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Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

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Neural Regeneration Research 2024年第7期19卷 1437-1445页

作者： Steinunn Sara Helgudóttir Anne Skøttrup Mørkholt Jacek Lichota Preben Bruun-Nyzell Mads Christian Andersen Nanna Marie Juhl Kristensen Amanda Krøger Johansen Mikela Reinholdt Zinn Hulda Maria Jensdóttir John Dirk Vestergaard Nieland 2N Pharma ApS NOVI Science ParkAalborgDenmark molecular pharmacology group Department of Health Science and TechnologyAalborg UniversityAalborgDenmark

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s *** the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these *** considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological *** innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers *** this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative *** provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ***,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter ***,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

关键词： brain disease carnitine palmitoyl transferase 1 epigenetics metabolism gut microbiome mitochondrial dysfunction neurodegeneration oxidative stress

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Modern approaches for detection of volatile organic compounds in metabolic studies focusing on pathogenic bacteria:Current state of the art

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Journal of Pharmaceutical Analysis 2024年第4期14卷 483-505页

作者： Karolina Zuchowska Wojciech Filipiak Department of Pharmacodynamics and molecular pharmacology Faculty of PharmacyCollegium Medicum in BydgoszczNicolaus Copernicus University in Torun85-089 BydgoszczPoland

Pathogenic microorganisms produce numerous metabolites,including volatile organic compounds(VOCs).Monitoring these metabolites in biological matrices(e.g.,urine,blood,or breath)can reveal the presence of specific microorganisms,enabling the early diagnosis of infections and the timely implementation of tar-geted ***,complex matrices only contain trace levels of VOCs,and their constituent com-ponents can hinder determination of these ***,modern analytical techniques enabling the non-invasive identification and precise quantification of microbial VOCs are *** this paper,we discuss bacterial VOC analysis under in vitro conditions,in animal models and disease diagnosis in humans,including techniques for offline and online analysis in clinical *** also consider the advantages and limitations of novel microextraction techniques used to prepare biological samples for VOC analysis,in addition to reviewing current clinical studies on bacterial volatilomes that address inter-species in-teractions,the kinetics of VOC metabolism,and species-and drug-resistance specificity.

关键词： Volatile organic compounds Pathogenic bacteria metabolites Metabolomics Microextraction techniques Gas chromatography-mass spectrometry In vivo breath analysis In vitro model

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Foraging valor linked with aggression:selection against completely abandoning aggression in the high-elevation ant Tetramorium alpestre?

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Insect Science 2024年第3期31卷 953-970页

作者： Marie-Luise Contala Patrick Krapf Florian M.Steiner Birgit C.Schlick-Steiner molecular Ecology group Department of EcologyUniversitat InnsbruckInnsbruckAustria rganismal&Evolutionary Biology Research Programme University of HelsinkiHelsinkiFinland

Aggression has multiple benefits and is often coupled with other behaviors("behavioral syndromes").The level of aggressiveness is influenced by an adaptive benefit-cost ratio suggesting that benefits should outweigh the costs of ***,we assess if several behaviors are coupled in two behaviorally different populations(aggressive,peaceful)of the high-elevation ant Tetramorium *** three weeks,we collected colony fragments and analyzed boldness,exploring,foraging,and risk-taking *** hypothesized that the aggressive population is bolder,more explorative and risk-prone,and forages more food than the peaceful *** test whether(a)the combination of experiments and parameters used yields a good setup,(b)populations differ behaviorally,and(c)populations display behavioral syndromes,we assessed(a)the frequency of repeatable behaviors of each experiment,(b)the behavioral means among populations,and(c)the behavioral repeatability,*** found that(a)boldness and exploring were most repeatable and represent a good experimental setup,(b)the aggressive population was bolder and more explorative and risk-prone than the peaceful population,(c)boldness and exploring behaviors were highly repeatable in both populations,thus corroborating our *** results suggest that boldness,exploring,and risk-taking but not foraging are presumably coupled with aggression and indicate the presence of behavioral syndromes in this *** specific ecological conditions,aggression may be coupled with other behaviors and important for finding *** is probably adaptive in ***,possibly indicating that selection favors aggression at least partially,which may counteract the complete loss of intraspecific aggression.

关键词： adaptive value behavioral syndromes boldness exploration repeatability trade-off

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G protein-mediated signal transduction: a molecular choreography of G protein activation after GTP binding

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3155-3157页

作者： Evi Kostenis Lars Jurgenliemke Judith Alenfelder Department of molecular- Cellular-and PharmacobiologyInstitute of Pharmaceutical BiologyUniversity of BonnBonnGermany Graduate Training group RTG2873 University of BonnBonnGermany

A recent report from the Skiniotis group,'published in Nature,provides fascinating insight into the molecular choreography underlying a quintessential cellular signaling mechanism:G protein-mediated signal *** time-resolved cryo-EM,the authors pieced together many sequential structural snapshots to visualize how a trimeric aβy G protein-after being convinced by its activated G protein-coupled receptor(GPCR)to release GDP-picks up GTP,to set in motion finely tuned conformational transitions that lead to the conversion into the active state and,finally,subunit dissociation as well as disengagement from the receptor.

关键词： Skin activation finally

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Modular Synthesis of Multi-substituted Cyclobutanones Enabled by Oxyallyl Cations

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Chinese Journal of Chemistry 2024年第5期42卷 459-463页

作者： Meng Wang Zhonggui Wang Ping Lu Research Center for molecular Recognition and Synthesis Department of ChemistryFudan University220 Handan LuShanghai200433 China Present address: Department of Cancer Biology Dana-Farber Cancer Institute Department of Biological Chemistry and molecular pharmacology Harvard Medical SchoolBostonMA 02115USA

Stereoselective synthesis of multi-substituted cyclobutanes with different substituents is still a daunting challenge in organic *** report here a practical and facile approach to synthesizing all-trans 2,3,4-trisubstituted cyclobutanones from readily available *** substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic *** transformation to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was also explored.

关键词： Diastereoselectivity Modular synthesis Nucleophilic substitution Organohalides Oxyallyl cation Precision functionalization Strained molecules 1,2,3,4-Tetrasubstituted cyclobutanes

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Enantioselective Synthesis of Benzimidazole Atropisomers Featuring a N-N Axis

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Chinese Journal of Chemistry 2024年第7期42卷 711-718页

作者： Fang-Bei Ge Qi-Kun Yin Chuan-Jun Lu Xuan Xuan Jia Feng Ren-Rong Liu College of Chemistry and Chemical Engineering Qingdao UniversityQingdaoShandong 266071China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationYantai UniversityYantaiShandong 264005China

Atroposelective synthesis of N-N atropisomers is an emerging area but remains underexplored;in particular,the synthesis of N-N benzimidazole atropisomers is still ***,the first enantioselective synthesis of N-N benzimidazole atropisomers via the palladium-catalyzed de novo construction of benzimidazole skeleton is *** readily available palladium catalyst and biphosphine ligand,a broad range of nonbiaryl benzimidazole and indole-benzimidazole atropisomers were conveniently ac-cessed in high yields and with excellent ***,these N-N benzimidazole atropisomers showed great anti-tumor activity and selectivity to breast cancer MCF-7 *** simple catalytic system,broad substrate scope,high enantioselectivi-ty,and good bioactivity make this approach highly attractive.

关键词： Asymmetric synthesis Atropisomerism Palladium Benzimidazole Antitumor

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Ailanthone ameliorates pulmonary fibrosis by suppressing JUN-dependent MEOX1 activation

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3543-3560页

作者： Lixin Zhao Yuguang Zhu Hua Tao Xiying Chen Feng Yin Yingyi Zhang Jianfeng Qin Yongyin Huang Bikun Cai Yonghao Lin Jiaxiang Wu Yu Zhang Lu Liang Ao Shen Xi-Yong Yu The Fifth Affiliated Hospital Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical PharmacologyNMPA&State Key LaboratorySchool of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China

Pulmonary fibrosis poses a significant health threat with very limited therapeutic options *** this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic *** high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing *** demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-b1(TGF-b1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory ***,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and *** summary,our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in ***,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppression of JUN-dependent MEOX1 activation.

关键词： Ailanthone MEOX1 Pulmonary fibrosis JUN TGF-b1 High-throughput screening Natural product

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High glucose microenvironment and human mesenchymal stem cell behavior

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World Journal of Stem Cells 2024年第3期16卷 237-244页

作者： Muhammad Abdul Mateen Nouralsalhin Alaagib Khawaja Husnain Haider Basic Sciences Sulaiman AlRajhi UniversityAlQaseem 52736Saudi Arabia Cellular and molecular pharmacology Sulaiman AlRajhi Medical SchoolAl Bukairiyah 51941Saudi Arabia

High glucose(HG)culture conditions in vitro and persistent exposure to hyperglycemia in diabetes patients are detrimental to stem cells,analogous to any other cell type in our *** interferes with diverse signaling pathways,*** target of rapamycin(mTOR)-phosphoinositide 3-kinase(PI3K)-Akt signaling,to impact physiological cellular functions,leading to low cell survival and higher cell apoptosis *** elucidating the underlying mechanism responsible for the apoptosis of adipose tissue-derived mesenchymal stem cells(MSCs),a recent study has shown that HG culture conditions dysregulate mTORPI3K-Akt signaling in addition to mitochondrial malfunctioning due to defective mitochondrial membrane potential(MtMP)that lowers ATP *** organelle-level dysfunction energy-starves the cells and increases oxidative stress and ultrastructural *** of the mitochondrial electron transport chain produces an altered mitochondrial NAD+/NADH redox state as evidenced by a low NAD+/NADH ratio that primarily contributes to the reduced cell survival in *** previous studies have also reported altered mitochondrial membrane polarity(causing hyperpolarization)and reduced mitochondrial cell mass,leading to perturbed mitochondrial *** hostile microenvironment created by HG exposure creates structural and functional changes in the mitochondria,altering their bioenergetics and reducing their capacity to produce *** are significant data,as MSCs are extensively studied for tissue regeneration and restoring their normal functioning in cell-based ***,MSCs from hyperglycemic donors should be cautiously used in clinical settings for cell-based therapy due to concerns of their poor sur-vival rates and increased rates of post engraftment *** hypergly-cemia alters the bioenergetics of donor MSCs,rectifying the loss of MtMP may be an excellent target for future research to restore the normal functioning of MSCs i

关键词： Adipose tissue Apoptosis Bioenergetics Cell survival Cell therapy Hyperglycemia Mitochondria Mesenchymal stem cells Stem cells

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Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

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Neural Regeneration Research 2024年第3期19卷 529-535页

作者： Sandro Huenchuguala Juan Segura-Aguilar Escuela de Tecnología Médica Facultad de SaludUniversidad Santo TomásLos CarrerasOsornoChile molecular&Clinical pharmacology Instituto de Ciencias Biomedicas(ICBM)Faculty of medicineUniversity of ChileIndependenciaSantiagoChile

The positive effect of levodopa in the treatment of Parkinson’s disease,although it is limited in time and has severe side effects,has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal *** preclinical studies with coenzyme Q10,mitoquinone,isradipine,nilotinib,TCH346,neurturin,zonisamide,deferiprone,prasinezumab,and cinpanemab prompted clinical ***,these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease,despite its severe side effects after 4–6 years of chronic *** lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big *** our opinion,the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body,such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine,that induce a very fast,massive and expansive neurodegenerative process,which contrasts with the extremely slow one of neuromelanin-containing dopaminergic *** exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to(i)a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron,(ii)a neurotoxic event that is not expansive and(iii)the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic *** endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome,since it(i)is generated within neuromelanin-containing dopaminergic neurons,(ii)does not cause an expansive neurotoxic effect and(iii)triggers all the mechanisms involved in t

关键词： 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 6-hydroxydopamine aminochrome dopaminergic neurons DT-diaphorase exogenous neurotoxins glutathione transferase M2-2

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Site-specific incorporation of reduction-controlled guest amino acids into proteins for cucurbituril recognition

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Chinese Chemical Letters 2024年第5期35卷 193-196页

作者： Zhen Dai Linzhi Tan Yeyu Su Kerui Zhao Yushun Tian Yu Liu Tao Liu College of Chemistry State Key Laboratory of Elemento-Organic ChemistryNankai UniversityTianjin 300071China State Key Laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Protein recognition using host-guest recognition approach is of great interest but has been limited mainly to the protein N-terminal ***,we site-specific incorporated two novel non-canonical amino acids containing supramolecular guest motifs into protein via an expanded genetic *** Staudinger reduction reactions,the encoded unnatural residues on protein becoming activated and can be specifically recognized by cucurbit[7]uril(CB[7])and cucurbit[8]uril(CB[8]).We demonstrated that enzyme containing guest amino acid incorporated near the active site can be reversibly regulated by CB[7]recognition,and CB[8]recognition induces protein *** amino acids will make useful addition to the supramolecular toolbox for protein targeting using molecular recognition approaches.

关键词： Protein recognition Host-guest recognition Non-canonical amino acids Staudinger reduction Expanded genetic code

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