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Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

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Neural Regeneration Research 2024年第11期19卷 2467-2479页

作者： Yong Tang Jing Wei Xiao-Fang Wang Tao Long Xiaohong Xiang Liqun Qu Xingxia Wang Chonglin Yu Xingli Xiao Xueyuan Hu Jing Zeng Qin Xu Anguo Wu Jianming Wu Dalian Qin Xiaogang Zhou Betty Yuen-Kwan Law Dr.Neher’s Biophysics laboratory for Innovative drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao Special Administrative RegionChina Sichuan key Medical laboratory of New drug Discovery and druggability evaluation Luzhou key laboratory of Activity Screening and druggability evaluation for Chinese Materia Medica Southwest Medical UniversityLuzhouSichuan ProvinceChina Eye School and key laboratory of Sichuan province Ophthalmopathy Prevention&Cure and Visual Function Protection of Chengdu University of TCM ChengduSichuan ProvinceChina School of Basic Medical Sciences Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Ophthalmology The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan ProvinceChina Department of Neurology The First People’s Hospital of NeijiangNeijiangSichuan ProvinceChina

Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

关键词： Alzheimer’s disease amyloid-beta apoptosis autophagy Caenorhabditis elegans Citri Reticulatae Semen

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Oral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2006-2025页

作者： Bingwen Ding Zhu Zhu Cong Guo Jiaxin Li Yong Gan Miaorong Yu State key laboratory of drug Research and Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmacy Henan UniversityKaifeng 475004China NMPA key laboratory for quality Research and evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China

Diabetes,characterized by hyperglycemia,is a major cause of death and disability worldwide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body.Compared to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred approach.However,biological barriers significantly reduce the efficacy of oral peptide therapeutics.Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes.This review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological barriers.Additionally,the review will discuss the prospects in this field.The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

关键词： Oral peptides Diabetes Delivery platforms Insulin Glucagon-like peptide-1 Biodistribution Biological barriers Targeted delivery

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Palladium-catalyzed multi components oxy-aminofluorination and aminofluorination of gem-difluoroalkenes

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Chinese Chemical Letters 2024年第2期35卷 420-425页

作者： Fen Wu Xin Li Junbiao Chang Dachang Bai State key laboratory of Antiviral drugs NMPA Key Laboratory for Research and Evaluation of Innovative DrugKey Laboratory of Green Chemical Media and ReactionsMinistry of EducationSchool of Chemistry and Chemical EngineeringPingyuan LaboratoryHenan Normal UniversityXinxiang 453007China State key laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Organofluorine compounds are widely used in the realm of drug discovery and material science.Herein,we developed palladium catalyzed intermolecular aminofluorination and oxy-aminofluorination of gem‑difluoroalkenes with N-fluorobenzenesulfonimide(NFSI),in which NFSI was used as the nitrogen source and oxidant.The reaction provides an efficient and straightforward synthesis route of a series ofα-trifluoromethyl benzylic amines.Notably,three/four components oxy-aminofluorination processes were realized to giveα-trifluoromethyl benzylic ether with a terminal amino group,which proceed through C(sp^(3))-O bond cleavage of easily available ether and simultaneous introduced a fluorine,an amino and an oxy substituent in one pot with excellent regioselectivity.The divergent reactivity not only included the incorporation of one ether molecular,but also much more challenged two ether insertion with excellent selectivity through succession C(sp^(3))-O bonds cleavage.This protocol allows for concise synthesis of high value amines with fluoroalkyl-substituents and selectively transformation of easily available ethers by high-valent palladium catalysis.

关键词： Palladium Multi components Aminofluorination Oxy-aminofluorination C(sp^(3))-O bond cleavage

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Anion cascade reactions Ⅲ:Synthesis of 3-isoquinuclidone bridged polycyclic lactams

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Chinese Chemical Letters 2024年第2期35卷 426-430页

作者： Zhiguo Zhang Bingbing Shi Xiyang Cao Nana Ma Hao Wu Xingjie Zhang Guisheng Zhang key laboratory of Green Chemical Media and Reactions Ministry of EducationCollaborative Innovation Centre of Henan Province for Green Manufacturing of Fine ChemicalsNMPA Key Laboratory for Research and Evaluation of Innovative DrugSchool of Chemistry and Chemical EngineeringHenan Normal UniversityXinxiang 453007China

Bridged polycyclic lactams are important structural units in organic functional materials,natural products,and pharmaceuticals.A flexible and efficient anion cascade reaction was developed for the preparation of bridged polycyclic lactams from readily available malonamides and 1,4‑dien-3-ones.Various highly substituted bridged polycyclic lactams were synthesized in good to excellent yields by tandem nucleophilic sequences in the presence of t BuOK in commercially available EtOH solvent at 60℃.Notably,the simple reactions can be run on a gram scale.Mechanistically,bis-Michael addition reaction and hemiaminalization reactions are involved in the tandem transformation.

关键词： Anion cascade reactions 3-Isoquinuclidone Bridged polycyclic lactams Bis-Michael addition reaction Hemiaminalization

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The emerging roles of lysine-specific demethylase 4A in cancer:Implications in tumorigenesis and therapeutic opportunities

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Genes & Diseases 2024年第2期11卷 645-663页

作者： Guanjun Yang Changyun Li Fan Tao Yanjun Liu Minghui Zhu Yu Du Chenjie Fei Qiusheng She Jiong Chen State key laboratory for Managing Biotic and Chemical Threats to the quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China School of Life Science and Engineering Henan University of Urban ConstructionPingdingshanHenan 467044China laboratory of Biochemistry and Molecular Biology School of Marine SciencesNingbo UniversityNingboZhejiang 315211China key laboratory of Aquacultural Biotechnology Ministry of Education Ningbo UniversityNingboZhejiang 315211China

Lysine-specific demethylase 4 A(KDM4A,also named JMJD2A,KIA0677,or JHDM3A)is a demethylase that can remove methyl groups from histones H3K9me2/3,H3K36me2/3,and H1.4K26me2/me3.Accumulating evidence suggests that KDM4A is not only involved in body homeostasis(such as cell proliferation,migration and differentiation,and tissue development)but also associated with multiple human diseases,especially cancers.Recently,an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia.Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy,all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes,especially in tumorigenesis,which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers,discovering targeted selective KDM4A inhibitors,and exploring the adaptive profiles of KDM4A antagonists.Herein,we present the structure and functions of KDM4A,simply outline the functions of KDM4A in homeostasis and non-cancer diseases,summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers,systematically classify KDM4A inhibitors,summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs,and provide the corresponding solutions,which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy.

关键词： Cancer therapy drug resistance Histone demethylation JmjC domain KDM4A

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Proteomic study of vitreous in proliferative diabetic retinopathy patients after treatment with aflibercept:a quantitative analysis based on 4D label-free technique

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International Journal of Ophthalmology(English edition) 2024年第4期17卷 676-685页

作者： Ting-Ting Feng Xiang Gao An-Ran Liang Bo-Wen Zhao Guang-Hui He Song Chen Clinical College of Ophthalmology Tianjin Medical UniversityTianjin 300070China Tianjin key laboratory of Ophthalmology and Visual Science Tianjin Eye InstituteTianjin Eye HospitalTianjin 300020China key laboratory of Ophthalmology Anyang Eye HospitalAnyang 455000Henan ProvinceChina Department of Ophthalmology Jining No.1 People’s HospitalJining 272011Shandong ProvinceChina

AIM:To identify different metabolites,proteins and related pathways to elucidate the causes of proliferative diabetic retinopathy(PDR)and resistance to anti-vascular endothelial growth factor(VEGF)drugs,and to provide biomarkers for the diagnosis and treatment of PDR.METHODS:Vitreous specimens from patients with diabetic retinopathy were collected and analyzed by Liquid Chromatography-Mass Spectrometry(LC-MS/MS)analyses based on 4D label-free technology.Statistically differentially expressed proteins(DEPs),Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway representation and protein interactions were analyzed.RESULTS:A total of 12 samples were analyzed.The proteomics results showed that a total of 58 proteins were identified as DEPs,of which 47 proteins were up-regulated and 11 proteins were down-regulated.We found that C1q and tumor necrosis factor related protein 5(C1QTNF5),Clusterin(CLU),tissue inhibitor of metal protease 1(TIMP1)and signal regulatory protein alpha(SIRPα)can all be specifically regulated after aflibercept treatment.GO functional analysis showed that some DEPs are related to changes in inflammatory regulatory pathways caused by PDR.In addition,protein-protein interaction(PPI)network evaluation revealed that TIMP1 plays a central role in neural regulation.In addition,CD47/SIRPαmay become a key target to resolve anti-VEGF drug resistance in PDR.CONCLUSION:Proteomic analysis is an approach of choice to explore the molecular mechanisms of PDR.Our data show that multiple proteins are differentially changed in PDR patients after intravitreal injection of aflibercept,among which C1QTNF5,CLU,TIMP1 and SIRPαmay become targets for future treatment of PDR and resolution of anti-VEGF resistance.

关键词： vitreous proliferative diabetic retinopathy proteome 4D label-free

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

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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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Formulation,characterization and in vivo and in vitro evaluation of aloe-emodin-loaded solid dispersions for dissolution enhancement

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Journal of Traditional Chinese Medicine 2024年第1期44卷 54-62页

作者： LI Xiuyan LUO Yuting WANG Jinhui DU Zhimin key laboratory of Basic and Application Research of Beiyao Heilongjiang University of Chinese MedicineMinistry of EducationHarbin 150040China College of Pharmacy Harbin Medical UniversityHarbin 150081China Institute of Clinical Pharmacology the Second Affliated Hospital of Harbin Medical University(University Key aboratory of Drug ResearchHeilongjiang Province)Harbin 150086China Department of Clinical Pharmacology College of Pharmacy Harbin Medical UniversityHarbin 150081China State key laboratory of quality Research in Chinese Medicines Macao University of Science and TechnologyMacao 999078China

OBJECTIVE:To prepare aloe-emodin solid dispersion(AE-SD)and determine the metabolic process of AE and AE-SD in vivo.METHODS:AE-SD was prepared via solvent evaporation or solvent melting using PEG-6000 and PVP-K30 as carriers.Thermogravimetric analysis,X-ray diffraction spectroscopy,differential scanning calorimetry,Fourier transform infrared spectroscopy and scanning electron microscopy were used to identify the physical state of AESD.Optimal prescriptions were screened via the dissolution degree determination method.Using Phoenix software,AE suspension and AE-SD were subjected to a pharmacokinetic comparison study analyzing the alteration of behavior in vivo after AE was prepared as a solid dispersion.Acute toxicity was assessed in mice,and the physiological toxicity was used as the determination criterion for toxicity.RESULTS:AE-SD showed that AE existed in the carrier in an amorphous state.Compared with polyethylene glycol,polyvinylpyrrolidone(PVP)inhibited AE crystallization,causing the drug to transform from a dense crystalline state to an amorphous form and increasing the degree of drug dispersion.Therefore,it was more suitable as a carrier material for AE-SD.The addition of poloxamer(POL)was more beneficial to the stability of solid dispersions and could reduce the amount of PVP.The dissolution test confirmed that the optimal ratio of AE to the composite vector AE-PVP-POL was 1:2:2,and its dissolution effect was also optimal.Based on the pharmacokinetic comparison,the drug absorption was faster and quickly reached the peak of blood drug concentration in AE-SD compared to AE,the Cmax of AE-SD was greater than that of AE,and t1/2 and mean residence time of AE-SD were less than AE.The results showed that the drug metabolism in AE-SD was better,and the residence time was shorter.The toxicology study showed that both AE and AE-SD had no toxicity.CONCLUSION:This paper established that the solubility of the drug could be increased after preparing a solid dispersion,as demonstrated by in vitro dissolution experime

关键词： aloe-emodin solid dispersion solvent evaporation drug liberation pharmacokinetics

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Organic Integration of Traditional Chinese and Western Medicines—Future of Clinical Practice Guidelines of Integrated Traditional Chinese and Western Medicines

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Chinese Journal of Integrative Medicine 2024年第4期30卷 359-365页

作者： XIE Ying-lan HAN Fei JIN Ying-hui DING Yan-bing GUO Jing JI Dong-xiao ZHANG Teng CHENXiao-min SHANG Hong-cai Department of Traditional Chinese Medicine Encephalopathy Hubei Provincial Hospital of Traditional Chinese MedicineWuhan(430074)China Department of Traditional Chinese Medicine Encephalopathy Hubei Province Traditional Chinese Medicine Research InstituteWuhan(430074)China Xuanwu Hospital of Traditional Chinese Medicine Beijing(100000)China Center for Evidence-Based and Translational Medicine Zhongnan Hospital of Wuhan UniversityWuhan(430074)China College of Acupuncture and Massage College of Health and RehabilitationNanjing University of Chinese MedicineNanjing(210023)China Department of Ophthalmology Huaihe Hospital of Henan UniversityKaifengHenan Province(475000)China Ministry of Education and Beijing key laboratory of Internal Medicine of Traditional Chinese Medicine Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine/Ministry of Education and Beijing Key Laboratory of Internal Medicine of Traditional Chinese MedicineBeijing(100700)China

The transformation and implementation of clinical practice guidelines for integrated traditional Chinese medicine(TCM)and Western medicine(WM)is crucial to the adoption of medical science and technological findings and is an important way for TCM to be made available to the world.First,clinical practice guidelines(CPGs)of TCM and WM integration in recent years was analyzed to clarify the current situation and problems in the existing guidelines according to the following four perspectives:(1)perspective of TCM and WM integration in guidelines,(2)diagnosis Using integrated TCM and WM,(3)integration of TCM and WM treatment,(4)promoting TCM and WM integration.Secondly,the information and quality evaluation of CPGs for integrated Chinese and Western medicine in 2020–2022 were analyzed to explore the degree and methods of integration of Chinese and Western medicine guidelines.And last this study aimed to lay a foundation for the further establishment of Chinese characteristic,repeatable,and calculable clinical practice guidelines of TCM and WM integration.

关键词： clinical practice guidelines integrated traditional Chinese and Western medicine organic integration

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Research on the Assessment System of Computational Mechanics Courses Based on the TOPSIS Entropy Weight Model

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Journal of Contemporary Educational Research 2024年第6期8卷 166-182页

作者： Huijun Ning Ruhuan Yu Qianshu Wang Mingming Lin Institute of Science and Technology Development Henan University of Science and TechnologyLuoyang 471000Henan ProvinceChina School of Civil Engineering and Architecture Henan University of Science and TechnologyLuoyang 471000Henan ProvinceChina International Education College Henan University of Science and TechnologyLuoyang 471000Henan ProvinceChina

This paper takes the assessment and evaluation of computational mechanics course as the background,and constructs a diversified course evaluation system that is student-centered and integrates both quantitative and qualitative evaluation methods.The system not only pays attention to students’practical operation and theoretical knowledge mastery but also puts special emphasis on the cultivation of students’innovative abilities.In order to realize a comprehensive and objective evaluation,the assessment and evaluation method of the entropy weight model combining TOPSIS(Technique for Order Preference by Similarity to Ideal Solution)multi-attribute decision analysis and entropy weight theory is adopted,and its validity and practicability are verified through example analysis.This method can not only comprehensively and objectively evaluate students’learning outcomes,but also provide a scientific decision-making basis for curriculum teaching reform.The implementation of this diversified course evaluation system can better reflect the comprehensive ability of students and promote the continuous improvement of teaching quality.

关键词： TOPSIS entropy weight model Computational mechanics Course assessment and evaluation system Assessment model

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