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Targeting cholesterol trafficking to mitigate axonal degeneration in hereditary spastic paraplegia

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Neural Regeneration Research 2025年第5期20卷 1397-1398页

作者： Zhenyu Chen Xue-Jun Li Department of Biomedical Sciences University of Illinois College of Medicine RockfordRockfordILUSA Department of Bioengineering University of Illinois at ChicagoChicagoILUSA

Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.

关键词： degeneration diseases hereditary

Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling

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Zoological Research 2023年第3期44卷 650-662页

作者： Nicolas James Ho Xiao Chen Yong Lei Shen Gu School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina Dr.Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang 310058China Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province Zhejiang University School of MedicineHangzhouZhejiang 310058China Zhejiang University-University of Edinburgh Institute&School of Basic Medicine Zhejiang University School of MedicineHangzhouZhejiang 310058China Department of Sports Medicine Zhejiang University School of MedicineHangzhouZhejiang 310058China China Orthopedic Regenerative Medicine Group(CORMed) HangzhouZhejiang310058 China School of Medicine The Chinese University of Hong Kong(Shenzhen)ShenzhenGuangdong 518172China The Chinese University of Hong Kong(Shenzhen) Shenzhen Futian Biomedical Innovation R&D CenterShenzhenGuangdong 518172China Key Laboratory for Regenerative Medicine Ministry of EducationSchool of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongHong Kong SARChina Kunming Institute of Zoology-The Chinese University of Hong Kong(KIZ-CUHK)Joint Laboratory of Bioresources and Molecular Research of Common Diseases Hong Kong SARChina Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics The Chinese University of Hong KongHong Kong SARChina

hereditary spastic paraplegia(HSP)is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons.Due to the advancement of next-generation sequencing,more than 70 novel HSP disease-causing genes have been identified in the past decade.Despite this,our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor.One major challenge in studying HSP pathogenicity is selective neuronal vulnerability,characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations,despite the presence of germline disease-causing variants in every cell of the patient.Furthermore,disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration.In the current review,we explore the correlation between transcriptomic data and clinical manifestations,as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice,expression patterns of different genes in the brain during development,and single-cell transcriptomic data from related tissues.Furthermore,we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.

关键词： degeneration transcript hereditary

hereditary fructose intolerance: A comprehensive review

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World Journal of Clinical Pediatrics 2022年第4期11卷 321-329页

作者： Sumit Kumar Singh Moinak Sen Sarma Department of Pediatrics Sri Aurobindo Medical College and PGIIndore 453555Madhya PradeshIndia Department of Pediatric Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical SciencesLucknow 226014India

hereditary fructose intolerance(HFI)is a rare autosomal recessive inherited disorder that occurs due to the mutation of enzyme aldolase B located on chromosome 9q22.3.A fructose load leads to the rapid accumulation of fructose 1-phosphate and manifests with its downstream effects.Most commonly children are affected with gastrointestinal symptoms,feeding issues,aversion to sweets and hypoglycemia.Liver manifestations include an asymptomatic increase of transaminases,steatohepatitis and rarely liver failure.Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency.For confirmation,a genetic test is favored over the measurement of aldolase B activity in the liver biopsy specimen.The crux of HFI management lies in the absolute avoidance of foods containing fructose,sucrose,and sorbitol(FSS).There are many dilemmas regarding tolerance,dietary restriction and occurrence of steatohepatitis.Patients with HFI who adhere strictly to FSS free diet have an excellent prognosis with a normal lifespan.This review attempts to increase awareness and provide a comprehensive review of this rare but treatable disorder.

关键词： hereditary Fructose Intolerance Children Liver Steatohepatitis Aldolase

Short-term nitisinone discontinuation of hereditary tyrosinemia type 1 mice causes metabolic alterations in glutathione metabolism/biosynthesis and multiple amino acid degradation pathways

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Genes & Diseases 2023年第5期10卷 1759-1762页

作者： Colemonts-Vroninks Haaike Norman P.Brendan Van Laere Sven Davison S.Andrew Marcélis Lionel Casimir Georges Goyens Philippe Claes Paul De Bundel Dimitri Martens Geert Ranganath Lakshminarayan Rao Vanhaecke Tamara Gallagher James A De Kock Joery Vrije Universiteit Brussel Liver Therapy&Evolution TeamIn Vitro Toxicology and Dermato-Cosmetology(IVTD)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium Vrije Universiteit Brussel Experimental Pharmacology(EFAR)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium University of Liverpool Dept.of Musculoskeletal&Ageing ScienceInstitute of Life Course&Medical SciencesLiverpool L78TXUnited Kingdom Vrije Universiteit Brussel Interfaculty Center Data Processing and StatisticsFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium Liverpool University Hospitals NHS Foundation Trust Clinical Biochemistry and Metabolic MedicineLiverpool L35PSUnited Kingdom UniversitéLibre de Bruxelles Laboratoire de PédiatrieBrussels B-1050Belgium Vrije Universiteit Brussel In Vitro Liver Disease Modelling TeamIn Vitro Toxicology and Dermato-Cosmetology(IVTD)Research GroupFaculty of Medicine and PharmacyLaarbeeklaan 103Brussels B-1090Belgium AZ Delta General Hospital Department of Laboratory MedicineRoeselare 8800Belgium Ghent University Department of Biomolecular MedicineGhent 9052Belgium

hereditary tyrosinemia type 1(HT1)is a life-threatening disease caused by the patient's inability to break down tyrosine due to loss-of-function mutations in the fumarylacetoacetate hydrolase(FAH)enzyme(Fig.S1).Currently,the only available life-saving treatment is nitisinone(NTBC).However,nitisinone therapy comes with debilitating side effects and requires a strict drug regime combined with a tyrosine-and phenylalanine-restricted diet.Consequently,therapy adherence is often experienced as an additional burden.In this study,transcriptional profiling was conducted parallel to high-resolution metabolomics on,respectively,liver tissue and serum samples of Fah-deficient mice.The experimental workflow of our study is shown in Figure 1A.Canonical pathway analyses showed manifest activation of the NRF2-stress response,associated with hepatocellular damage and mainly driven by a markedly increased oxidative burden.Other altered canonical pathways were primarily a downstream consequence of the latter.Furthermore,we observed an overall aminoacidemia and changes related to aminoacyl-tRNA biosynthesis,which postulates that short-term nitisinone discontinuation can already put the patient at risk for hepatocellular carcinoma development.Finally,we did not only identify changes in numerous pathways,directly and indirectly,related to the metabolism of tyrosine and glutathione but also the presence of“side-chain”metabolites,such as y-glutamyl-and N-acetyl-coupled amino acids,indicating that non-directly related pathways like phase II biotransformation reactions are also affected.

关键词： continuation Figure hereditary

Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis

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International Journal of Oral Science 2023年第3期15卷 489-501页

作者： Jianfan Chen Xueqing Xu Song Chen Ting Lu Yingchun Zheng Zhongzhi Gan Zongrui Shen Shunfei Ma Duocai Wang Leyi Su Fei He Xuan Shang Huiyong Xu Dong Chen Leitao Zhang Fu Xiong Department of Medical Genetics Experimental Education/Administration CenterSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina Experimental Department of Obstetrics and Gynecology Institute The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Precision Medicine Shenzhen HospitalSouthern Medical UniversityShenzhenChina Department of Stomatology Nanfang HospitalSouthern Medical UniversityGuangzhouChina Department of Stomatology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Guangdong Provincial Key Laboratory of Single Cell Technology and Application GuangzhouChina Department of Fetal Medicine and Prenatal Diagnosis Zhujiang HospitalSouthern Medical UniversityGuangzhouChina

hereditary gingival fibromatosis(HGF)is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity.Five distinct loci related to non-syndromic HGF have been identified;however,only two diseasecausing genes,SOS1 and REST,inducing HGF have been identified at two loci,GINGF1 and GINGF5,respectively.Here,based on a family pedigree with 26 members,including nine patients with HGF,we identified double heterozygous pathogenic mutations in the ZNF513(c.C748T,p.R250W)and KIF3C(c.G1229A,p.R410H)genes within the GINGF3 locus related to HGF.Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo.ZNF513,a transcription factor,binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts.Furthermore,a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513(p.R250W)or Kif3c(p.R412H)alone do not led to clear phenotypes with gingival fibromatosis,whereas the double mutations led to gingival hyperplasia phenotypes.In addition,we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1.Moreover,the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels.ZNF513 combined with KIF3C regulates gingival fibroblast proliferation,migration,and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways.In summary,these results demonstrate ZNF513+KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.

关键词： gingival KIF hereditary

hereditary benign telangiectasia without family history in China

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Chinese Medical Journal 2011年第5期124卷 795-796页

作者： CAI Lin SUN Qing-miao ZANG Dong-jie ZHANG Jian-zhong Department of Dermatology Peking University People's Hospital Beijing 100044 China

A case of hereditary benign telangiectasia without family history was reported. A 39-year-old woman presented with small and tiny telangiectases on the face, neck, upper trunk and forearms at birth. The numbers and sizes of the lesions increased gradually and she had no hemorrhagic diathesis and systemic diseases. No similar patients were found in her family. Upon physical examination, telangiectases were found on the face, neck, upper trunk and forearms; and a telangiectatic erythema was found on the right forearm 25 mm ×40 mm in size. Histopathology examination showed a normal epidermis and dilation of the capillaries at upper dermis. hereditary benign telangiectasia without family history was diagnosed.

关键词： hereditary benign telangiectasia

hereditary diffuse gastric cancer: One family's story

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World Journal of Clinical Cases 2018年第1期6卷 1-5页

作者： Haley M Zylberberg Keith Sultan Steven Rubin Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Division of Gastroenterology Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

hereditary diffuse gastric cancer(HDGC) is an inherited form of gastric cancer that carries a poor prognosis. Most HDGCs are caused by an autosomal dominant genetic mutation in the CDH1 gene, which carries a 70%-80% lifetime risk of gastric cancer. Given its submucosal origin, endoscopic surveillance is an unreliable means of early detection, and prophylactic gastrectomy is recommended for CDH1 positive individuals older than age 20 years. We describe the case of a male with recurrent gastric cancer who was diagnosed with HDGC secondary to the CDH1 mutation, and we also describe the patient's pedigree and outcomes of recommended genetic testing.

关键词： hereditary diffuse gastric cancer Genetic testing Genetic diseases Gastric cancer Lobular breast cancer Inheritable diseases

Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias

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Neural Regeneration Research 2019年第4期14卷 574-577页

作者： Yongchao Mou Xue-Jun Li Department of Biomedical Sciences University of Illinois College of Medicine Rockford Department of Bioengineering University of Illinois at Chicago

Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.

关键词： hereditary spastic paraplegia axonal degeneration mitochondrial dynamics fission fusion dynamin-related protein 1 mitochondrial dysfunction induced pluripotent stem cells

hereditary hemorrhagic telangiectasia presenting as a recurrent epistaxis in an adolescent:A case report

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World Journal of Clinical Pediatrics 2021年第1期10卷 1-6页

作者： Ratna Acharya Katherin Portwood Kiran Upadhyay Department of Pediatrics University of FloridaGainesvilleFL 32610United States

BACKGROUND Epistaxis can be an isolated finding or a manifestation of a systemic disease.Some of the potential etiologies are usage of anticoagulants,bleeding disorders,vascular aneurysms,nasal neoplasm,hypertension and nasal steroids.hereditary hemorrhagic telangiectasia(HHT)as a cause of recurrent epistaxis is uncommon.CASE SUMMARY In this report,we describe an 18-year-old adolescent with recurrent epistaxis,mucocutaneous telangiectasia and family history of HHT,consistent with HHT.CONCLUSION Timely diagnosis is needed not only to treat the epistaxis but also to be vigilant for other serious manifestations of this condition.

关键词： Epistaxis Telangiectasia Hemorrhagic hereditary Pediatrics Case report