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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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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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Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

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Neural Regeneration Research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen department of pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province Key Laboratory of Inflammation and molecular Drug Target NantongJiangsu ProvinceChina department of Pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

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Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2969-2981页

作者： Mackenzie M.Spicer Jianqi Yang Daniel Fu Alison N.DeVore Marisol Lauffer Nilufer S.Atasoy Deniz Atasoy Rory A.Fisher department of Neuroscience and pharmacology University of Iowa Carver College of MedicineIowa CityIAUSA Iowa Neuroscience Institute University of Iowa Carver College of MedicineIowa CityIAUSA Interdisciplinary Graduate program in molecular Medicine University of Iowa Carver College of MedicineIowa CityIAUSA Neural Circuits and Behavior Core University of Iowa Carver College of MedicineIowa CityIAUSA

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s *** hippocampal neurogenesis is reduced in patients with Alzheimer’s *** stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s ***,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly ***,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in ***,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse *** found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control *** cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal *** hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor ***6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing ***,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

关键词： adult hippocampal neurogenesis Alzheimer’s disease dentate gyrus exercise learning/memory neural precursor cells regulator of G protein signaling 6(RGS6)

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Supramolecular organizing centers(SMOCs) as signaling machines in innate immune activation

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Science China(Life Sciences) 2015年第11期58卷 1067-1072页

作者： QIAO Qi WU Hao department of Biological Chemistry and molecular pharmacology Harvard Medical School program in Cellular and molecular Medicine Boston Children's Hospital

Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.

关键词： innate immunity caspase-recruitment domain pyrin domain supramolecular organizing centers filament

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Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines

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Acta Pharmacologica Sinica 2004年第2期25卷 3-10页

作者： Lian-qing GUO1, Yasushi YAMAZOE2department of clinical pharmacology, Jinling Hospital, Nanjing 210002, China 2Division of Drug Metabolism and molecularToxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan department of clinical pharmacology Jinling Hospital Division of Drug Metabolism and molecular Toxicology Graduate School of Pharmaceutical Sciences Tohoku University

Furanocoumarins (psoralens) exist in various plants and some of them are used to cure skin diseases. Thesechemicals draw attentions recently because of their abilities to arouse drug interaction through inhibition of cyto-chrome P450. Grapefruit juice is a well-known example for food-drug interaction. But in vitro and in vivo studieshave shown that the causative components are mainly furanocoumarin derivatives with geranyloxy side chains. Invitro experiments confirmed that furanocoumarins from grapefruit juice are both competitive and mechanism-based inhibitors of CYP3A4. Although the inhibition appeared to be stronger in the dimers than that in the monomers,all contribute comprehensively to the grapefruit juice-drug interaction. Further experiments with other furanocoumarinsand related citrus fruits or umbelliferous herbal medicines indicate that drug interaction might also occur with stuffsother than grapefruit juice, especially with traditional medicine.

关键词： psoralens grapefruit juice herbal medicine enzyme inhibitors cytochrome P-450 enzyme system drug interaction

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Receptor for advanced glycation end-products axis and coronavirus disease 2019 in inflammatory bowel diseases:A dangerous liaison?

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World Journal of Gastroenterology 2021年第19期27卷 2270-2280页

作者： Armando Rojas Ivan Schneider Cristian Lindner Ileana Gonzalez Miguel Angel Morales Medicine Faculty Catholic University of MauleTalca 3634000Chile department of molecular and clinical pharmacology program Institute of Biomedical SciencesUniversity of ChileSantiago 8320000Chile

Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical *** the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of *** the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)*** soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.

关键词： COVID-19 Inflammatory bowel diseases Advanced glycation Angiotensinconverting enzyme 2 Alarmins Receptor for advanced glycation end-products Receptor for advanced glycation end-products axis Inflammation

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Targeting resolvins in cholestatic liver injury

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Hepatobiliary Surgery and Nutrition 2021年第5期10卷 689-691页

作者： Luis AVidela Rodrigo Valenzuela molecular and clinical pharmacology program Institute of Biomedical ScienceSantiagoChile department of Nutrition Faculty of MedicineUniversity of ChileSantiagoChile

In general terms,the acute inflammatory reaction in conditions of infection or tissue damage is a response of the immune system to cope with survival and return to ***,the reaction is initiated by edema followed by the progressive accumulation of polymorphonuclear leukocytes(PMN)and monocytes that differentiate into macrophages,with production of pro-inflammatory mediators such as leukotrienes(e.g.,LTB4)and prostaglandins(e.g.,PGE2,PGI2,PGF2),which in excess may progress to chronic inflammation(1).Considering that the acute inflammatory response is a protective and self-limited phenomenon,its resolution is an active programmed reaction that is set in by specific pro-resolving mediators(SPMs),which are derived from n-3 polyunsaturated fatty acids(n-3 PUFAs).

关键词： protective acute homeostasis

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Comparative research between Bai-hua Qian-hu,a Chinese traditional plant, and its active ingredient on nuclear factor-κB and tumor necrosis factor-α in isolated ischemia-reperfusion heart of rat

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Chinese Medical Journal 2004年第3期117卷 461-463页

作者：王弛常天辉 department of clinical pharmacology China Medical University

Ischemia-reperfusion (I/R) injury is a complicated pathophysiological process, which is involved in calcium overload, free radical production, metabolic abnormalities, and inflammatory reaction. With the development of modern molecular biology, the expression and regulation of gene in myocardial I/R injury are focused on NF-κB.1Inflammatory reactions play an important role in I/R injury.2 TNF-α, an important inflammatory cytokine, is regulated by NF-κB and counteracts the activation of NF-κB. Sometimes, improper activation of NF-κB can induce excessive inflammatory responses and injury, so, modulation of NF-κB activation may dedicate a new target in alleviation of myocardial I/R injury.3Our previous studies have proved that Bai-hua Qian-hu (Peucedanum praeruptorum Dunn, BQ), a Chinese traditional plant had cardioprotective action in I/R animals.4 Its active ingredient Pd-Ia, a Ca2+-influx blocker5 and K+-channel opener,6 had similar effects. Meanwhile, it relieved inflammatory reaction and apoptosis in I/R myocardium through inhibition of interleukin-6 and Fas, bax, bcl-2 protein expression.7 However, the effects of BQ and Pd-Ia on the activation of NF-κB and the expression of TNF-α in I/R myocardium have not been clear yet. In this study, the effects of BQ and Pd-Ia on these two factors were investigated to further ascertain the molecular protective mechanism of BQ in I/R myocardium.

关键词： Peucedanum praeruptorum Dunn · dl-praeruptorin A · myocardium · ischemia · reperfusion · nuclear factor-κB · t umor necrosis factor-α

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Cannabidiol preferentially binds TRPV2: a novel mechanism of action

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Neural Regeneration Research 2022年第12期17卷 2693-2694页

作者： Elisa Landucci Domenico E.Pellegrini-Giampietro Alessandra Gianoncelli Giovanni Ribaudo department of Health Sciences Section of Clinical Pharmacology and OncologyUniversity of FlorenceFirenzeItaly department of molecular and Translational Medicine University of BresciaBresciaItaly

Plants from the genus Cannabis,and strains of Cannabis sativa in particular,have been used in medicine since ancient *** Cannabis plant contains more than 500 chemical compounds,with two main phytocannabinoids consisting of Δ9-tetrahydrocannabinol(THC),the psychoactive constituent,and cannabidiol(CBD),which does not bear this *** paper aims at providing a perspective on the potential therapeutic effects of CBD based on its preferential interaction with transient potential receptor V2(TRPV2).Many formulations based on Cannabis extract have been licensed for therapeutic use in some Western *** these,the most relevant are Sativex(THC+CBD,used mainly for the treatment of spasticity in multiple sclerosis)and Epidyolex(purified plant-derived CBD,used for some rare childhood epilepsies).

关键词： effect mechanism formulation

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