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A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases(vol 66, pg 2330, 2023)

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JOURNAL OF MEDICINAL CHEMISTRY 2023年第4期66卷 2330-2346页

作者： Fontana, Igor C. Souza, Debora G. Souza, Diogo O. Gee, Antony Zimmer, Eduardo R. Bongarzone, Salvatore School of Biomedical Engineering and Imaging Sciences St Thomas’ Hospital King’s College London London SE1 7EH United Kingdom Graduate Program in Biological Sciences: Biochemistry Universidade Federal do Rio Grande do Sul Rua Ramiro Barcelos 2600 90035-003 Porto Alegre Brazil Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet Blickagången 16 - Neo floor seventh 141 83 Stockholm Sweden Brain Institute of Rio Grande do Sul Pontifical Catholic University of Rio Grande do Sul Av. Ipiranga 6681 Porto Alegre Brazil Department of Biochemistry Universidade Federal do Rio Grande do Sul Rua Ramiro Barcelos 2600 90035-003 Porto Alegre Brazil Department of Pharmacology Universidade Federal do Rio Grande do Sul Av. Sarmento Leite 500 sala 90035-003 Porto Alegre Brazil Graduate Program in Biological Sciences: Biochemistry (PPGBioq) and Pharmacology and Therapeutics (PPGFT) Universidade Federal do Rio Grande do Sul Av. Sarmento Leite 500 sala 305 Porto Alegre Brazil McGill University Research Centre for Studies in Aging McGill University Montreal Quebec H4H 1R3 Canada

The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure–activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).

关键词： Central nervous system Monomers Peptides and proteins Rodent models Selectivity

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A Neuronal Activity-Boosting Microglial Function in Post-Anesthetic Emergence:How Microglial-Neuronal Crosstalk May Alter States of Consciousness

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Neuroscience Bulletin 2024年第10期40卷 1590-1592页

作者： Jared VanderZwaag Marie-Eve Tremblay Division of Medical Sciences University of VictoriaVictoriaBCCanada Neuroscience Graduate Program University of VictoriaVictoriaBCCanada Centre for Advanced Materials and Related Technology(CAMTEC) University of VictoriaVictoriaBCCanada Département de médecine moléculaire UniversitéLavalQuébec CityQCCanada Axe Neurosciences Centre de Recherche du CHU de QuébecUniversitéLavalQuébec CityQCCanada Neurology and Neurosurgery Department McGill UniversityMontrealQCCanada Department of Biochemistry and Molecular Biology University of British ColumbiaVancouverBCCanada Institute for Aging and Lifelong Health University of VictoriaVictoriaBCCanada

Glial cells have often been referred to as the support cells of the *** they do have numerous supportive functions,there is emerging research showing they play an active role in shaping the brain and *** the cellular and molecular crosstalk between brain cell types is immensely valuable as this research topic continues to demonstrate that many brain functions are a result of a system of cells working together,rather than any cell type independently.

关键词： showing Boosting immense

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Another wrinkle with age: Aged collagen and intra-peritoneal metastasis of ovarian cancer

Aging and Cancer

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Aging and Cancer 2022年第2期3卷 116-129页

作者： Harper, Elizabeth I. Hilliard, Tyvette S. Sheedy, Emma F. Carey, Preston Wilkinson, Paul Siroky, Michael D. Yang, Jing Agadi, Elizabeth Leonard, Annemarie K. Low, Ethan Liu, Yueying Biragyn, Arya Annunziata, Christina M. Stack, Mary Sharon Department of Chemistry and Biochemistry University of Notre Dame Notre Dame IN United States Harper Cancer Research Institute University of Notre Dame Notre Dame IN United States Integrated Biomedical Sciences Graduate Program University of Notre Dame Notre Dame IN United States National Institute on Aging Bethesda MD United States National Cancer Institute Bethesda MD United States

Background: Age is the most significant risk factor for ovarian cancer (OvCa), the deadliest gynecologic malignancy. Metastasizing OvCa cells adhere to the omentum, a peritoneal structure rich in collagen, adipocytes, and immune cells. Ultrastructural changes in the omentum and the omental collagen matrix with aging have not been evaluated. Aim: The aim of this study was to test the hypothesis that age-related changes in collagen in the ovarian tumor microenvironment promote OvCa metastatic success in the aged host. Methods/Results: Young (3–6 months) and aged mice (20–23 months) were used to study the role of aging in metastatic success. Intra-peritoneal (IP) injection of ID8Trp53^–/– OvCa cells showed enhanced IP dissemination in aged versus young mice. In vitro assays using purified collagen demonstrated reduced collagenolysis of aged fibers, as visualized using scanning electron microscopy (SEM) and quantified with a hydroxyproline release assay. Omental tumors in young and aged mice showed similar collagen deposition;however enhanced intra-tumoral collagen remodeling was seen in aged mice probed with a biotinylated collagen hybridizing peptide (CHP). In contrast, second harmonic generation (SHG) microscopy showed significant differences in collagen fiber structure and organization in omental tissue, and SEM demonstrated enhanced omental fenestration in aged omenta. Combined SHG and Alexa Fluor-CHP microscopy in vivo demonstrated that peri-tumoral collagen was remodeled more extensively in young mice. This collagen population represents truly aged host collagen, in contrast to intra-tumoral collagen that is newly synthesized, likely by cancer-associated fibroblasts. Conclusions: Our results demonstrate that tumors in an aged host can grow with minimal collagen remodeling, while tumors in the young host must remodel peri-tumoral collagen to enable effective proliferation, providing a mechanism whereby age-induced ultrastructural changes in collagen and

关键词： aging collagen metastasis omentum ovarian cancer

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Dysregulated microRNAs in type 2 diabetes and breast cancer:Potential associated molecular mechanisms

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World Journal of Diabetes 2024年第6期15卷 1187-1198页

作者： Alex Cleber Improta-Caria Filipe Ferrari João Lucas Penteado Gomes Paloma Brasilio Villalta Úrsula Paula RenóSoci Ricardo Stein Edilamar M Oliveira Laboratory of Biochemistry and Molecular Biology of the Exercise Physical Education and Sport SchoolUniversity of São PauloSão Paulo 05508-030Brazil Graduate Program in Cardiology and Cardiovascular Sciences Federal University of Rio Grande do SulHospital de Clínicas de Porto AlegrePorto Alegre 90035003Brazil Laboratory of Metabolic Disorders(Labdime) School of Applied SciencesUniversity of Campinas-UNICAMPCampinas 13484-350Brazil Departments of Internal Medicine Molecular Pharmacology and PhysiologyCenter for Regenerative MedicineUSF Health Heart InstituteMorsani College of MedicineUniversity of South FloridaTampaFL 33602United States

Type 2 diabetes(T2D)is a multifaceted and heterogeneous syndrome associated with complications such as hypertension,coronary artery disease,and notably,breast cancer(BC).The connection between T2D and BC is established through processes that involve insulin resistance,inflammation and other *** this comprehension the specific cellular and molecular mechanisms linking T2D to BC,especially through microRNAs(miRNAs),remain *** are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological ***,the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been *** review aims to identify dysregulated miRNAs in both T2D and BC,exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

关键词： Type 2 diabetes Breast cancer MicroRNAs Molecular mechanisms

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Undernutrition during development modulates endoplasmic reticulum stress genes in the hippocampus of juvenile rats: Involvement of oxidative stress

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Brain Research 2022年第0期1797卷 000-000页

作者： Fernandes, Matheus Santos Pedroza, Anderson Apolônio de Andrade Silva, Severina Cássia de Lemos, Maria Daniele Teixeira Bernardo, Elenilson M. Pereira, Allifer R dos Santos, Tony Meireles Lagranha, Claudia Graduate Program in Neuropsychiatry and Behavioral Sciences Federal University of Pernambuco PE Recife Brazil Graduate Program in Biochemistry and Physiology Federal University of Pernambuco PE Recife Brazil Laboratory of Biochemistry and Exercise Biochemistry / CAV Federal University of Pernambuco Vitoria de Santo Antão PE Brazil Physical Education and Sport Department Federal University of Pernambuco PE Recife Brazil

To evaluate whether exercise training mitigates the deleterious effects of undernutrition during the developmental period in juvenile Wistar rats. Pregnant Wistar rats were fed with a diet containing 17 % or 8 % casein during pregnancy and lactation. At 30 days of life, male offspring were divided into 4 groups: Low-Protein non-trained (LS), Low-Protein Trained (LT), Normoprotein non-trained (NS), and Normoprotein Trained (NT). Trained rats performed aerobic exercise training (AET) for 4 weeks, 5 days a week, 1 h a day. 24 h from the last day of training, the animals were sacrificed. The tissues were removed to analyze indicators of mitochondrial metabolism, oxidative stress, and gene expression of GRP78, PERK, ATF6 ER stress markers, and BDNF. The results showed that undernutrition during development promotes deleterious effects on mitochondrial oxidative metabolism and induces reticulum stress in the hippocampus of juvenile rats. On the other hand, AET improves mitochondrial function and increases enzymatic and non-enzymatic antioxidant capacity, as well as declines ER stress. AET at moderate intensity for 4 weeks in male juvenile Wistar rats acts as a lifestyle intervention opposing the negative effects induced by a protein-restricted maternal diet. © 2022

关键词： Brain ER Stress Maternal Low Protein Diet Mitochondria Oxidative Stress Physical Exercise

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The role of exercise in brain DNA damage

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Neural Regeneration Research 2020年第11期15卷 1981-1985页

作者： Thais Cereser Vilela Vanessa Moraes de Andrade Zsolt Radak Ricardo Aurino de Pinho Laboratory of Translational Biomedicine Graduate Program of Health SciencesUniversity of Southern Santa Catarina–UNESCCriciumaSCBrazil Research Institute of Sport Science University of Physical EducationBudapestHungary Laboratory of Exercise Biochemistry in Health Graduate Program in Health SciencesSchool of MedicinePontificia Universidade Catolica do ParanaCuritibaPRBrazil

Cells are constantly subjected to cytotoxic and genotoxic insults resulting in the accumulation of unrepaired damaged DNA,which leads to neuronal *** this way,DNA damage has been implicated in the pathogenesis of neurological disorders,cancer,and *** factors,such as physical exercise,are neuroprotective and increase brain function by improving cognition,learning,and memory,in addition to regulating the cellular redox *** mechanisms are associated with the effects of exercise in the brain,such as reduced production of oxidants,up-regulation of antioxidant capacity,and a consequent decrease in nuclear DNA ***,physical exercise is a potential strategy for further DNA damage ***,the neuroplasticity molecules that respond to different aspects of physical exercise remain *** this review,we discuss the influence of exercise on DNA damage and adjacent mechanisms in the *** discuss the results of several studies that focus on the effects of physical exercise on brain DNA damage.

关键词： aerobic exercise apoptosis brain-derived neurotrophic factor brain DNA damage DNA repair neurodegenerative disease oxidative stress physical exercise strength exercise

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Freedericskz Transitions in the Nematic and Smectic ZA Phases of DIO

arXiv

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arXiv 2025年

作者： Gleeson, J.T. Sprunt, S.N. Jákli, A. Guragain, P. Twieg, R.J. Department of Physics Kent State University KentOH44242 United States Materials Science Graduate Program and Advanced Materials and Liquid Crystal Institute Kent State University KentOH44242 United States Department of Chemistry and Biochemistry Kent State University KentOH44242 United States

The remarkable material DIO presents fascinating behaviors. It has been extensively studied as one of the first materials exhibiting a ferroelectric nematic phase. However, at higher temperatures it exhibits what has been termed the Smectic ZA: identified as an orientationally ordered, antiferroelectric phase with a density modulation in direction perpendicular to the optic axis. At even higher temperatures, this transitions to an apparently normal nematic phase. We have studied the splay-bend Freedericksz transition in the nematic and SmZA phases of the material DIO. Both the magnetic and electric field transitions were utilized. We observed the transitions by measuring effective birefringence and capacitance as well as with polarizing light microscopy. In both the nematic and the SmZA states the field induced transitions resemble (in numerous aspects) the classical Freedericksz transition. These enable determinations of several fundamental material parameters and also reveal intriguing aspects of the SmZA phase, including the surprising behavior of the elastic constants and the dielectric anisotropy. Detailed comparison with Frank elastic theory of the Freedericksz transition [1] shows that the N phase behaves largely as expected, but the transition in the SmZA phase differs significantly. Two specific examples of this are the onset of striations in the Freedericksz distorted state, and the presence of optical biaxiality. The former may be related to the periodic Freedericksz transition [2] as it coincides with a large increase in the splay elastic constant. The latter has been predicted for the SmZA phase, but not previously observed. [3] © 2025, CC BY.

关键词： Antiferroelectricity

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Involvement of matrix metalloproteinase 1 and urokinase-type plasminogen activator in the PKCα-p38 MAPK pathway-mediated progression of human liver cancer cells

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Drug Development Research 2023年第4期84卷 767-776页

作者： Ye, Je-Chiuan Hsieh, Yih-Shou Chen, Pei-Ni Liu, Jer-Yuh Hsieh, Yi-Hsien Department of Bachelor's Degree Program for Indigenous Peoples in Senior Health and Care Management National Taitung University Taitung Taiwan Master Program in Biomedical Science National Taitung University Taitung Taiwan Department of Biochemistry School of Medicine Chung Shan Medical University Taichung Taiwan Clinical Laboratory Chung Shan Medical University Hospital Taichung Taiwan Institute of Medicine Chung Shan Medical University Taichung Taiwan Department of Medical Research Chung Shan Medical University Hospital Taichung Taiwan Center for Molecular Medicine China Medical University Hospital Taichung Taiwan Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan

Our previous studies have shown that the plasminogen activator (PA) and matrix metalloproteinases (MMPs) proteinase systems were highly expressed in highly malignant liver cancer cells and regulated by PKCα. This study investigates whether the PKCα regulation of PA and MMPs systems is conducted through p38 mitogen-activated protein kinase (MAPK) signaling and the pathway is responsible for promoting cell progression. We found that the expressions of p38 MAPK in both highly malignant HA22T/VGH and SK-Hep-1 liver cancer cells were higher than that in other lower malignancy liver cancer cells. Since PKCα activates p38 MAPK in progression of liver cancer, we suspected the PKCα/p38 MAPK signaling pathway to be involved in the regulation of MMPs and PA systems. When SK-Hep-1 cells were treated with SB203580 or DN-p38, only MMP-1 and u-PA mRNA expressions decreased. The p38 MAPK inhibition also decreased the cell migration and invasion. In addition, the mRNA decay assays showed that the higher expressions of MMP-1 and u-PA mRNA in SK-Hep-1 cells were due to the alteration of mRNA stability by p38 MAPK inhibition. Zymography of SK-Hep-1 cells treated with siPKCα vector also showed the decrease of the activity of MMP-1 and u-PA and confirmed changes in mRNA level. Furthermore, only the transfection of MKK6 to the siPKCα-treated SK-Hep-1 stable clone cell restored the attenuation of MMP-1 and u-PA expressions. The treatment of SK-Hep-1 cells with either inhibitor of MMP-1 or u-PA reduced migration, and the reduction was enhanced with both inhibitors. In addition, tumorigenesis was also reduced with both inhibitors. These data suggest a novel finding that MMP-1 and u-PA are critical components in PKCα/MKK6/p38 MAPK signaling pathway which mediates liver cancer cell progression, and that the targeting of both genes may be a viable approach in liver cancer treatment. © 2023 The Authors. Drug Development Research published by Wiley Periodicals LLC.

关键词： liver cancer MMP-1 p38 MAPK PKCα u-PA

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Chaperone proteins as ameliorators of α-synuclein-induced synaptic pathologies: insights into Parkinson’s disease

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Neural Regeneration Research 2021年第6期16卷 1198-1199页

作者： Susan M.L.Banks Audrey T.Medeiros Rui Sousa Eileen M.Lafer Jennifer R.Morgan Department of Biology Florida Southern CollegeLakelandFLUSA Neuroscience Graduate Program Brown UniversityProvidenceRIUSA Department of Biochemistry and Structural Biology and Center for Biomedical Neuroscience The University of Texas Health Science Center at San AntonioSan AntonioTXUSA The Eugene Bell Center for Regenerative Biology&Tissue Engineering Marine Biological LaboratoryWoods HoleMAUSA

α-Synuclein accumulation causes synaptic vesicle trafficking defects and may underlie neurodegenerative disorders:Neurodegenerative disorders,such as Parkinson’s disease(PD)and other synucleinopathies,impact the lives of millions of patients and their *** include PD,dementia with Lewy Bodies(DLB),multiple system atrophy,and several Alzheimer’s Disease *** are clinically characterized by intracellular inclusions called Lewy Bodies,which are rich in atypical aggregates of the protein α-*** dopaminergic neurons in the substantia nigra are particularly susceptible toα-synuclein-induced aggregation and neurodegeneration,glutamatergic neurons in other brain regions(***)are also frequently affected in PD and other synucleinopathies(Schulz-Schaeffer 2010).

关键词： cortex Alzheimer insight

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Influence of conformational change of chain unit on the intrinsic negative thermal expansion of polymers

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Chinese Chemical Letters 2021年第4期32卷 1515-1518页

作者： Qiangsheng Sun Ke Jin Yuhui Huang Jia Guo Thanyada Rungrotmongkol Phornphimon Maitarad Changchun Wang State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science Fudan UniversityShanghai 200433.China Biocatalyst and Environmental Biotechnology Research Unit Department of BiochemistryFaculty of Science and Program in Bioinformatics and Computational BiologyGraduate SchoolChulalongkom UniversityBangkok 10330Thailand Research Center of Nano Science and Technology Shanghai UniversityShanghai 200444China

Negative thermal expansion(NTE) behavior has roused wide interest for the control of thermomechanical properties of functional *** NTE behaviors have been found in kinds of compounds,it remains challenging for polymers to achieve intrinsic NTE *** this work,we systematically studied the conformational change of dibenzocyclooctadiene(DBCOD) derivatives between chair(C) and twist-boat(TB) forms based on density-functional theo ry(DFT) calculations,and found clear evidence of the relationship between the structure of DBCOD units and the thermal contraction behavior of the related *** order to obtain the polymer with NTE property,two conditions should be met for the thermal contracting DBCOD related units as follows:(i) the TB conformation can turn into C conformation as the temperature increases,and(ii) the volume of C conformation is smaller than that of TB *** rule should offer a guidance to exploration of the new intrinsic NTE polymers in the future.

关键词： Negative thermal expansion Conformational change Polyarylamides Density-functional theory Dibenzocyclooctadiene

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