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

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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Apolipoprotein E elicits targetdirected miRNA degradation to maintain neuronal integrity

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Neural Regeneration research 2025年第9期20卷 2577-2578页

作者： Jiazi Tan Chin-Tong Ong Temasek Life Sciences Laboratory National University of SingaporeSingapore department of Biological Sciences National University of SingaporeSingapore

Apolipoprotein E has diverse functions in neurons:Apolipoprotein E(ApoE)is a glycoprotein that primarily regulates lipid metabolism and transport in the central nervous *** are three predominant human ApoE protein isoforms with cysteine and arginine substitutions at amino acid positions 112 and 158 that impact their lipidation and related functions(Flowers and Rebeck,2020).ApoE2 is characterized by Cys112 and Cys158,ApoE3 by Cys112 and Arg158,whereas ApoE4 contains Arg112 and Arg158.

关键词： metabolism glycoprotein maintain

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Boosting hydrocarbon conversion via Cu-doping induced oxygen vacancies on CeO2 in CO2 electroreduction

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Journal of Energy Chemistry 2025年第1期100卷 66-76页

作者： Lei Xue Tong Shi Chenhui Han Heng Zhang Fenrong Liu Haorun Li Yan Wang Xiaojun Gu Shanghong Zeng Inner Mongolia Key Laboratory of Chemistry and Physics of Rare Earth Materials School of Chemistry and Chemical Engineering Inner Mongolia University State Key Laboratory of Coal Conversion Institute of Coal Chemistry Chinese Academy of Sciences Institute of Catalysis Department of Chemistry Zhejiang University national Key Laboratory of Baiyunobo Rare Earth Resource research and Comprehensive Utilization Baotou Research Institute of Rare Earths

Conversion of CO2back to hydrocarbons is the most direct way of closing the“carbon cycle”,and its significance is further enlarged if this process is driven by renewable energies such as ***,precisely controlling the product selectivity towards hydrocarbons against the competitive hydrogen evolution remains challenging,especially for Cu-based ***,we report a novel defect engineering strategy,by which Cu-doping-induced oxygen vacancies on CeO2nanorods were effectively created,with adjustable vacancy/Cu *** resulting optimum catalyst shows up to 79% catalytic current density to hydrocarbons （excluding CO）,with 49% faradaic efficiency to *** and density functional theory unveil that the ratio between oxygen vacancy and Cu affects significantly the formation of*CHO and activation of H2O,which leads to the following deep hydrogenation to *** findings may spur new insights for designing and developing more controllable chemical process relevant to CO2utilization.

关键词： Oxygen vacancy Hydrocarbon production Reaction mechanism

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New trends in pharmacological treatment of acute kidney injury

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Asian Pacific Journal of Tropical Biomedicine 2021年第7期11卷 285-297页

作者： Heba M.I.Abdallah department of pharmacology Medical Research DivisionNational Research CentreGiza 12622Egypt

Acute kidney injury,previously known as acute renal failure(AKI),is defined as an abrupt decrease in kidney function that occurs within hours or *** new nomenclature opens a new door for possibility of treatment of developing renal injury before progression to unresolved renal *** arises due to diverse etiologic factors that rely mainly on three categories namely,prerenal,intrinsic renal,and post-renal factors with different clinical pictures,and confers a spectrum of injury ranging from mild to severe and sometimes leads to end-stage renal *** of pathogenesis and other factors generate barriers to developing effective treatments despite a large number of experimental and clinical *** this review,recent advances in the potential of the currently used drugs for renoprotection,novel pharmacological targets,and prospective therapeutics for AKI are *** information in this review was extracted from electronic resources(Pub Med,Google Scholar,Wiley,Science Direct,Springer),and English scientific books by using keywords including kidney,injury,recent therapy,and pharmacological *** articles were carefully checked for their relevance to the current *** targets of cellular repair or regenerative processes involved in AKI such as autophagy,ferroptosis inhibition,and p53 antagonism seem to be effective in disease *** may help researchers and clinicians to understand how to target the interrelated molecular and cellular mechanisms underlying the pathogenesis of AKI.

关键词： Acute kidney injury Recent therapy Promising pharmacological targets

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Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

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Neural Regeneration research 2025年第11期20卷 3193-3206页

作者： Ling-Xiao Yi Hui Ren Woon Genevieve Saw Li Zeng Eng King Tan Zhi Dong Zhou national Neuroscience Institute Singapore Nanyang Technology University Singapore department of Neurology Singapore General HospitalSingapore Signature research Program in Neuroscience and Behavioral Disorders Duke-NUS Medical SchoolSingapore

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative *** the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and *** induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease *** current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem *** benefits of induced pluripotent stem cell-based research are *** dopaminergic neuron differentiation protocols from induced pluripotent stem cells are *** emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are ***,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

关键词： dopaminergic neurons induced pluripotent stem cells Parkinson's disease stem cell approaches

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Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

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Neural Regeneration research 2025年第3期20卷 873-886页

作者： Ying Wang Xiang Zhang Henrik Biverstål Nicolas GBazan Shuai Tan Nailin Li Makiko Ohshima Marianne Schultzberg Xiaofei Li department of Neurobiology Care Sciences&SocietyDivision of NeurogeriatricsKarolinska InstitutetStockholmSweden department of Neurology Neuroscience CenterThe First Hospital of Jilin UniversityChangchunJilin ProvinceChina department of Physiology and pharmacology Karolinska InstitutetStockholmSweden department of Biosciences and Nutrition Karolinska InstitutetHuddingeSweden Neuroscience Center of Excellence Louisiana State UniversityNew OrleansLAUSA department of Medicine SolnaClinical Pharmacology GroupKarolinska University HospitalStockholmSweden

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

关键词： Alzheimer's disease amyloid-β maresin microglia monocyte neuroinflammation resolution RNA-sequencing specialized pro-resolving lipid mediator

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Protective effects of D-002 on experimentally induced gastroesophageal reflux in rats

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World Journal of Gastroenterology 2014年第8期20卷 2085-2090页

作者： Zullyt Zamora Vivian Molina Rosa Mas Yazmin Ravelo Yohany Perez Ambar Oyarzabal department of pharmacology Centre of Natural ProductsNational Centre for Scientific ResearchHavana 10600Cuba

AIM: To investigate the effects of beeswax alcohols (D-002) on the esophageal damage induced by gastroesophageal reflux (GER) in rats.

关键词： D-002 Beeswax alcohols Esophagitis Gastroesophageal reflux Oxidative stress

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Clinical benefits of biochemical markers of bone turnover in Egyptian children with chronic liver diseases

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World Journal of Gastroenterology 2007年第5期13卷 785-790页

作者： Karam A Mahdy Hanaa H Ahmed Fathia Mannaa Azza Abdel-Shaheed Medical Biochemistry department National Research Centre Egypt Hormones department National Research Centre Egypt Medical Physiology department National Research Centre Egypt Child Health department National Research Centre Egypt

AIM： To investigate the association between serum insulin-like growth factor 1 （IGF-1）, osteocalcin, and parathyroid hormone （PTH） levels with the etiology and clinical condition of patients with chronic liver disease. METHODS： Eighty children with hepatocellular damage were divided into 3 groups according to the etiology of disease infection： bilharziasis （9 patients）, hepatitis B virus （HBV, 12 patients） and hepatitis C virus （HCV, 29 patients）. The Child score index was found as A in 24 patients, B in 22 patients, C in 4 patients. Thirty healthy children served as control ***, HBcAbIgM, HBcAbIgG, and anti-HCV were detected using ELISA technique. HCV-RNA was measured by reverse transcription polymerase chain reaction （RT-PCR）. Antibllharzial antibodies were detected by indirect haemagglutination test. Liver function tests were performed using autoanalyser. Serum IGF-1, osteocalcin and PTH levels were measured by ELISA technique. Abdominal ultrasonography was also conducted. RESULTS： Serum IGF-1 level was significantly lower in all patient groups with liver diseases, while serum osteocalcin and PTH levels were significantly elevated in patients with HBV and HCV infections compared with the control group. Serum osteocalcin and PTH concentrations were measured with the severity of liver disease from Child A to C. Child A patients unexpectedly showed significantly reduced IGF-1 levels in comparison to patients staged as Child B or C. Serum osteocalcin level was negatively correlated with albumin （14.7 ± 0.54 vs 3.6 ± 0.10, P 〈 0.05）, while that for PTH was positively correlated with total protein （70.1 ± 2.17 vs 6.7 ± 0.10, P 〈 0.05） in patients with HCV infection.

关键词： Liver disease Bone turnover Insulin-like growth factor-1 Osteocalcin Parathyroid hormone

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Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

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Neural Regeneration research 2025年第9期20卷 2454-2463页

作者： Victoria Jiménez Carretero IrisÁlvarez-Merz Jorge Hernández-Campano Sergei A.Kirov Jesús M.Hernández-Guijo department of pharmacology and Therapeutic School of MedicineUniv.Autónoma de MadridMadridSpain Ramón y Cajal Institute for Health research(IRYCIS) Neurobiology-Research ServiceHospital Ramón y CajalMadridSpain Institute of Neurobiology Faculty of Mathematics and Natural SciencesHeinrich Heine University DüsseldorfDüsseldorfGermany department of Neuroscience and Regenerative Medicine&department of Neurosurgery Medical College of Georgia at Augusta UniversityAugustaGAUSA

The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is ***,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely *** release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the *** findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma *** amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate *** N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during *** is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor ***,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain *** these pathways co uld highlight new therapeutic targets to mitigate brain injury.

关键词： cell swelling N-methyl-D-aspartate receptor non-excitatory amino acids stroke synaptic transmission

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Mechanisms behind elevated serum levels of plasminogen activator inhibitor-1 in frontotemporal lobar degeneration

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Neural Regeneration research 2025年第8期20卷 2317-2318页

作者： Francesco Angelucci Jakub Hort Memory Clinic Department of NeurologySecond Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic International Clinical research centre St.Anne’s University HospitalBrnoCzech Republic

Frontotemporal lobar degeneration(FTLD)is a form of progressive dementia characterized by degeneration of the frontal and temporal lobes of the *** pathology involves a series of cognitive,behavioral,and neurological ... 详细信息

关键词： degeneration elevated pathology

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