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Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system

Neural Regeneration Research 2017年第8期12卷 1231-1240页

作者： Julia J.Segura-Uribe Rodolfo Pinto-Almazán Angélica Coyoy-Salgado Claudia E.Fuentes-Venado christian guerra-araiza Unidad de Investigacion Modica en Enfermedades Neurologicas Hospital de Especialidades Centro Medico Nacional Siglo XXI Instituto Mexicano del Seguro Social Mexico City Mexico Seccion de Estudios de Posgrado e Investigacion Escuela Superior de Medicina Instituto Politecnico Nacional Mexico City Mexico Unidad de Investigacion Hospital Regional de Alta Especialidad Ixtapaluca Ixtapaluca Mexico Institute for the Developing Mind Children's Hospital Los Angeles Los Angeles CA USA Department of Pediatrics Keck School of Medicine University of Southern California Los Angeles CA USA Consejo Nacional de Ciencia y Tecnologia Mexico City Mexico Clinica de Trastornos del Sueno Universidad Autonoma Metropolitana-Iztapalapa Mexico City Mexico Servicio de Medicina Fisica y Rehabilitacion Hospital General de Zona No. 197 Texcoco Mexico Unidad de Investigacion Modica en Farmacologla Hospital de Especialidades Centro Medico Nacional Siglo XXI Instituto Mexicano del Seguro Social Mexico City Mexico

Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.

关键词： estrogen receptor modulators selective estrogen receptor modulators microtubules neurofilaments tibolone tamoxifen raloxifene

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Effect of tibolone pretreatment on kinases and phosphatases that regulate the expression and phosphorylation of Tau in the hippocampus of rats exposed to ozone

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Neural Regeneration Research 2018年第3期13卷 440-448页

作者： Rodolfo Pinto-Almazán Julia J. Segura-Uribe Marvin A. Soriano-Ursúa Eunice D. Farfán-García Juan M. Gallardo christian guerra-araiza Unidad de Investigación Hospital Regional de Alta Especialidad Ixtapaluca Carretera Federal México-Puebla km 34.5 C.P. 56530. Ixtapaluca State of Mexico Mexico Institute for the Developing Mind Children's Hospital Los Angeles Los Angeles CA USA Department of Pediatrics Keck School of Medicine University of Southern California Los Angeles CA USA Unidad de Investigación Médica en Enfermedades Neurológicas Hospital de Especialidades Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social Av. Cuauhtémoc 330 Col. Doctores. C. P. 06720. Mexico City Mexico Escuela Superior de Medicina Instituto Politécnico Nacional Plan de San Luis y Diaz Mirón Col. Casco de Santo Tomis. C. P. 11340. Mexico City Mexico Unidad de Investigación Médica en Enfermedades Nefrológicas Hospital de Especialidades Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social Av. Cuauhtémoc 330 Col. Doctores. C. P. 06720. Mexico City Mexico Unidad de Investigación Médica en Farmacologia Hospital de Especialidades Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social Av. Cuauhtémoc 330 Col. Doctores. C. P. 06720. Mexico City Mexico

Oxidative stress （OS） is a key process in the development of many neurodegenerative diseases, memory disorders, and other pathological processes related to aging. Tibolone （TIB）, a synthetic hormone used as a treatment for menopausal ymptoms, decreases lipoperoxidation levels, prevents memory impairment and learning disability caused by ozone （O3） exposure. However, it is not clear if TIB could prevent the increase in phosphorylation induced by oxidative stress of the microtubule-associated protein Tau. In this study, the effects of TIB at different times of administration on the phosphorylation of Tau, the activation of glycogen synthase kinase-3β （GSK3β）, and the inactivation of Akt and phosphatases PP2A and PTEN induced by O3 exposure were assessed in adult male Wistar rats. Rats were divided into 10 groups： control group （ozone-free air plus vehicle [C]）, control ＋ TIB group （ozone-free air plus TIB 1 mg/kg [C ＋ TIB]）; 7,15, 30, and 60 days of ozone exposure groups [O3] and 7, 15, 30, and 60 days of TIB 1 mg/kg before ozone exposure groups [O3 ＋ TIB]. The effects of O3 exposure and TIB administration were assessed by western blot analysis of total and phosphorylated Tau, GSK3β, Akt, PP2A, and PTEN proteins and oxidative stress marker nitrotyrosine, and superoxide dismutase activity and lipid peroxidation of malondialdehyde by two different spectrophotometric methods （Marklund and TBARS, respectively）. We observed that O3 exposure increases Tau phosphorylation, which is correlated with decreased PP2A and PTEN protein levels, diminished Akt protein levels, and increased GSK3β protein levels in the hippocampus of adult male rats. The effects of O3 exposure were prevented by the long-term treatment （over 15 days） with TIB. Malondialdehyde and nitrotyrosine levels increased from 15 to 60 days of exposure to O3 in comparison to C group, and superoxide dismutase activity decreased. Furthermore, TIB administration limited the changes induced by O3 exposure. Our results

关键词： tibolone oxidative stress ozone exposure Tau GSK3 hippocampus neuroprotection

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Tibolone modulates neuronal plasticity through regulating Tau, GSK3β/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice

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Neural Regeneration Research 2017年第4期12卷 588-595页

作者： Teresa Neri-Gomez Judith Espinosa-Raya Sofia Diaz Cintra Julia Segura-Uribe Sandra Orozco-Suarez Juan Manuel Gallardo christian guerra-araiza Unidad de Investigación Médica en Farmacología Hospital de Especialidades Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social Ciudad de México México Laboratorio de Farmacología Conductual Escuela Superior de Medicina Instituto Politécnico Nacional Plan de San Luis y Díaz Mirón Col. Sto. Tomás Ciudad de México México Departamento de Neurobiología del Desarrollo y Neurofisiología Instituto de Neurobiología Universidad Nacional Autónoma de México Campus Juriquilla Querétaro Querétaro México Enfermedades Neurológicas (Neurological Diseases) Hospital de Especialidades Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social Ciudad de México México Enfermedades Nefrológicas (Kidney Diseases) Hospital de Especialidades Centro Medico Nacional Siglo XXI Instituto Mexicano del Seguro Social Ciudad de Mexico Mexico

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles （NFTs）; these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone （TIB） have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB （0.01 mg/kg and 1mg/kg, intragastrically for 12 weeks） on the content of total and hyperphosphorylated Tau （PHF-1） proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB： it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes.

关键词： nerve regeneration Tibolone hippocampus aged mice sex steroids Akt GSK3β PI3K neuralplasticity Tau neurofibrillary tangles neural regeneration

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Cellular models of stress resistance may pave ways to fight neurodegenerative diseases

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Neural Regeneration Research 2025年第9期20卷 2579-2580页

作者： Thu Nguyen Minh Pham christian Behl Institute of Pathobiochemistry University Medical Center of the Johannes Gutenberg UniversityMainzGermany

Alzheimer's disease(AD),the most common form of neurodegeneration,is characterized by selective neuronal vulnerability and brain regionselective neuron *** entorhinal cortex and hippoc,ampal CA1 projection neurons are at greater risk in AD whereas other regions display resistance to ***,the cerebellum,a phylogenetically very old region,is affected only very late in the disease progression.

关键词： cortex resistance Alzheimer

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Many faces of neuronal activity manipulation in Drosophila

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Neural Regeneration Research 2025年第9期20卷 2574-2576页

作者： Amber Krebs Steffen Kautzmann christian Klämbt Institut für Neuro-und Verhaltensbiologie MünsterGermany

Animals exhibit complex responses to external and internal *** information is computed by interconnected neurons that express numerous ion channels,which modulate the neuronal membrane *** can neuronal activity orchestrate complex motor patterns or allow learning from previous experience?To answer such questions,we need the ability not only to record,but also to modulate neuronal activity in both space(e.g.,neuronal subsets)and time.

关键词： manipulation potential. neuronal

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Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes

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Neural Regeneration Research 2013年第24期8卷 2290-2302页

作者： Farfán-García Eunice Dalet Trujillo-Ferrara José Guadalupe Castillo-Hernández María del Carmen guerra-araiza christian Humberto Soriano-Ursúa Marvin Antonio Escuela Superior de Medicina Instituto Politécnico Nacional. Plan de San Luis y Díaz Mirón s/n Col. Casco de Santo Tomas

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.

关键词： neural regeneration G-Protein coupled receptors structural biology drug design neurodegenera-tive disorders , oligomedzation biased signaling Parkinson's disease Alzheimer's disease dopa-mine receptors muscarinic receptors grants-supported paper neuroregeneration

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Benzyl Amino Purine and Gibberellic Acid Coupled to Nitrogen-Limited Stress Induce Fatty Acids,Biomass Accumulation,and Gene Expression in Scenedesmus Obliquus

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Phyton-International Journal of Experimental Botany 2021年第2期90卷 515-531页

作者： Hans christian Correa-Aguado Gloria Viviana Cerrillo-Rojas Alejandro Rocha-Uribe Ruth Elena Soria-guerra JoséFrancisco Morales-Domínguez Departamento de Química Centro de Ciencias BásicasUniversidad Autónoma de AguascalientesAguascalientes20131México Facultad de Ciencias Químicas Universidad Autónoma de San Luis PotosíSan Luis Potosí78210México Instituto Politécnico Nacional Unidad Profesional Interdisciplinaria de Ingeniería Campus ZacatecasBlvd.del Bote 202Cerro del Gato Ejido La EscondidaCol.Ciudad AdministrativaZacatecasZAC 98160Mexico

The need for renewable energy sources makes microalgae an essential feedstock for biofuels *** molecular aspects and the response to nitrogen(N)-limited conditions with a phytohormone stimulus in microalgae have been slightly *** this work,Scenedesmus obliquus was used as a study model to analyze the effect of benzyl amino purine(BAP)and gibberellic acid(GA)coupled to nitrogen limitation on cell growth,biomass and fatty *** selected 10^(-5)M BAP increased the biomass by 1.44-fold,and 10^(-6)M GA by *** total lipids also increased by 2.8 and 1.11-fold,*** 10^(-5)M BAP and 10^(-6)M GA addition to *** cultures at different initial nitrogen percentages(N-0,N-25,and N-50)showed a significant increase in cell growth and biomass productivity compared to the unstimulated *** N-0 and GA N-0 produced the highest lipid yields with 55%and 50%,*** lipid profile analysis revealed an increase,particularly in C18:1 and C16:0 fatty *** expression analysis showed an over-expression of acyl carrying protein(ACP),stearoyl-ACP desaturase(SAD),fatty acid acyl-ACP thioesterase(FATA),and diacylglycerol acyltransferase(DGAT)genes,which were mainly induced by nitrogen ***,BAP and GA produced a significant over-expression on these genes in the N-replete *** study shows that BAP and GA,coupled to N limitation stress,can be used to increase the biomass and lipid production in *** for sustainable biofuels.

关键词： Biodiesel gene expression lipids microalgae nitrogen deficiency phytohormones

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Schrodinger and Klein-Gordon theories of black holes from the quantization of the Oppenheimer and Snyder gravitational collapse

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Communications in Theoretical Physics 2023年第9期75卷 122-135页

作者： christian Corda SUNY Polytechnic Institute 13502 UticaNew YorkUSAIstituto Livi59100 PratoTuscanyItaly and International Institute for Applicable Mathematics and Information SciencesB M Birla Science CentreAdarshnagarHyderabad 500063India

The Schrodinger equation of the Schwarzschild black hole(BH) has been recently derived by the author and collaborators. The BH is composed of a particle, the 'electron', interacting with a central field, the 'nucleus'. Via de Broglie's hypothesis, one interprets the 'electron' in terms of BH horizon's modes. Quantum gravity effects modify the BH semi-classical structure at the Schwarzschild scale rather than at the Planck scale. The analogy between this BH Schrodinger equation and the Schrodinger equation of the s states of the hydrogen atom permits us to solve the same equation. The quantum gravitational quantities analogous of the fine structure constant and of the Rydberg constant are not constants, but the dynamical quantities have well-defined discrete spectra. The spectrum of the 'gravitational fine structure constant' is the set of non-zero natural numbers. Therefore, BHs are well-defined quantum gravitational systems obeying Schrodinger's theory: the 'gravitational hydrogen atoms'. By identifying the potential energy in the BH Schrodinger equation as being the gravitational energy of a spherically symmetric shell, a different nature of the quantum BH seems to surface. BHs are self-interacting, highly excited,spherically symmetric, massive quantum shells generated by matter condensing on the apparent horizon, concretely realizing the membrane paradigm. The quantum BH described as a'gravitational hydrogen atom' is a fictitious mathematical representation of the real, quantum BH, a quantum massive shell having a radius equal to the oscillating gravitational *** consequences emerge from this result:(i) BHs have neither horizons nor singularities;(ii) there is neither information loss in BH evaporation, nor BH complementarity, nor firewall paradox. These results are consistent with previous ones by Hawking, Vaz, Mitra and ***, the special relativistic corrections to the BH Schrodinger equation give the BH Klein–Gordon equation and the cor

关键词： quantum black holes information paradox quantum shells quantum levels Schrodinger and Klein-Gordon theories

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Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

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Neural Regeneration Research 2025年第5期20卷 1324-1335页

作者： Hassan Saad Bachar El Baba Ali Tfaily Firas Kobeissy Juanmarco Gutierrez Gonzalez Daniel Refai Gerald R.Rodts christian Mustroph David Gimbel Jonathan Grossberg Daniel L.Barrow Matthew F.Gary Ali M.Alawieh Department of Neurosurgery Emory University School of MedicineAtlantaGAUSA Department of Neurology Yale UniversityNew HavenCTUSA Center for Neurotrauma Multiomics&Biomarkers(CNMB)Morehouse School of MedicineAtlantaGAUSA

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this *** the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing *** this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the *** study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular *** effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord *** this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human *** review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

关键词： complement neuroinflammation neuroplasticity regeneration spinal cord injury targeted therapy

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Insensitive high explosives:Ⅳ. Nitroguanidine-Initiation & detonation

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Defence Technology（防务技术） 2019年第4期15卷 467-487页

作者： Ernst-christian Koch Lutradyn-Energetic Materials

This paper reviews the detonative properties of low bulk density(LBD),high bulk density(HBD)Nitroguanidine(NGu)(1),CAS-No:[556-88-7]and 82 explosive formulations based on NGu reported in the public *** rank the performance of those formulations they are compared with 15 reference compositions containing both standard high explosives such as octogen(HMX)(2),hexogen(RDX)(3),pentaerythritol tetranitrate(PETN)(4),2,4,6-trinitrotoluene(TNT)(5)as well as insensitive high explosives such as 3-nitro-1,2,4-triazolone(NTO)(6),1,3,5-triamino-2,4,6-trinitrobenzene(TATB)(7),1,1-diamino-2,2-dinitroethylene(FOX-7)(8)and N-Guanylurea dinitramide(FOX 12)(9).NGu based formulations are superior to those based on FOX-12 or TATB and are a close match with FOX-7 based explosives,the latter just having higher Gurney Energies(-10%)and slightly higher detonation pressure(+2%).NGu based explosives even reach up to 78% of the detonation pressure,82% Gurney energy and up to 95% of detonation velocity of ***-NGu dissolves in many melt cast eutectics forming dense charges thereby eliminating the need for costly High Bulk Density *** based formulations are at the rock bottom of sensitiveness among all the above-mentioned explosives which contributes to the safety of these *** review gives 132 references to the public *** a review on the synthesis spectroscopy and sensitiveness of Nitroguanidine see Ref.[1].

关键词： Cook-off Detonation Insensitive munitions Nitroguanidine Shock sensitvity

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