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In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

Acta Pharmaceutica Sinica B 2024年第5期14卷 2317-2332页

作者： Huijuan Zhang Xiangyang Xuan Yaping Wang Zijun Qi Kexuan Cao Yingmei Tian Chaoqun Wang Junbiao Chang Zhenzhong Zhang Lin Hou School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou 450001China collaborative innovation center of new drug research and safety evaluation Zhengzhou 450001China School of Chemistry and Molecular Engineering Zhengzhou UniversityZhengzhou 450001China

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

关键词： Autophagy Tumor phototherapy Synergistic sensitization HCQ TRANSFERRIN Disulfide bond reconstruction GSH Biomimetic mineralized nano-tellurium

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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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Ceria nanoparticles: biomedical applications and toxicity

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 361-388页

作者： Xiaoxuan FU Peng LI Xi CHEN Yuanyuan MA Rong WANG Wenxuan JI Jiakuo GU Bowen SHENG Yizhou WANG Zhuhong ZHANG School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University)Ministry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China Department of Nephrology Yantai Yuhuangding HospitalQingdao UniversityYantai 264005China Institute of Crop Science College of Agriculture and BiotechnologyZhejiang UniversityHangzhou 310058China

Ceria nanoparticles(CeO_(2) NPs)have become popular materials in biomedical and industrial fields due to their potential applications in anti-oxidation,cancer therapy,photocatalytic degradation of pollutants,sensors,etc.Many methods,including gas phase,solid phase,liquid phase,and the newly proposed green synthesis method,have been reported for the synthesis of CeO_(2) NPs.Due to the wide application of CeO_(2) NPs,concerns about their adverse impacts on human health have been raised.This review covers recent studies on the biomedical applications of CeO_(2) NPs,including their use in the treatment of various diseases(e.g.,Alzheimer's disease,ischemic stroke,retinal damage,chronic inflammation,and cancer).CeO_(2) NP toxicity is discussed in terms of the different systems of the human body(e.g.,cytotoxicity,genotoxicity,respiratory toxicity,neurotoxicity,and hepatotoxicity).This comprehensive review covers both fundamental discoveries and exploratory progress in CeO_(2) NP research that may lead to practical developments in the future.

关键词： Ceria nanoparticle Synthetic method Biomedical application Oxidative stress Toxicity

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Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1

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Science China(Life Sciences) 2024年第6期67卷 1212-1225页

作者： Zhijie Hu Mengxia Li Yufeng Chen Liutao Chen Yuting Han Chengyong Chen Xin Lu Nan You Yawen Lou Yingye Huang Zhanfeng Huo Chao Liu Cheng Liang Susu Liu Ke Deng Liangfu Chen Shangwu Chen Guohui Wan Xiaojian Wu Yonggui Fu Anlong Xu State Key Laboratory of Biocontrol Guangdong Province Key Laboratory of Pharmaceutical Functional GenesDepartment of BiochemistrySchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Department of General Surgery(Colorectal Surgery)&Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases&Biomedical innovation center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China National-Local Joint Engineering Laboratory of druggability and new drug evaluation National Engineering Research Center for New Drug and Druggability(cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China

Generally shortened 3′UTR due to alternative polyadenylation(APA)is widely observed in cancer,but its regulation mechanisms for cancer are not well characterized.Here,with profiling of APA in colorectal cancer tissues and poly(A)signal editing,we firstly identified that the shortened 3′UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and migration.We found that liquid-liquid phase separation(LLPS)of PABPN1 is reduced albeit with higher expression in cancer,and the reduction of LLPS leads to the shortened 3′UTR of CTNNBIP1and promotes cell proliferation and migration.Notably,the splicing factor SNRPD2 upregulated in colorectal cancer,can interact with glutamic-proline(EP)domain of PABPN1,and then disrupt LLPS of PABPN1,which attenuates the repression effect of PABPN1 on the proximal poly(A)sites.Our results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1,suggesting that regulation of APA by interfering LLPS of 3′end processing factor may have the potential as a new way for the treatment of cancer.

关键词： alternative polyadenylation colorectal cancer CTNNBIP1 PABPN1 liquid-liquid phase separation SNRPD2

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The Probability Density Function Related to Shallow Cumulus Entrainment Rate and Its Influencing Factors in a Large-Eddy Simulation

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Advances in Atmospheric Sciences 2024年第1期41卷 173-187页

作者： Lei ZHU Chunsong LU Xiaoqi XU Xin HE Junjun LI Shi LUO Yuan WANG Fan WANG collaborative innovation center on Forecast and evaluation of Meteorological Disasters(CIC-FEMD)and Key Laboratory for Aerosol-Cloud-Precipitation of China Meteorological Administration Nanjing University of Information Science and TechnologyNanjing 210044China Nanjing Joint Institute for Atmospheric Sciences Nanjing 210019China College of Aviation Meteorology Civil Aviation Flight University of ChinaGuanghan 618307China collaborative innovation center for Western Ecological safety Lanzhou UniversityLanzhou 730000China Department of Geography Hong Kong Baptist UniversityHong Kong SAR 999077China

The process of entrainment-mixing between cumulus clouds and the ambient air is important for the development of cumulus clouds.Accurately obtaining the entrainment rate(λ)is particularly important for its parameterization within the overall cumulus parameterization scheme.In this study,an improved bulk-plume method is proposed by solving the equations of two conserved variables simultaneously to calculateλof cumulus clouds in a large-eddy simulation.The results demonstrate that the improved bulk-plume method is more reliable than the traditional bulk-plume method,becauseλ,as calculated from the improved method,falls within the range ofλvalues obtained from the traditional method using different conserved variables.The probability density functions ofλfor all data,different times,and different heights can be well-fitted by a log-normal distribution,which supports the assumed stochastic entrainment process in previous studies.Further analysis demonstrate that the relationship betweenλand the vertical velocity is better than other thermodynamic/dynamical properties;thus,the vertical velocity is recommended as the primary influencing factor for the parameterization ofλin the future.The results of this study enhance the theoretical understanding ofλand its influencing factors and shed new light on the development ofλparameterization.

关键词： large-eddy simulation cumulus clouds entrainment rate probability density functions spatial and temporal distribution

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Improvement of cloud microphysical parameterization and its advantages in simulating precipitation along the Sichuan-Xizang Railway

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Science China Earth Sciences 2024年第3期67卷 856-873页

作者： Xiaoqi XU Zhiwei HENG Yueqing LI Shunjiu WANG Jian LI Yuan WANG Jinghua CHEN Peiwen ZHANG Chunsong LU China Meteorological Administration Transportation Meteorology Key Laboratory Nanjing Joint Institute for Atmospheric SciencesNanjing 210041China Heavy Rain and Drought-Flood Disasters in Plateau and Basin Key Laboratory of Sichuan Province Institute of Plateau MeteorologyCMAChengdu 610072China State Key Laboratory of Disaster Weather Chinese Academy of Meteorological SciencesBeijing 100081China collaborative innovation center for Western Ecological safety Lanzhou UniversityLanzhou 730000China China Meteorological Administration Aerosol-Cloud and Precipitation Key Laboratory and collaborative innovation center on Forecast and evaluation of Meteorological Disasters(CIC-FEMD) Nanjing University of Information Science and TechnologyNanjing 210044China

The Sichuan-Xizang Railway is an important part of the railway network in China, and geological disasters, such as mountain floods and landslides, frequently occur in this region. Precipitation is an important cause of these disasters;therefore,accurate simulation of the precipitation in this region is highly important. In this study, the descriptions for uncertain processes in the cloud microphysics scheme are improved;these processes include cloud droplet activation, cloud-rain autoconversion, rain accretion by cloud droplets, and the entrainment-mixing process. In the default scheme, the cloud water content of different sizes corresponds to the same cloud droplet concentration, which is inconsistent with the actual content;this results in excessive cloud droplet size, unreasonable related conversion rates of microphysical process(such as cloud-rain autoconversion), and an overestimation of precipitation. Our new scheme overcomes the problem of excessive cloud droplet size. The processes of cloudrain autoconversion and rain accretion by cloud droplets are similar to the stochastic collection equation, and the mixing mechanism of cloud droplets is more consistent with that occurred during the actual physical process in the cloud. Based on the new and old schemes, multiple precipitation processes in the flood season of 2021 along the Sichuan-Xizang Railway are simulated, and the results are evaluated using ground observations and satellite data. Compared to the default scheme, the new scheme is more suitable for the simulation of cloud physics, reducing the simulation deviation of the liquid water path and droplet radius from 2 times to less than 1 time and significantly alleviating the overestimation of precipitation intensity and range of precipitation center. The average root-mean-square error is reduced by 22%. Our results can provide a scientific reference for improving precipitation forecasting and disaster prevention in this region.

关键词： The Sichuan-Xizang Railway Cloud microphysics Precipitation Model improvement

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Nanotechnology’s frontier in combatting infectious and inflammatory diseases:prevention and treatment

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Signal Transduction and Targeted Therapy 2024年第3期9卷 998-1047页

作者： Yujing Huang Xiaohan Guo Yi Wu Xingyu Chen Lixiang Feng Na Xie Guobo Shen Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu 610041China

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases,which continuously pose one of the most serious threats to human health,attributed to factors such as the emergence of new pathogens,increasing drug resistance,changes in living environments and lifestyles,and the aging population.Despite rapid advancements in mechanistic research and drug development for these diseases,current treatments often have limited efficacy and notable side effects,necessitating the development of more effective and targeted anti-inflammatory therapies.In recent years,the rapid development of nanotechnology has provided crucial technological support for the prevention,treatment,and detection of inflammation-associated diseases.Various types of nanoparticles(NPs)play significant roles,serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability.NPs can also directly combat pathogens and inflammation.In addition,nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases.This review categorizes and characterizes different types of NPs,summarizes their applications in the prevention,treatment,and detection of infectious and inflammatory diseases.It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects.In conclusion,nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

关键词： prevention inflammatory treatment

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research Progress on Targets and Selective Inhibitors of Polo-like Kinase-1(PLK-1)

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Medicinal Plant 2024年第1期15卷 51-56页

作者： Xin WANG Qin ZENG Guangying DU University collaborative innovation center of Shandong Province Key Laboratory of Molecular Pharmacology and Drug Evaluation of Ministry of EducationYantai UniversityYantai 264005China

In this paper,the biological function of PLK-1,the correlation between PLK-1 and tumors,and the latest research progress on PLK-1 inhibitors under study are reviewed,in order to provide references for the research and... 详细信息

关键词： Polo-like kinase-1 PLK-1 inhibitor Cell cycle Mitosis Cancer

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Isolation and microbial transformation of tea sapogenin from seed pomace of Camellia oleifera with anti-inflammatory effects

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Chinese Journal of Natural Medicines 2024年第3期22卷 280-288页

作者： SHEN Pingping JIANG Xuewa ZHANG Jingling WANG Jiayi Raj Richa LI Guolong GE Haixia WANG Weiwei YU Boyang ZHANG Jian State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Co-construction collaborative innovation center for Chinese Medicine Resources Industrialization by Shaanxi&Education Ministry Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation ResearchShaanxi University of Chinese MedicineXianyang 712046China School of Life Sciences Huzhou UniversityHuzhou 313000China Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing 210046China Jiangsu Key Laboratory of TCM evaluation and Translational research China Pharmaceutical UniversityNanjing 211198China

In the current study,tea saponin,identified as the primary bioactive constituent in seed pomace of Camellia oleifera Abel.,was meticulously extracted and hydrolyzed to yield five known sapogenins:16-O-tiglogycamelliagnin B(a),camelliagnin A(b),16-O-angeloybarringtogenol C(c),theasapogenol E(d),theasapogenol F(e).Subsequent biotransformation of compound a facilitated the isolation of six novel metabolites(a1−a6).The anti-inflammatory potential of these compounds was assessed using pathogenassociated molecular patterns(PAMPs)and damage-associated molecular patterns molecules(DAMPs)-mediated cellular inflammation models.Notably,compounds b and a2 demonstrated significant inhibitory effects on both lipopolysaccharide(LPS)and high-mobility group box 1(HMGB1)-induced inflammation,surpassing the efficacy of the standard anti-inflammatory agent,carbenoxolone.Conversely,compounds d,a3,and a6 selectivity targeted endogenous HMGB1-induced inflammation,showcasing a pronounced specificity.These results underscore the therapeutic promise of C.oleifera seed pomace-derived compounds as potent agents for the management of inflammatory diseases triggered by infections and tissue damage.

关键词： Camellia oleifera Seed pomace Tea sapogenin Microbial transformation Damage-associated molecular patterns and Pathogen-associated molecular patterns Anti-inflammatory activity

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Impacts of external forcing and internal variability on the North Atlantic multidecadal variations since 1950

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Science China Earth Sciences 2024年第8期67卷 2699-2701页

作者： Wenjian HUA Aiguo DAI Key Laboratory of Meteorological Disaster Ministry of Education/Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters Nanjing University of Information Science and Technology Department of Atmospheric and Environmental Sciences University at Albany State University of New York

The physical formation mechanisms of the Atlantic Multidecadal Variability (AMV) in the context of global warming have been a key research topic (Vecchi et al., 2017). The conventional view is that the AMV is mainly driven by internal dynamics within the climate system, especially in the Atlantic Ocean (Zhang et al., 2019). However, some studies suggest that decadal to multidecadal variations in North Atlantic sea surface temperature (SST) since around 1950 are related to anthropogenic and natural aerosol emissions (Otter? et al., 2010; Booth et al., 2012; Hua et al., 2019).

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