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Potential of molecular chaperones for treating Alzheimer’s disease

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Neural Regeneration Research 2024年第11期19卷 2343-2344页

作者： Gefei Chen Jan Johansson Department of Biosciences and Nutrition Karolinska InstitutetHuddingeSweden Department of Cell and Molecular Biology Uppsala UniversityUppsalaSweden

Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal *** the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).

关键词： Alzheimer inflammation Aβ

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

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Neural Regeneration Research 2025年第1期20卷 41-53页

作者： Alessio Canovai Pete A.Williams Department of Biology University of PisaPisaItaly Department of Clinical Neuroscience Division of Eye and VisionSt.Erik Eye HospitalKarolinska InstitutetStockholmSweden

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/*** quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary *** quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many *** this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian *** the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and *** quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully ***,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological *** addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

关键词： metabolism mitochondria neurodegenerative disease neuroprotection pyrroloquinoline quinone retinal diseases

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

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General Psychiatry 2024年第1期37卷 103-111页

作者： Viktor H Ahlqvist Christina Dardani Paul Madley-Dowd Harriet Forbes Jessica Rast Caichen Zhong Renee M Gardner Christina Dalman Kristen Lyal cRAIG Newschaffer Torbjorn Tomson Michael Lundberg Daniel Berglind Neil M Davies Brian K Lee Cecilia Magnusson Dheeraj Rai Department of Global Public Health Karolinska InstitutetStockholmSweden Medical Research Council Integrative Epidemiology Unit Bristol Medical SchoolUniversity of BristolBristolUK Centre for Academic Mental Health Population Health SciencesBristol Medical SchoolUniversity of BristolBristolUK Faculty of Epidemiology and Population Health London School of Hygiene and Tropical MedicineLondonUK A.J.Drexel Autism Institute Drexel UniversityPhiladelphiaPAUSA Department of Epidemiology and Biostatistics School of Public HealthDrexel UniversityPhiladelphiaPAUSA College of Health and Human Development Pennsylvania State UniversityState CollegePAUSA Department of Clinical Neuroscience Karolinska InstitutetStockholmSweden Centre for Epidemiology and Community Medicine Region StockholmStockholmSweden K.G Jebsen Center for Genetic Epidemiology Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway Division of Psychiatry University Collge LondonLondonUK Department of Statistical Sciences University Cllge LondonLondonK NIHR Biomedical Research Centre University of BristoBristolUK Avon and Wiltshire Partnership NHS Mental Health TrustBristolUK

Background Psychiatric comorbidities are common in patients with *** for the co-occurrence of psychiatric conditions and epilepsy remain poorly *** We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these *** Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with *** then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score ***,we assessed the potential bidirectional relationships using two-sample Mendelian *** In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric *** example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric *** Psychiatric comorbidities are common in patients with *** correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric *** findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psy

关键词： epilepsy Psychiat lifetime

Novel rodent models of penetrating traumatic brain injury

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Neural Regeneration Research 2015年第7期10卷 1047-1049页

作者： Stefan Plantman Department of Neuroscience Retziusvag 8 Karolinska Institutet

A penetrating traumatic brain injury（pTBI）occurs when an object impacts the head with sufficient energy to penetrate skin,cranial bone and meninges to inflict injury directly to the brain *** type of injury is parti... 详细信息

关键词： TBI Novel rodent models of penetrating traumatic brain injury

Steroids reduce local inflammatory mediator secretion and mucosal permeability in collagenous colitis patients

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World Journal of Gastroenterology 2006年第43期12卷 7012-7018页

作者： Yesuf Taha Yngve Raab Marie Carlson Anders Larsson Mikael Lrdal Lars Lf Magnus Thrn Departments of Medical Sciences University Hospital Uppsala Sweden Department of Medicine KarolinskaInstitutet Karolinska University Hospital Huddinge Sweden Departments of Medical Sciences University Hospital Uppsala Sweden Departments of Clinical Chemistry University Hospital Uppsala Sweden Department of Medicine KarolinskaInstitutet Karolinska University Hospital Huddinge Sweden Center for Clinical Research Central Hospital Vsters Sweden Department of Surgery Karolinska Institutet South Stockholm General Hospital Stockholm Sweden

AIM：. To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein （ECP）, myeloperoxidase （NPO）, basic fibroblast growth factor （bFGF）, vascular endothelial growth factor （VEGF） and albumin in patients with collagenous colitis （CC）. METHODS： A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice （one and four weeks） after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochemical methods in perfusates and in serum. RESULTS： Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective wellbeing at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant.CONCLUSION： Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.

关键词： Collagenous colitis Inflammatory mediator Steroid treatment Eosinophil cationic protein Basicfibroblast growth factor Vascular endothelial growthfactor

Relationship between abdominal adiposity, cardiovascular fitness, and biomarkers of cardiovascular risk in British adolescents

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Journal of Sport and Health Science 2020年第6期9卷 634-644页

作者： Moira S.Lewitt Julien S.Baker School of Health and Life Sciences University of the West of ScotlandPaisley PA12BEScotlandUK Institute of Clinical Exercise and Health Science School of Health and Life SciencesUniversity of the West of ScotlandLanarkshire G720LHScotlandUK

Background:Puberty is a critical time in the development of overweight and *** aim of this study was to examine relationships between measures of adiposity,cardiovascular fitness,and biomarkers of cardiovascular disease risk in ***:In a cross-sectional study design,129 girls and 95 boys aged 12.9-14.4 years at various stages of puberty were included,along with their mothers(n=217)and fathers(n=207).Anthropometric assessments of adiposity were made,along with cardiovascular physical fitness,using the 20-m shuttle run test,and biomarkers associated with cardiovascular risk,including glucose,insulin,triglyceride,fibrinogen,and C-reactive protein(CRP)***:Waist-to-height ratio values were similar in boys and girls and correlated positively with diastolic blood pressure,insulin,triglyceride,fibrinogen,and CRP concentrations,and inversely with cardiovascular fitness *** thickness measurements were higher in ***-molecular-weight adiponectin concentrations were lower in boys than girls,particularly in late puberty,and CRP levels were *** fitness,maternal body mass index(BMI),and paternal BMI contributed independently to the variance in waist measurements in girls and ***,triceps skinfold thickness,and weight-to-height ratio,but not parental BMI,contributed independently to the variance in cardiovascular ***:There is a relationship between measures of adolescent adiposity and parental weight that involves factors other than cardiovascular *** boys have relatively more abdominal fat than girls and a tendency to have a proinflammatory profile of *** observations suggest that family and social environmental interventions are best undertaken earlier in childhood,particularly among boys.

关键词： Adiposity Cardiovascular fitness Cardiovascular risk Inflammation Puberty

Inhibition of p53 inhibitors:progress,challenges and perspectives

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Journal of Molecular Cell Biology 2019年第7期11卷 586-599页

作者： Gema Sanz Madhurendra Singh Sylvain Peuget Galina Selivanova Department of Microbiology Tumor and Cell BiologyBiomedicum 8CKarolinska InstituteSE17165Sweden

p53 is the major tumor suppressor and the most frequently inactivated gene in cancer.p53 could be disabled either by mutations or by upstream negative regulators,including,but not limited to MDM2 and MDMX.p53 activity is required for the prevention as well as for the eradication of *** of p53 activity in mouse models leads to the suppression of established tumors of different *** findings provide a strong support to the anti-cancer strategy aimed for p53 *** this review,we summarize recent progress in the development of small molecules,which restore the tumor suppressor function of wild-type p53 and discuss their clinical *** discuss different aspects of p53-mediated response,which contribute to suppression of tumors,including non-canonical p53 activities,such as regulation of immune *** targeting p53 inhibitors is a very promising approach,there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

关键词： p53 tumor suppression anti-cancer therapy targeted drugs transcription factor immune response

Surgical reconstruction of spinal cord circuit provides functional return in humans

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Neural Regeneration Research 2017年第12期12卷 1960-1963页

作者： Thomas Carlstedt Nicholas James Marten Risling The Wolfson Centre for Age-Related Diseases King's College London Department of Neuroscience Karolinska Institutet

This mini review describes the current surgical strategy for restoring function after traumatic spinal nerve root avulsion in brachial or lumbosacral plexus injury in man. As this lesion is a spinal cord or central nervous injury functional return depends on spinal cord nerve cell growth within the central nervous system. Basic science, clinical research and human application has demonstrated good and useful motor function after ventral root avulsion followed by spinal cord reimplantation. Recently, sensory return could be demonstrated following spinal cord surgery bypassing the injured primary sensory neuron. Experimental data showed that most of the recovery depended on new growth reinnervating peripheral receptors. Restored sensory function and the return of spinal reflex was demonstrated by electrophysiology and functional magnetic resonance imaging of human cortex. This spinal cord surgery is a unique treatment of central nervous system injury resulting in useful functional return. Further improvements will not depend on surgical improvements. Adjuvant therapy aiming at ameliorating the activity in retinoic acid elements in dorsal root ganglion neurons could be a new therapeutic avenue in restoring spinal cord circuits after nerve root avulsion injury.

关键词： plexus injury root avulsion spinal cord surgery motor sensory recovery adjuvant therapy

VEGFR2 inhibition hampers breast cancer cell proliferation via enhanced mitochondrial biogenesis

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Cancer Biology & Medicine 2021年第1期18卷 139-154页

作者： Hao Ni Min Guo Xuepei Zhang Lei Jiang Shuai Tan Juan Yuan Huanhuan L Cui Yanan Min Junhao Zhang Susanne Schlisio Chunhong Ma Wangjun Liao Monica Nister Chunlin Chen Shuijie Li Nailin Li Department of Gynaecology and Obstetrics Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China karolinska institutet Department of Medicine-SolnaClinical Pharmacology GroupKarolinska University Hospital-SolnaStockholm 17176Sweden karolinska institutet Department of Oncology-PathologyBio ClinicumSolna 17164Sweden State Key Laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China Department of Pathology Zhejiang Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingbo 315211China Department of Hematology Affiliated Hospital of Jining Medical UniversityJining 272000China Department of Cell and Molecular Biology Stockholm 17177Sweden karolinska institutet Department of MicrobiologyTumor and Cell BiologyStockholm 17177Sweden Shandong University Cheeloo Medical College School of Basic MedicineDepartment of ImmunologyJinan 250000China Department of Oncology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China

Objective:Vascular endothelial growth factor(VEGF),apart from its predominant roles in angiogenesis,can enhance cancer cell proliferation,but its mechanisms remain *** purpose of the present study was therefore to identify how VEGF regulates cancer cell ***:VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor,Ki8751,and the breast cancer cell lines,MCF-7 and MDA-MB-231,using flow cytometry,mass spectrometry,immunoblotting,and confocal *** were analyzed using one-way analysis of variance followed by Tukey’s multiple comparison ***:VEGF blockade by Ki8751 significantly reduced cancer cell proliferation,and enhanced breast cancer cell *** spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins,suggesting the involvement of mitochondrial *** microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells,induced endomitosis,and arrested cancer cells in the high aneuploid ***2 knockdown by sh RNAs showed similar effects to those of Ki8751,confirming the specificity of Ki8751 *** mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species(ROS)production,which induced cancer cell ***,Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α,and translocated PGC1αinto the *** PGC1αalterations increased mitochondrial transcription factor A(TFAM)expression and subsequently increased mitochondrial ***:VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis,ROS production,and cell *** findings suggested the anticancer potential of Ki8751 via increased mitochondrial biogenesis and ROS production.

关键词： Breast cancer VEGF VEGFR2 mitochondria TFAM ROS apoptosis