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Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models

Translational Neurodegeneration 2023年第1期12卷 479-499页

作者： Alice Drobny Fanni Annamária Boros Denise Balta Susy Prieto Huarcaya Deniz Caylioglu Niyeti Qazi Julia Vandrey Yanni Schneider Jan Philipp Dobert Caleb Pitcairn Joseph Robert Mazzulli Friederike Zunke Department of Molecular Neurology University Hospital ErlangenFriedrich-Alexander University Erlangen-Nürnberg91054 ErlangenGermany Institute of Biochemistry Christian-Albrechts-University KielKielGermany The Ken and Ruth Davee Department of Neurology Northwestern University Feinberg School of MedicineChicagoIL 60611USA.

Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of *** PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid *** aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and *** these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive *** We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical *** We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the *** a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein *** Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal *** appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.

关键词： Dopaminergic neurons iPSC-derived models Lysosome Parkinson’s disease Protein trafficking Synucleinopathy

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A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis

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World Journal of Gastroenterology 2005年第7期11卷 990-999页

作者： Tamás Letoha Csaba Somlai Tamáas Takács Annamária Szabolcs Katalin Jármay Zoltán Rakonczay Jr Péter Hegyi ilona Varga József Kaszaki István Krizbai Imre Boros Ern(?) Duda Erzsébet Kusz Botond Penke Department of Medical Chemistry First Department of Medicine Department of Genetics and Molecular Biology Institute of Surgical Research Institute of Biophysics Institute of Biochemistry

AIM: To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-κB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-κB p50 ***: Pancreatitis was induced in male Wistar rats by administering 2×100 μg/kg body weight of cholecystokininoctapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of ***: All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity,pancreatic levels of TNF-α and il-6, degree of lipid peroxidation, reduced glutathione levels, NF-κB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 *** to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute ***: Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-κB might be clinically useful for the suppression of the severity of acute pancreatitis.

关键词： Acute pancreatitis Peptide delivery Penetratin NF-κB inhibition

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Visual-Motor Perceptual and Reading Processes of Schoolchildren With Attention Deficit Hyperactivity Disorder

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Psychology Research 2021年第5期11卷 236-247页

作者： Isabela Pires Metzner Simone Aparecida Capellini il.ria D’Angelo Noemi Del Bianco Catia Giaconi São Paulo State University“Júlio de Mesquita Filho”(UNESP) São PauloBrazil il.ria D’Angelo Noemi Del BiancoCatia Giaconi

Objectives:Compare and relate the performance of schoolchildren with Attention Deficit Hyperactivity Disorder(ADHD)and with good academic performance in the visual-motor perceptual and reading ***:Twenty schoolchildren,of both genders,aged between nine and 11 years old,participated in this *** were divided into two groups:Group I(GI):comprising 10 students diagnosed with ADHD;and Group II(GII):10 students with good academic performance paired according to gender,age group,and educational level with *** students were submitted to the Developmental Test of Visual Perception(DTVP 3)and Reading Processes Assessment Protocol(PROLEC).Results:There was lower performance of GI compared to GII in the subtests of copying,eye-hand coordination,and figure-ground in the standard score of general visual perception and visual-motor *** presented lower performance in all reading processes except for the punctuation marks *** was a statistically significant difference in the comparison between GI and GII regarding the classification of reading processes.A relationship was identified between the reading and visual perception subtests in the GI students,demonstrating a relationship between the visual perceptual motor skills and the reading processes in the group of students with ***:Schoolchildren with ADHD performed less well than their peers with good academic performance in the visual-motor perceptual and reading skills;such that the worse their performance in the visual-motor perceptual processes,the worse their performance in the reading processes.

关键词： reading assessment visual-motor perception Attention Deficit Hyperactivity Disorder(ADHD) reading

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Phase angle obtained by bioelectrical impedance analysis independently predicts mortality in patients with cirrhosis

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World Journal of Hepatology 2017年第7期9卷 401-408页

作者： Giliane Belarmino Maria Cristina Gonzalez Raquel S Torrinhas Priscila Sala Wellington Andraus Luiz Augusto Carneiro D'Albuquerque Rosa Maria R Pereira Valéria F Caparbo Graziela R Ravacci Lucas Damiani Steven B Heymsfield Dan L Waitzberg Department of Gastroenterology Surgical DivisionFaculdade de Medicina da Universidade de Sao Paulo Postgraduate Program in Health and Behavior Universidade Católica de Pelotas Pennington Biomedical Research Center Laboratory of Bone Metabolism Rheumatology DivisionFaculdade de Medicina da Universidade de Sao Paulo Research Institute Hospital do Coracao de Sao Paulo

AIM To evaluate the prognostic value of the phase angle(PA)obtained from bioelectrical impedance analysis(BIA) for mortality prediction in patients with cirrhosis. METHODS In total, 134 male cirrhotic patients prospectively completed clinical evaluations and nutritional assessment by BIA to obtain PAs during a 36-mo follow-up period. Mortality risk was analyzed by applying the PA cutoff point recently proposed as a malnutrition marker(PA ≤ 4.9°) in Kaplan-Meier curves and multivariate Cox regression models. RESULTS The patients were divided into two groups according to the PA cutoff value(PA > 4.9°, n = 73; PA ≤ 4.9°, n = 61). Weight, height, and body mass index were similar in both groups, but patients with PAs > 4.9° were younger and had higher mid-arm muscle circumference, albumin, and handgrip-strength values and lower severe ascites and encephalopathy incidences, interleukin(il)-6/il-10 ratios and C-reactive protein levels than did patients with PAs ≤ 4.9°(P ≤ 0.05). Forty-eight(35.80%) patients died due to cirrhosis, with a median of 18 mo(interquartile range, 3.3-25.6 mo) follow-up until death. Thirty-one(64.60%) of these patients were from the PA ≤ 4.9° group. PA ≤ 4.9° significantly and independently affected the mortality model adjusted for Model for End-Stage Liver Disease score and age(hazard ratio = 2.05, 95%CI: 1.11-3.77, P = 0.021). In addition, Kaplan-Meier curves showed that patients with PAs ≤ 4.9° were significantly more likely to die. CONCLUSION In male patients with cirrhosis, the PA ≤ 4.9° cutoff was associated independently with mortality and identified patients with worse metabolic, nutritional, and disease progression profiles. The PA may be a useful and reliable bedside tool to evaluate prognosis in cirrhosis.

关键词： Bioelectrical impedance analysis Body composition Phase angle Nutritional assessment Liver disease Cirrhosis Mortality

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Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin,TGF-β1,il-13 and oxidative stress

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World Journal of Gastroenterology 2017年第28期23卷 5146-5157页

作者： Veruska Cintia Alexandrino de Souza Thiago Almeida Pereira Valéria Wanderley Teixeira Helotonio Carvalho Maria Carolina Accioly Brelaz de Castro Carolline Guimaraes D’assuncao Andreia Ferreira de Barros Camila Lima Carvalho Virgínia Maria Barros de Lorena Vláudia Maria Assis Costa Alvaro Aguiar Coelho Teixeira Regina Celia Bressan Queiroz Figueiredo Sheilla Andrade de Oliveira Centro de Pesquisas Aggeu Magalhaes Fundacao Oswaldo Cruz Immunopathogenesis Section Laboratory of Parasitic DiseasesNational Institute of Allergy and Infectious DiseaseNational Institutes of HealthBethesdaMDUSA and Laboratório de Doencas Parasitárias e infecciosasFaculdade de MedicinaUniversidade Federal de Minas Gerais Departamento de Morfologia e Fisiologia Animal Universidade Federal Rural de Pernambuco Departamento de Biofísica e Radiobiologia Universidade Federal de Pernambuco Centro Acadêmico de Vitória Universidade Federal de Pernambuco Departamento de Medicina Tropical Universidade Federal de Pernambuco

To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver *** liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent ***11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (il)-6 and il-1β, in addition to pro-fibrotic factors, such as il-13, transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased, while il-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and *** therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.

关键词： Monocytes Bone marrow mononuclear cells Cell therapy Macrophages Glutathione Liver fibrosis

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Restoration of Motor Function through Delayed Intraspinal Delivery of Human il-10-Encoding Nucleoside-Modified mRNA after Spinal Cord Injury

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Research 2023年第4期2023卷 131-144页

作者： LászlóGál Tamás Bellák Annamária Marton Zoltán Fekécs Drew Weissman Dénes Török Rachana Biju Csaba Vizler Rebeka Kristóf Mitchell B.Beattie Paulo J.C.Lin Norbert Pardi Antal Nógrádi Krisztián Pajer Department of Anatomy Histology and EmbryologyAlbert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary National Biotechnology Laboratory Institute of GeneticsBiological Research CentreSzegedHungary Institute of Biochemistry Biological Research CentreSzegedHungary Department of Medicine University of PennsylvaniaPhiladelphiaPA19104USA Acuitas Therapeutics VancouverBCV6T 1Z3Canada

Efficient in vivo delivery of anti-inflammatory proteins to modulate the microenvironment of an injured spinal cord and promote neuroprotection and functional recovery is a great ***-modified messenger RNA(mRNA)has become a promising new modality that can be utilized for the safe and efficient delivery of therapeutic ***,we used lipid nanoparticle(LNP)-encapsulated human interleukin-10(hil-10)-encoding nucleoside-modified mRNA to induce neuroprotection and functional recovery following rat spinal cord contusion *** administration of hil-10 mRNA-LNP to rats led to a remarkable reduction of the microglia/macrophage reaction in the injured spinal segment and induced significant functional recovery compared to ***,hil-10 mRNA treatment induced increased expression in tissue inhibitor of matrix metalloproteinase 1 and ciliary neurotrophic factor levels in the affected spinal segment indicating a time-delayed secondary effect of il-105 d after *** results suggest that treatment with nucleoside-modified mRNAs encoding neuroprotective factors is an effective strategy for spinal cord injury repair.

关键词： protective Restoration utilized

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