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Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients:a rare occurrence?

Neural Regeneration Research 2025年第1期20卷 130-138页

作者： Ilaria Martinelli Jessica Mandrioli Andrea Ghezzi Elisabetta Zucchi Giulia Gianferrari Cecilia Simonini Francesco Cavallieri Franco Valzania Department of Neurosciences Azienda Ospedaliero Universitaria di ModenaModenaItaly Clinical and Experimental Medicine Ph.D.Program University of Modena and Reggio EmiliaModenaItaly Department of Biomedical Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly Neurology Unit Neuromotor&Rehabilitation DepartmentAzienda USL-IRCCS di Reggio EmiliaReggio EmiliaItaly

Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

关键词： amyotrophic lateral sclerosis(ALS) autonomic extramotor genotype-phenotype multisystem involvement Parkinson’s disease sensory SOD1 superoxide dismutase 1 urinary vocal cord palsy

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The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis

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Neural Regeneration Research 2023年第7期18卷 1427-1433页

作者： Ilaria Martinelli Elisabetta Zucchi Cecilia Simonini Giulia Gianferrari Giovanna Zamboni Marcello Pinti Jessica Mandrioli Clinical and Experimental Medicine PhD Program University of Modena and Reggio EmiliaModenaItaly Department of Neurosciences Azienda Ospedaliero-Universitaria di ModenaModenaItaly Department of Biomedical Metabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModenaItaly Department of Life Sciences University of Modena and Reggio EmiliaModenaItaly

Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases,the discovery of this gene has been crucial for amyotrophic lateral sclerosis research.Since the identification of superoxide dismutase 1 in 1993,the field of amyotrophic lateral sclerosis genetics has considerably widened,improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis.In this review,we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients.Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients,but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations.We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation.Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis,enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes,which is important for the therapeutic strategy targeting genetic mutations.Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors,including environment and other unidentified agents including modifier genes.

关键词： amyotrophic lateral sclerosis cognitive impairment genotype-phenotype correlation superoxide dismutase 1

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NRF2 signaling cascade in amyotrophic lateral sclerosis:bridging the gap between promise and reality

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Neural Regeneration Research 2024年第5期19卷 1006-1012页

作者： Pauline Tarot Christelle Lasbleiz Jean-Charles Liévens MMDN Univ MontpellierEPHEINSERMMontpellierFrance CNRS ParisFranceEPHEINSERMMontpellierFrance

Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.

关键词： amyotrophic lateral sclerosis C9orf72 NRF2 oxidative defense oxidative stress sulforaphane superoxide dismutase 1 TDP43

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Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

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Neural Regeneration Research 2023年第8期18卷 1679-1683页

作者： Bruno P.Imbimbo Viviana Triaca Camillo Imbimbo Robert Nisticò Department of Research&Development Chiesi FarmaceuticiParmaItaly Institute of Biochemistry and Cell Biology National Research CouncilRomeItaly Department of Brain and Behavioral Sciences University of PaviaPaviaItaly School of Pharmacy Department of BiologyUniversity of Tor Vergataand European Brain Research Institute(EBRI)RomeItaly

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type var

关键词： Alzheimer's disease amyotrophic lateral sclerosis amyloid precursor protein glucocerebrosidase huntingtin Huntington's disease Parkinson's disease presenilin 1 presenilin 2 superoxide dismutase 1

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A candidate protective factor in amyotrophic lateral sclerosis:heterogenous nuclear ribonucleoprotein G

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Neural Regeneration Research 2023年第7期18卷 1527-1534页

作者： Fang Yang Wen-Zhi Chen Shi-Shi Jiang Xiao-Hua Wang Ren-Shi Xu Department of Neurology Jiangxi Provincial People’s HospitalThe Clinical College of Nanchang Medical CollegeThe First Affiliated Hospital of Nanchang Medical CollegeNanchangJiangxi ProvinceChina Department of Geriatrics and General Practice/General Family Medicine Jiangxi Provincial People’s HospitalThe Clinical College of Nanchang Medical CollegeThe First Affiliated Hospital of Nanchang Medical CollegeNanchangJiangxi ProvinceChina

Heterogenous nuclear ribonucleoprotein G is down-regulated in the spinal cord of the Tg(SOD1*G93A)1Gur(TG)amyotrophic lateral sclerosis mouse model.However,most studies have only examined heterogenous nuclear ribonucleoprotein G expression in the amyotrophic lateral sclerosis model and heterogenous nuclear ribonucleoprotein G effects in amyotrophic lateral sclerosis pathogenesis such as in apoptosis are unknown.In this study,we studied the potential mechanism of heterogenous nuclear ribonucleoprotein G in neuronal death in the spinal cord of TG and wild-type mice and examined the mechanism by which heterogenous nuclear ribonucleoprotein G induces apoptosis.Heterogenous nuclear ribonucleoprotein G in spinal cord was analyzed using immunohistochemistry and western blotting,and cell proliferation and proteins(TAR DNA binding protein 43,superoxide dismutase 1,and Bax)were detected by the Cell Counting Kit-8 and western blot analysis in heterogenous nuclear ribonucleoprotein G siRNA-transfected PC12 cells.We analyzed heterogenous nuclear ribonucleoprotein G distribution in spinal cord in the amyotrophic lateral sclerosis model at various time points and the expressions of apoptosis and proliferation-related proteins.Heterogenous nuclear ribonucleoprotein G was mainly localized in neurons.Amyotrophic lateral sclerosis mice were examined at three stages:preonset(60-70 days),onset(90-100 days)and progression(120-130 days).The number of heterogenous nuclear ribonucleoprotein G-positive cells was significantly higher in the anterior horn of the lumbar spinal cord segment of TG mice at the preonset stage than that of control group but lower than that of the control group at the onset stage.The number of heterogenous nuclear ribonucleoprotein G-positive cells in both central canal and surrounding gray matter of the whole spinal cord of TG mice at the onset stage was significantly lower than that in the control group,whereas that of the lumbar spinal cord segment of TG mice was significantly higher than that in the control gr

关键词： amyotrophic lateral sclerosis Bax heterogenous nuclear ribonucleoprotein G heterogenous nuclear ribonucleoprotein G-siRNA neuron death superoxide dismutase 1 TAR DNA binding protein 43 TG(SOD1*G93A)1Gur mice

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Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

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Phenomics 2023年第2期3卷 167-181页

作者： Siqi Dong Xianhong Yin Kun Wang Wenbo Yang Jiatong Li Yi Wang Yanni Zhou Xiaoni Liu Jiucun Wang Xiangjun Chen Department of Neurology Huashan Hospital and Institute of NeurologyFudan UniversityShanghai 200040China National Center for Neurological Disorders Shanghai 200040China Department of Anthropology and Human Genetics School of Life SciencesFudan UniversityShanghai 200438China Human Phenome Institute Fudan UniversityShanghai 200433China

Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity.Recent studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects.To assess the contribution of possible oligogenic inheritance,we profiled a panel of 43 relevant genes in 57 sporadic ALS(sALS)patients and eight familial ALS(fALS)patients from five pedigrees in east China.We filtered rare variants using the combination of the Exome Aggregation Consortium,the 1000 Genomes and the HuaBiao Project.We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype cor-relation.Overall,we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes,among which two sALS and four fALS patients harbored two or more variants.Of note,the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants.Typically,in one fALS pedigree with three variants,the family member with three variants(superoxide dismutase 1(SOD1)p.V48A,Optineurin(OPTN)p.A433V and TANK binding kinase 1(TBK1)p.R573H)exhibited much more severe disease phenotype than the member carrying one variant(TBK1 p.R573H).Our findings suggest that rare variants could exert a negative prognostic effect,thereby supporting the oligogenic inheritance of ALS.

关键词： Amyotrophic lateral sclerosis Oligogenic inheritance Survival superoxide dismutase 1 TANK-binding kinase 1 Optineurin

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TBN improves motor function and prolongs survival in SOD1G93A and TDP-43M337V mouse model of amyotrophic lateral sclerosis

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中国药理学与毒理学杂志 2021年第9期35卷 647-648页

作者： HUANG Chun-hui LI Jun ZHANG Gui-liang LIN Ying-qi LI Cai-juan ZHENG Xiao SONG Xi-cheng HAN Bo-feng GUO Bao-jian TU Zhu-chi ZHANG Jun SUN Ye-wei WANG Yu-qiang YAN Sen ZHANG Zai-jun Institute of New Drug Research Jinan University College of PharmacyGuangzhou 510632China

OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative dis⁃ease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy,weakness and paralysis.Oxida⁃tive stress plays a key role in the pathogenesis of ALS,including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase 1(SOD1).Moreover,although the pathogenesis of ALS is unclear,the abnormal accumulation of TAR DNA-binding pro⁃tein of 43 ku(TDP-43)is a pathological feature that exists in almost all patients.Thus far,there is no drug that can cure ALS/FTLD.Tetramethyl⁃pyrazine nitrone(TBN)is a derivative of tetra⁃methylapyrazine,derived from the traditional Chinese medicine Ligusticum chuanxiong,which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases.TBN is currently under clinical investi⁃gation for several indications including a phaseⅡtrial of ALS.Here,we explored the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse model.METHODS In the SOD1G93A transgenic mouse model,TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits.At the same time,we unilaterally and bilaterally injected the TDP-43M337V virus into the striatum of the WT mouse,and gave the TBN treatment after the mice developed a phenotype.After administering these two models for a period of time,we con⁃ducted behavioral tests,including rotarod test,balance beam test,climbing pole test,etc,to evaluate the efficacy of TBN on SOD1G93A and TDP-43M337V models.Furthermore,we explored the possible mechanism of action of TBN in the treatment of ALS through Western blotting and immunohistochemistry/immunofluorescence staining analysis.RESULTS In the SOD1G93A transgenic mouse model,TBN slowed the pro⁃gression of motor neuron disease as evidenced by improved motor performance,reduced spinal motor neuron loss and the associated glial response,and decreased skeletal muscle fiber denervatio

关键词： amyotrophic lateral sclerosis tetra⁃methylpyrazine nitrone superoxide dismutase 1

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S-adenosyl-L-methionine modifies antioxidant-enzymes,glutathione-biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells

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World Journal of Gastroenterology 2016年第14期22卷 3746-3757页

作者： Sonia Amelia Lozano-Sepulveda Eduardo Bautista-Osorio Jose Angel Merino-Mascorro Marta Varela-Rey Linda Elsa Munoz-Espinosa Paula Cordero-Perez María Luz Martinez-Chantar Ana Maria Rivas-Estilla Department of Biochemistry and Molecular Medicine School of Medicine Autonomous University of Nuevo Leon Monterrey Metabolomic Unit CIC bio GUNE CIBERehd Parque Tecnológico de Bizkaia Liver Unit School of Medicine and Hospital Universitario Autonomous University of Nuevo Leon

AIM: To elucidate the mechanism(s) by which S-adenosyl-L-methionine(SAM) decreases hepatitis C virus(HCV) expression.METHODS: We examined the effects of SAM on viral expression using an HCV subgenomic replicon cell culture system. Huh7 HCV-replicon cells were treated with 1 mmol/L SAM for different times(24-72 h), then total RNA and proteins were isolated. c DNA was synthesized and real time-PCR was achieved to quantify HCV-RNA, superoxide dismutase 1 and 2(SOD-1, SOD-2) catalase, thioredoxin 1, methionine adenosyltransferase 1A and 2A(MAT1A, MAT2A) expression, and GAPDH and RPS18 as endogenous genes. Expression of cellular and viral protein was evaluated by western-blot analysis using antibodies vs HCV-NS5 A, SOD-1, SOD-2, catalase, thioredoxin-1, MAT1 A, MAT2 A, GAPDH and actin. Total glutathione levels were measured at different times by Ellman's recycling method(0-24 h). Reactive oxidative species(ROS) levels were quantified by the dichlorofluorescein assay(0-48 h); Pyrrolidin dithiocarbamate(PDTC) was tested as an antioxidant control and H2O2 as a positive oxidant agent.RESULTS: SAM exposition decreased HCV-RNA levels 50%-70% compared to non-treated controls(24-72 h). SAM induced a synergic antiviral effect with standard IFN treatment but it was independent of IFN signaling. In addition, 1 mmol/L SAM exposition did not modify viral RNA stability, but it needs cellular translation machinery in order to decrease HCV expression. Total glutathione levels increased upon SAM treatment in HCV-replicon cells. Transcriptional antioxidant enzyme expression(SOD-1, SOD-2 and thioredoxin-1) was increased at different times but interestingly, there was no significant change in ROS levels upon SAM treatment, contrary to what was detected with PDTC treatment, where an average 40% reduction was observed in exposed cells. There was a turnover from MAT1A/MAT2 A, since MAT1 A expression was increased(2.5 fold-times at 48 h) and MAT2 A was diminished(from 24 h) upon SAM treatment at both the transcriptional and translational lev

关键词： Hepatitis C virus S-adenosyl-L-methionine superoxide dismutase 1 superoxide dismutase 2 Replication Hepatitis C virus-RNA NS5A Oxidative stress Antioxidants Viral proteins Reactive oxygen species Pyrrolidine dithiocarbamate

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Inhibition of sonic hedgehog signaling aggravates brain damage associated with the down-regulation of Gli1,Ptch1 and SOD1 expression in acute ischemic stroke

Inhibition of sonic hedgehog signaling aggravates brain dama...

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2014中国医师协会中西医结合医师大会

作者：季辉苗江永张祥建杜媛媛刘海超河北医科大学第二医院神经内科

Background and object:Oxidative and cytotoxic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment.Recent studies have indicated that sonic hedgehog(Shh)signaling could protect neurons against oxidative stress by increasing superoxide dismutase 1(SOD1)activity.Gliomaassociated oncogene homolog 1(Gli1)and patched-1(Ptch1)are both components and transcriptional targets of the Shh pathway.Here,we designed this study to determine the effect of inhibition of Shh pathway on the development of cerebral ischemia injury.Methods:Male,Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion(pMCAO).Cyciopamine(0.18 mg/kg),the classical inhibitor of Shh signaling,was stereotactic injected into the lateral cerebral ventricle immediately after pMCAO.At 24 h neurological deficit was evaluated using a modified six point scale;brain water content was measured;infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride(TTC).Immunohistochemistry,reverse transcription-polymerase chain reaction(RT-PCR),Western Blotting and activity assay were used to analyze the expression of Gli1,Ptch1 and SOD1.Results;Compared with Vehicle group,cyciopamine downregulated Gli1,Ptchl and SOD1 in pMCAO-affected brain tissue(P 1.

关键词： Middle cerebral artery occlusion Cyclopamine Glioma-associated oncogene homolog 1 Patched-1 superoxide dismutase 1

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