Sciences Sun Yat-sen University Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine Department of Biomedical Sciences City University of Hong Kong Institute of Systems and Physical Biology Shenzhen Bay Laboratory

Mitochondria undergo fission and fusion that are critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamics remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer（CRC） cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione（GSH） via the upregulation of RRM2B——a p53-inducible ribonucleotide reductase subunit with anti-reactive oxygen species potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3 UTR of RRM2B increased its m RNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the coding sequence（CDS） of OPA1——an essential GTPase protein for mitochondrial inner membrane fusion——also increased m RNA stability and triggered mitochondria fusion. Targeting m6A through the methyltransferase inhibitor STM2457 or the dm6ACRISPR system significantly suppressed mitochondria fusion. In vivo and clinical data confirmed the positive roles of the m6A/mitochondrial dynamics in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression, which facilitated cancer cell growth and CRC development.

关键词： m6A mitochondrial fusion glutathione OPA1 colorectal cancer

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RNA acC modification in cancer biology: from regulatory mechanisms to clinical applications

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Science China Life Sciences 2024年

作者： lijun Tao Yunqing Lu Zhuojia Chen Lichen Ge Junming He Jianxin peng Hongsheng Wang School of Pharmaceutical Sciences Sun Yat-sen University Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Hepatobiliary Surgery Guangdong Province Traditional Chinese Medical Hospital

RNA modifications are increasingly recognized for their significance in diverse physiological and pathological processes,with over 170 types of chemical modifications having been discovered since the1960s. Among these modifications, N4-acetylcytidine(ac4C) is the first acetylated modification identified on eukaryotic RNAs, previously reported in transfer RNA(tRNA) and ribosomal RNA(rRNA),and subsequently found in messenger RNA(mRNA). At present, the methods reported for detecting ac4C modification encompass borohydride-based Sanger sequencing, LC-MS/HPLC-MS, HPLC-CE,acRIP-seq, affinity reagents in vitro transcription(IVT), and more(Jin et al.,2020). The N4 position of cytosine can be acetylated by ac4C “writer”, with Nacetyltransferase 10(NAT10) currently recognized as the sole enzyme responsible for ac4C acetylation. Figure 1 illustrates the biological roles and related mechanisms of ac4C modification in various cancers. Collectively, ac4C modification can regulate various aspects of tumor biology, including proliferation, metastasis, metabolism, drug resistance, ferroptosis and apoptosis, by influencing RNA stability and translation. This ultimately contributes to tumor development.

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Self-oriented central-tumor delivery of legumain-cleavable vehicles governed by circulating monocyte/macrophage for precise tumor enrichment and immune activation

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Nano Research 2023年第4期16卷 5189-5205页

作者： Fangying Yu Xuwei Shang Yun Zhu lijun peng Simin Chen Tingting Meng Hong Yuan Fuqiang Hu College of Pharmaceutical Science Zhejiang UniversityHangzhou 310058China Department of Pharmacy Nanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China

Compressed blood and intratumoral lymphatic vessels induced by proliferated tumor cells and elevated interstitial fluid pressure produce regional hypoxic and necrotic region within tumors,which severely reduced the accessibility of immunogenic cell death(ICD)related drugs and immune-related cells.Herein,the strategy of self-oriented deep tumor delivery by circulating monocyte/macrophage was proposed.Briefly,CS-AI including an indoleamine 2,3-dioxygenase(IDO)inhibitor indoximod(IND)and hydrophilic chitosan(CSO)linked with alanine-alanine-asparagine(AAN)was prepared,which could be selectively cleaved by legumain overexpressed in macrophages and promote the collapse in structure.Then,CS-AI was modified with mannose on the surface and further encapsulated the ICD inducer doxorubicin(DOX)to obtain M-CS-AI/DOX.Upon intravenous injection,MCS-AI/DOX was specially recognized and internalized by circulating monocyte in vivo.The formed drugs/monocyte tend to distribute in hypoxia/necrosis region guided by the homing signals released by tumor.Accumulated monocytes then further differentiated into macrophages,up-regulating the expression of legumain and promoting the sensitive-release of chemo-drug DOX,IND,and the mannose-modified CSO(M-CSO).The released IND would specifically regulate immunosuppressive tumor microenvironment,and synergistically inhibit tumor growth with immune activation elements,ICD-induced DOX,and the favorable adjuvant M-CSO.In summary,the self-oriented deep tumor delivery of legumain-cleavable nanovesicles through circulating monocyte makes it possible for reaching tumor regions inaccessible for nanoparticles and provides a novel insight for precise tumor enrichment and immune activation.

关键词： self-oriented circulating monocyte/macrophage hitchhike legumain-sensitive vehicles precise central-tumor enrichment immune activation

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Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia:targeted immunotherapy for acute lymphoblastic leukemia

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Frontiers of Medicine 2022年第1期16卷 139-149页

作者： Sisi Wang lijun peng Wenqian Xu Yuebo Zhou Ziyan Zhu Yushan Kong Stewart Leung Jin Wang Xiaoqiang Yan Jian-Qing Mi Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Pôle Franco-Chinois de Recherche en Sciences du Vivant et Genomique Shanghai 200025China Shanghai Blood Center Shanghai 200051China Generon Biomed Shanghai 201210China

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.However,several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight,and thus its clinical use is limited.Furthermore,multiple trials have shown that approximately 30%of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells.Here,we design and characterize two novel antibodies,A-319 and A-2019.Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures,and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function.Our in vitro,ex vivo,and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells,enhancing T-cell function,mediating B-cell depletion,and eventually inhibiting tumor growth in Raji xenograft models.The two molecules are complementary in terms of efficacy and specificity profile.The activity of A-319 demonstrated superior to that of A-2019,whereas A-2019 has an additional capability to target CD20 in cells missing CD19,suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia bispecific antibody trispecific antibody CD19 CD20

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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

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Frontiers of Medicine 2022年第3期16卷 442-458页

作者： Mengping Xi Shanshan Guo Caicike Bayin lijun peng Florent Chuffart Ekaterina Bourova-Flin Sophie Rousseaux Saadi Khochbin Jian-Qing Mi Jin Wang Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Pôle de Recherches Sino-Français en Science du Vivant et Génomique Shanghai 200025China CNRS UMR 5309/INSERM U1209/UniversitéGrenoble Alpes/Institute for Advanced Biosciences 38706 La TroncheFrance

T-cell acute lymphoblastic leukemia(T-ALL)is one of the most dangerous hematological malignancies,with high tumor heterogeneity and poor prognosis.More than 60%of T-ALL patients carry NOTCH1 gene mutations,leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways.We found that chidamide,an HDAC inhibitor,exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity.In particular,chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1(NICD1)as well as MYC,partly through their ubiquitination and degradation by the proteasome pathway.We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease(MRD)in patients and is well tolerated.Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients,including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia HDAC inhibitor chidamide NOTCH1 MYC ubiquitination

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大学与科研机构科教融汇协同育人机制建构——基于资源依赖理论的视角

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研究生教育研究 2024年第2期 73-79页

作者：彭莉君中国科学技术大学马克思主义学院合肥230026

科教融汇协同育人机制是面向关键核心技术攻关需求,将科研机构的科研资源全面汇入大学的人才培养资源之中,通过强化教学与科研之间的互动联系共同培养人才,着力提升基础学科拔尖创新人才培养质量和自主培养能力的一项创新机制。研究基... 详细信息

科教融汇协同育人机制是面向关键核心技术攻关需求,将科研机构的科研资源全面汇入大学的人才培养资源之中,通过强化教学与科研之间的互动联系共同培养人才,着力提升基础学科拔尖创新人才培养质量和自主培养能力的一项创新机制。研究基于资源依赖理论的视角,从分析中国科学院大学与中国科学技术大学科教融合协同育人机制出发,探讨了两所大学科教融合协同育人的特点及不足,提出了厘清培养需求、搭建合作关系、提升合作层次、加强顶层设计等建构科教融汇协同育人机制的建议。

关键词：科教融汇科教融合资源依赖理论协同育人

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高阶剪切变形理论下Pasternak地基上FG-CNTRC梁自由振动及屈曲分析

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振动与冲击 2024年第2期43卷 1-11页

作者：杨立军彭林欣陈卫湖南文理学院芙蓉学院湖南常德415000 广西大学土木建筑工程学院南宁530004 南华大学土木工程学院湖南衡阳421001

功能梯度碳纳米管增强复合材料(functionally graded carbon nanotube-reinforced composite,FG-CNTRC)作为新一代先进复合材料,因其优越的力学性能而被研究者们广泛关注。该研究以Pasternak地基上FG-CNTRC梁为研究对象,基于不同高阶剪... 详细信息

功能梯度碳纳米管增强复合材料(functionally graded carbon nanotube-reinforced composite,FG-CNTRC)作为新一代先进复合材料,因其优越的力学性能而被研究者们广泛关注。该研究以Pasternak地基上FG-CNTRC梁为研究对象,基于不同高阶剪切变形理论,将一种具有插值特性的无网格法——稳定移动克里金插值(stabilized moving Kriging interpolation,SMKI)应用于求解Pasternak地基上FG-CNTRC梁的自由振动及屈曲问题。基于稳定移动克里金插值和不同高阶剪切变形理论给出FG-CNTRC梁的位移场,利用Hamilton原理和最小势能原理分别推导了Pasternak地基上FG-CNTRC梁的自由振动和屈曲控制方程。采用MATLAB软件编制了相关程序,将该研究解与解析解或文献解对比,证明了该方法在计算Pasternak地基上FG-CNTRC梁自由振动与屈曲的有效性及准确性。最后,还讨论了不同高阶剪切变形理论、地基系数、碳纳米管体积分数等对其自振频率和屈曲临界荷载的影响。

关键词：功能梯度碳纳米管增强复合材料(FG-CNTRC)梁稳定移动克里金插值(SMKI) 不同高阶剪切变形理论 Pasternak地基自由振动屈曲

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Choledocholithiasis caused by anatomical variation of cystic duct: A case report

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Laparoscopic, Endoscopic and Robotic Surgery 2022年第1期5卷 40-44页

作者： Meng Tong Yumeng Li Xuedi Sun Yingli Wang Shuai Yang Bocheng Zhang Feiyu Jia lijun peng Jinghua Liu Department of General Surgery Jinzhou Medical UniversityJinzhou 121001China Graduate Management Office Education and Teaching DepartmentLinyi People's HospitalLinyi 276000China Department of Gastroenterology Linyi People's HospitalLinyi 276000China Department of Hepatobiliary Surgery Linyi People's HospitalLinyi 276000China Minimally Invasive Institute of Digestive Surgery and Prof.Cai's Laboratory Linyi People's HospitalLinyi 276000China

Laparoscopic cholecystectomy(LC)has gradually become the first choice for the treatment of cholecystolithiasis in recent years.Iatrogenic bile duct injury(IBDI)is an important clinical problem in LC.The anatomical variation of the cystic duct increases the probability of IBDI and the difficulty of operation.We present a case of a 44-year-old male with a anatomical variation of the cystic duct complicated with cholecystolithiasis and choledocholithiasis,who successfully underwent choledocholithotomy,choledochoscopic exploration and T-tube drainage surgery.The patient recovered well and was discharged home on postoperative day 10.The T-tube was removed at 1 month postoperatively after cholangiography examination of no choledocholithiasis left.

关键词： Cholecystolithiasis Choledocholithiasis Anatomical variation of cystic duct Laparoscopic cholecystectomy Choledocholithotomy

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