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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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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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CRABP1-mediated non-canonical retinoic acid signaling in motor neurons and neural stem cells

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Neural Regeneration Research 2024年第6期19卷 1169-1170页

作者： Li-Na Wei department of pharmacology University of Minnesota Medical School

Retinoic acid(RA), the active metabolite of vitamin A(the retinoids), elicits a wide spectrum of biological activities critical to the development and health of most of the organ systems including the nervous systems(Corcoran et al., 2002). The effects of RA are mediated by two very distinct pathways; the first is manifested in the nucleus by binding to a large family of nuclear RA receptors(RARs) to regulate proper expression of RAtargeted genes,

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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and department of pharmacology University of North Carolina–Chapel HillChapel HillNCUSA department of medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3266-3280页

作者： Wenfeng Li Shuming Chen Jing Lang Jing Luo Jiahui Chen Liping Zhang Zhijie Sun Deli Dong department of pharmacology China Pharmaceutical UniversityNanjing 210009China

The drugs extending healthspan in clinic have always been *** is an FDA-approved clinical antiprotozoal *** is rapidly metabolized to tizoxanide after absorption in *** previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and ***,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 ***,both nitazoxanide and tizoxanide improve high glucose-induced shortening of *** *** has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.

关键词： Nitazoxanide Tizoxanide C.elegans Healthspan Lifespan AMPK Akt Mitochondrial uncoupling

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Isoimperatorin alleviates acetic acid-induced colitis in rats

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Asian Pacific Journal of Tropical Biomedicine 2024年第4期14卷 147-153页

作者： Saied Goodarzi Amir Hossein Abdolghaffari Behnaz Najafi Mostafa Pirali Hamedani Saeed Tavakoli Mahshad Marvi Maryam Baeeri Narguess Yassa Abbas Hadjiakhoondi Mohammad Abdollahi Zahra Tofighi medicinal Plants Research Center Faculty of PharmacyTehran University of Medical SciencesTehranIran department of Toxicology and pharmacology Faculty of PharmacyTehran Medical SciencesIslamic Azad UniversityTehranIran department of Pharmacognosy Faculty of PharmacyTehran University of Medical SciencesTehranIran medicinal Plants Research Center Institute of Medicinal PlantsACECRKarajIran International Campus School of Pharmacy Tehran University of Medical SciencesTehranIran Toxicology and Diseases group The Pharmaceutical Sciences Research CenterTehran University of Medical SciencesTehranIran department of Toxicology and pharmacology Faculty of PharmacyTehran University of Medical SciencesTehranIran

Objective:To investigate the effect of isoimperatorin on histopathological and biochemical changes in acetic acid-induced colitis ***:Colitis was induced by intracolonic administration of acetic acid solution(4%v/v)in *** were divided into six groups including the sham group,the negative control group,the dexamethasone-treated group,and the groups treated with isoimperatorin(0.1,1,and 10 mg/kg/d by gavage).The treatments were administered for three days and then colonic status was assessed by macroscopic,histopathological,and biochemical ***:Isoimperatorin significantly alleviated colonic damage in a dose-dependent manner and improved histological changes in rats with acetic acid-induced *** also significantly reduced myeloperoxidase,TNF-α,IL-1β,and malodialdehyde ***:Isoimperatorin alleviates acetic acid-induced colitis in rats and may be a potential therapeutic agent for the treatment of colitis.

关键词： Isoimperatorin Inflammatory bowel disease Acetic acid Colitis TNF-α IL-1β

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Multi-omics:Powerful accelerator for uncovering plant specialized metabolic pathways:The case of leonurine

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molecular Plant 2024年第1期17卷 13-15页

作者： Priyanka Gupta Anuj Sharma Dinesh A.Nagegowda molecular Plant Biology and Biotechnology Lab CSIR-Central Institute of Medicinal and Aromatic PlantsResearch CentreBengaluru 560065India Academy of Scientific and Innovative Research Ghaziabad 201002India

As sessile organisms,plants employ a unique adaptive strategy to survive harsh terrestrial environments and defend against or interact with coevolving animals and *** strategy involves expanding their metabolic systems,resulting in the production of plant specialized metabolites(PSMs)or natural ***,PSMs constitute a highly diverse group of compounds based on their common core structure,comprising terpenoids,phenylpropanoids,benzenoids,alkaloids and nitrogen-containing compounds,glucosinolates,indoles and sulfur-containing indole compounds,phenolics,and fatty acid derivatives(Garagounis et al.,2021).

关键词： expanding alkaloids sulfur

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Modern View on Potentials of Forensic Pharmaceutical and Pharmacological Expertise

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Journal of Forensic Science and Medicine 2024年第1期10卷 62-67页

作者： Elena M.Vazhnichaya Nataliia M.Deviatkina department of pharmacology Clinical Pharmacology and PharmacyPoltava State Medical UniversityPoltavaUkraine

The great number of drugs and their variety have increased the potential of therapy but increased the risks of crimes related to the production,sale,and use of *** prosecution of such crimes requires pharmaceutical or pharmacological *** development of forensic pharmacy and forensic pharmacology is relevant and needs consideration of their modern *** purpose of the work is to analyze literature data on the scientific basis of forensic pharmaceutical and pharmacological expertise and their modern *** texts of articles,book chapters,and websites were studied using keywords relevant to the purpose of the *** is shown,that modern forensic pharmaceutical expertise is a separate type of expertise that focuses on the study of drugs and documents that regulate the production,distribution,and quality of *** uses the latest analytical methods of pharmacy.A pharmacologist analyzes body fluids and tissues and interprets the resulting data to help courts and investigators assess the role of a drug in the person’s behavior,illness,injury,or *** range of issues included in the pharmacological examination is fully within the competence of the forensic medical examination,which can be appointed in civil cases or criminal proceedings connected with harm to health or *** pharmacology is not the same as forensic toxicology or pharmacovigilance and requires a separate approach based on purely pharmacological knowledge.

关键词： Drug expertise forensic pharmacology forensic pharmacy

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Therapeutic potential and pharmacological mechanism of visnagin

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Journal of Integrative Medicine 2024年第4期22卷 399-412页

作者： Poonam Yadav Sumeet Kumar Singh Sayantap Datta Saloni Verma Aarti Verma Arnab Rakshit Anjana Bali Jasvinder Singh Bhatti Amit Khurana Umashanker Navik department of pharmacology School of Health SciencesCentral University of PunjabBathindaPunjab 151401India department of Pharmacological and Pharmaceutical Sciences College of PharmacyUniversity of HoustonHoustonTX 77204-5000USA department of Human Genetics and molecular Medicine School of Health SciencesCentral University of PunjabBathindaPunjab 151401India

Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga(L.)Lam(a synonym of Visnaga daucoides Gaertn.)plant,which is used to cure various *** investigations into the bioactive properties of visnagin have been studied to *** literature on visnagin demonstrates its biological properties,including anti-inflammatory,anti-diabetic,and beneficial effects in cardiovascular and renal ***,visnagin improves sperm quality parameters,stimulates steroidogenesis,and increases serum gonadotropins and testosterone levels,while decreasing proinflammatory cytokines,oxidative damage,genomic instability,and it modulates ***,visnagin has emerged as an exciting lead for further research,owing to its potential in various unmet clinical *** current review summarized its basic structure,pharmacokinetics,and pharmacological effects,focusing on its mechanisms of *** review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin’s safe clinical use.

关键词： Visnagin Phytochemical Anti-inflammatory Ammi visnaga L. Visnaga daucoides Gaertn Cancer

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medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

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Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key Laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors medicinal chemistry strategies

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