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Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation

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Chinese Journal of Natural Medicines 2024年第5期22卷 387-401页

作者： FENG Qianwen SUN Lu Muhammad Jibran Sualeh ZHAO Qingli ZHAO Songji CUI Zhengguo INADERA Hidekuni Department of Public Health Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyama 930-8501Japan Department of Pediatric Cardiology Heart CenterGuangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangzhou 510000China Department of Basic Medical sciences College of MedicineUniversity of SharjahSharjah 57545United Arab Emirates Department of Radiology Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyama 930-8501Japan Advanced Clinical Research Center Fukushima Global Medical Science CenterFukushima Medical UniversityFukushima CityFukushima 960-8074Japan Department of Environmental Health School of Medical SciencesUniversity of FukuiFukui 910-8580Japan

Hernandezine(Her),a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum,is recognized for its range of biological activities inherent to this herbal medicine.Despite its notable properties,the anti-cancer effects of Her have remained largely unexplored.In this study,we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms.Furthermore,Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems,leading to LC3 lipidation.Our findings revealed that Her caused damage to the mitochondrial membrane,with the damaged mitochondria undergoing mitophagy,as evidenced by the elevated expression of mitophagy markers.Conversely,Her disrupted autophagic flux,demonstrated by the upregulation of p62 and accumulation of autolysosomes,as observed in the RFP-GFP-LC3 reporter assay.Initially,we determined that Her did not prevent the fusion of autophagosomes and lysosomes.However,it inhibited the maturation of cathepsin D and increased lysosomal pH,indicating an impairment of lysosomal function.The use of the early-stage autophagy inhibitor,3-methyladenine(3-MA),did not suppress LC3II,suggesting that Her also induces noncanonical autophagy in autophagosome formation.The application of Bafilomycin A1,an inhibitor of noncanonical autophagy,diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her,thereby augmenting Her-induced cell death.These observations imply that while autophagy initially plays a protective role,the disruption of the autophagic process by Her promotes programmed cell death.This study provides the first evidence of Her’s dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death.These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death,offering potential avenues for enhancing cancer prevention and therapeutic strategies.

关键词： Hernandezine Apoptosis Mitophagy Autophagic flux Lysosome Noncanonical autophagy

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Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models

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Neural Regeneration Research 2024年第9期19卷 1954-1960页

作者： Kinya Matsuo Hideaki Nshihara Yamaguchi University graduate school of Medicine YamaguchiJapan Department of Neurotherapeutics Yamaguchi UniversityUbeJapan

The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research.

关键词： Alzheimer’s disease blood-brain barrier human induced pluripotent stem cells

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Dynamics of 2×2 matrix non-Hermitian quantum systems on Bloch sphere

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Communications in Theoretical Physics 2024年第4期76卷 66-71页

作者： Libin Fu graduate school of China Academy of Engineering Physics Beijing 100193China

By casting evolution to the Bloch sphere, the dynamics of 2 × 2 matrix non-Hermitian systems are investigated in detail. This investigation reveals that there are four kinds of dynamical modes for such systems. The different modes are classified by different kinds of fixed points, namely,the elliptic point, spiral point, critical node, and degenerate point. The Hermitian systems and the unbroken PT non-Hermitian cases belong to the category with elliptic points. The degenerate point just corresponds to the systems with exceptional point(EP). The topological properties of the fixed point are also discussed. It is interesting that the topological charge for the degenerate point is two, while the others are one.

关键词： non-Hermitian quantum system two-level system dynamics on the Bloch sphere PT-symmetry fixed points

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Matrix Assisted Laser Desorption Ionization Time of Flight(MALDI-TOF)-Mass Spectrometry and^(13)C-NMR-Identified New Compounds in Paraberlinia bifoliolata(Ekop-Beli)Bark Tannins

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Journal of Renewable Materials 2024年第3期12卷 553-568页

作者： Liliane Nga Benoit Ndiwe Achille Bernard Biwolé Antonio Pizzi Jean Jalin Eyinga Biwole Joseph Zobo Mfomo Laboratory of Forest Resources and Wood Valorization Training Unit in Engineering SciencesPost Graduate School of Fundamental and Applied SciencesUniversity of DoualaP.O.Box 1872DoualaCameroun Laboratory of Mechanics Training Unit in Engineering SciencesPost Graduate School of Fundamental and Applied SciencesUniversity of DoualaP.O.Box 2701DoualaCameroun Laboratory of Studies and Research on Wood Material(LERMAB) University of LorraineNancyFrance

Extracts of plant origin,particularly tannins,are attracting growing interest for the sustainable development of materials in the industrial sector.The discovery of new tannins is therefore necessary.The aim of this work was to contribute to the understanding of the properties of Paraberlinia bifoliolata tannin by Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectroscopy MALDI-TOF/MS and Carbon 13 Nuclear Magnetic Resonance(13C NMR).The chemical composition of tannin extracted from Paraberlinia bifoliolata bark was determined,as was the mechanical strength of the resin hardened with Acacia nilotica extracts.Yield by successive water extraction was 35%.MALDI-TOF/MS analysis revealed the presence of three new compounds in this tannin,previously unknown in this family of extracts.These are 3-hydroxyproline acid,N-methyl-4-hydroxypipecolic acid and N-methyl-5-dihydroxypipecolic acid.The identification of the above molecules means that this tannin can be used for industrial applications,as a resin in the manufacture of particleboard and in the formulation of green corrosion inhibitors.This information is reinforced by 13C NMR spectrometry,which indicates the presence of several polyflavonoid units,confirming the condensed nature of the tannin.Thermomechanical analysis of the resin formed by the purified tannin of Paraberlinia bifoliolata to which a vegetal biohardener has been added provided a Modulus of Elasticity(MOE)value of 4840 MPa at 150℃,confirming its possible use as a binder resin in the manufacture of wood panels as well as for the formulation of a corrosion inhibitor.

关键词： Tannin Paraberlinia bifoliolata Central African wood species MALDI-TOF/MS 13C NMR bark extracts thermomechanical behaviour wood-binder

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Induced pluripotent stem cells(iPSCs):molecular mechanisms of induction and applications

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2065-2090页

作者： Jonas Cerneckis Hongxia Cai Yanhong Shi Department of Neurodegenerative Diseases Beckman Research Institute of City of HopeDuarteCA 91010USA Irell&Manella graduate school of Biological sciences Beckman Research Institute of City of HopeDuarteCA 91010USA

The induced pluripotent stem cell(iPSC)technology has transformed in vitro research and holds great promise to advance regenerative medicine.iPSCs have the capacity for an almost unlimited expansion,are amenable to genetic engineering,and can be differentiated into most somatic cell types.iPSCs have been widely applied to model human development and diseases,perform drug screening,and develop cell therapies.In this review,we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications.We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs.We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency.Subsequently,we discuss various iPSC-based cellular models,from mono-cultures of a single cell type to complex three-dimensional organoids,and how these models can be applied to elucidate the mechanisms of human development and diseases.We use examples of neurological disorders,coronavirus disease 2019(COVID-19),and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells.We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies.Finally,we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.

关键词： mechanisms programming holds

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Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1428-1440页

作者： Youngjoo Lee Sukyung Song Suah Yang Jinseong Kim Yujeong Moon Nayeon Shim Hong Yeol Yoon Sehoon Kim Man Kyu Shim Kwangmeyung Kim KU-KIST graduate school of Converging Science and Technology Korea UniversitySeoul 02841Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul 03760Republic of Korea Department of Bioengineering Korea UniversitySeoul 02841Republic of Korea

Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells.The ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis.When ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosome

关键词： Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Crosslinked lipid nanoparticles Anti-PD-L1 peptide Tumor-targeting PD-L1 multivalent binding Lysosomal PD-L1 degradation

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Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

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Chinese Medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang Department of Physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China Department of Physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Department of Physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China school of Life sciences Westlake UniversityHangzhouZhejiang 310024China Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin Methotrexate Nucleotide synthesis Chemotherapy

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Breeding maize of ideal plant architecture for high-density planting tolerance through modulating shade avoidance response and beyond

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Journal of Integrative Plant Biology 2024年第5期66卷 849-864页

作者： Fereshteh Jafari Baobao Wang Haiyang Wang Junjie Zou Biotechnology Research Institute Chinese Academy of Agricultural SciencesBeijing 100081China graduate school of Chinese Academy of Agricultural sciences Beijing 100081China National Nanfan Research Institute CAASSanya 572025China State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources College of Life SciencesSouth China AgriculturalUniversityGuangzhou 510642China

Maize is a major staple crop widely used as food,animal feed,and raw materials in industrial production.High-density planting is a major factor contributing to the continuous increase of maize yield.However,high planting density usually triggers a shade avoidance response and causes increased plant height and ear height,resulting in lodging and yield loss.Reduced plant height and ear height,more erect leaf angle,reduced tassel branch number,earlier flowering,and strong root system architecture are five key morphological traits required for maize adaption to high-density planting.In this review,we summarize recent advances in deciphering the genetic and molecular mechanisms of maize involved in response to high-density planting.We also discuss some strategies for breeding advanced maize cultivars with superior performance under high-density planting conditions.

关键词： flowering time high-density planting leaf angle maize plant architecture plant height/ear height root architecture tasselbranch

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Neural plasticity in Parkinson's disease: a neuroimaging perspective

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Neural Regeneration Research 2024年第6期19卷 1203-1205页

作者： Christina Andica Koji Kamagata Department of Radiology Juntendo University Graduate School of Medicine Faculty of Health Data Science Juntendo University

Parkinson’s disease(PD) is a progressive neurodegenerative disorder characterized primarily by classical motor signs of bradykinesia,rigidity,tremors,and postural instability usually manifesti ng unilate rally or at least asymmetrically.The disease involves a loss of dopaminergic neurons projecting from the substantia nigra pars compacta to the dorsal striatum,

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Environmental arsenic(As)and its potential relationship with endemic disease in southwestern China

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Journal of Environmental sciences 2024年第5期139卷 46-59页

作者： Donglin Li Hucai Zhang Fengqin Chang Lizeng Duan Yang Zhang Institute for Ecological Research and Pollution Control of Plateau Lakes School of Ecology and Environmental ScienceYunnan UniversityKunming 650500China Southwest United graduate school Kunming 650500China

Many cases of an unknown disease exhibiting the clinical features of limb gangrene,blisters,ulceration,and exfoliation have been reported in Daping village(DV)in southwestern China.However,the pathogenesis is unknown and has puzzled doctors for many years.A preliminary study on heavy metals and symptoms indicated that arsenic might pose the greatest threat to the health of local residents.Here,to explore the sources of and factors influencing arsenic enrichment in DV,whose residents exhibit signs of arsenic poisoning,the As contents in soil,water,and plants were systematically measured.The results indicated high As contents in plant and soil samples obtained from the area,and the source of As may be linked to the weathering of black shale rock.Ingestion of soil and consumption of plants were the two main As exposure pathways among children and adults,respectively,and children exhibited a higher health risk than adults.We presume and emphasize that when extreme drought events occur,humans might face unusual risks resulting from exposure to toxic elements and the direct consumption of highly polluted water.Our study provides a new perspective and sheds light on the environmental geochemistry and health links of this disease.

关键词： Endemic disease Arsenic(As) Risk assessment Black shale Climate change

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