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Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease

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Neural Regeneration research 2024年第4期19卷 725-727页

作者： Jeong Hyun Yoon Chiao-Yin Lee Anthony HV Schapira department of clinical and Movement Neurosciences University College London Institute of Neurology Faculty of Medicine Imperial College London Aligning Science Across Parkinson's(ASAP)Collaborative research Network

Parkinson’s disease(PD,OMIM#168600)is a common neurodegenerative disorder with a global prevalence of approximately 8.5 *** is characterized by four cardinal motor symptoms:bradykinesia,rigidity,resting tremor,and subsequently by postural *** usually involves non-motor symptoms such as rapid eye movement sleep disorder,dementia,anosmia,and autonomic *** gene glucocerebrosidase 1(GBA1),which encodes the lysosomal enzyme glucocerebrosidase(GCase)(IUBMB:EC 3.***.1.45),shows strong linkage with PD;variants of GBA1 are the commonest genetic association with PD(Sidransky et al.,2009).Several mechanisms may underlie the relationship between GBA1 mutations/variants and the molecular pathology of PD(Figure 1A and B).

关键词： cerebro consequences

Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open- label, controlled trial

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Stroke & Vascular neurology 2024年第1期9卷 82-89页

作者： Yunyun Xiong Bruce C V Campbell Marc Fisher Lee H Schwamm Mark Parsons Hao Li Yuesong Pan Xia Meng Xingquan Zhao Yongjun Wang neurology Beijing Tiantan HospitalBeijingChina China National clinical research Center for Neurological Diseases BeijingChina department of Medicine and neurology The University of MelbourneMelbourneVictoriaAustralia neurology Beth Israel Deaconess Medical CenterBostonMassachusettsUSA department of neurology and Comprehensive Stroke Center Massachusetts General HospitalBostonMassachusettsUSA department of neurology University of New South Wales South Western Sydney Clinical SchoolLiverpoolNew South WalesAustralia

Background and purpose Recombinant human TNK tissue-type plasminogen activator(rhTNK-tPA)was not inferior to alteplase for ischaemic stroke within *** study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion(LVO)of anterior circulation beyond *** and design Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III(TRACE III)is a multicentre,prospective,randomised,open-label,blind endpoint,controlled clinical *** who had an ischaemic stroke due to anterior circulation LVO(internal carotid artery,middle cerebral artery M1 and M2 segments)within 4.5–24hours from last known well(including wake-up stroke and no witness stroke)and with salvageable tissue(ischaemic core volumeinstitutes of Health Stroke Scale(NIHSS)at 72 hours,mRS score≤2 at 90 days,the rate of improvement on Tmax>6s at 24 hours and NIHSS score change from baseline at *** outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 *** TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond *** registration number NCT05141305.

关键词： Therapy random Rational

Activation of cerebral Ras-related C3 botulinum toxin substrate(Rac) 1 promotes post-ischemic stroke functional recovery in aged mice

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Neural Regeneration research 2024年第4期19卷 881-886页

作者： Fan Bu Jia-Wei Min Md Abdur Razzaque Ahmad El Hamamy Anthony Patrizz Li Qi Akihiko Urayama Jun Li department of neurology University of Texas Health Science Center department of neurology&Psychology The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine

Brain functional impairment after stroke is common;however,the molecular mechanisms of post-stroke recovery remain *** is well-recognized that age is the most important independent predictor of poor outcomes after stroke as older patients show poorer functional outcomes following *** evidence suggests that axonal regeneration and angiogenesis,the major forms of brain plasticity responsible for post-stroke recovery,diminished with advanced *** studies suggest that Ras-related C3 botulinum toxin substrate(Rac)1 enhances stroke recovery as activation of Rac1 improved behavior recovery in a young mice stroke ***,we investigated the role of Rac1 signaling in long-term functional recovery and brain plasticity in an aged(male,18 to 22 months old C57BL/6J)brain after ischemic *** found that as mice aged,Rac1 expression declined in the *** overexpression of Rac1,using lentivirus encoding Rac1 injected day 1 after ischemic stroke,promoted cognitive(assessed using novel object recognition test)and sensorimotor(assessed using adhesive removal tests)recovery on days 14–*** was accompanied by the increase of neurite and proliferative endothelial cells in the periinfarct zone assessed by *** a reverse approach,pharmacological inhibition of Rac1 by intraperitoneal injection of Rac1 inhibitor NSC23766 for 14 successive days after ischemic stroke worsened the outcome with the reduction of neurite and proliferative endothelial ***,Rac1 inhibition reduced the activation of p21-activated kinase 1,the protein level of brain-derived neurotrophic factor,and increased the protein level of glial fibrillary acidic protein in the ischemic brain on day 28 after *** work provided insight into the mechanisms behind the diminished plasticity after cerebral ischemia in aged brains and identified Rac1 as a potential therapeutic target for improving functional recovery in the older adults after stroke.

关键词： aging angiogenesis brain-derived neurotrophic factor(BDNF) cerebral ischemia cognitive recovery neurite Pak1 Rac1 sensorimotor recovery

Relationship Between Short-chain Fatty Acids and Parkinson’s Disease:A Review from Pathology to Clinic

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Neuroscience Bulletin 2024年第4期40卷 500-516页

作者： Wen-Xiang Duan Fen Wang Jun-Yi Liu Chun-Feng Liu department of neurology and clinical research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversitySuzhou215004China department of neurology Dushu Lake Hospital affiliated to Soochow UniversitySuzhou215125China Jiangsu Key Laboratory of Neuropsychiatric Diseases and institute of Neuroscience Soochow UniversitySuzhou215123China

Parkinson’s disease(PD)is a complicated neurodegenerative disease,characterized by the accumulation ofα-synuclein(α-syn)in Lewy bodies and neurites,and massive loss of midbrain dopamine *** evidence suggests that gut microbiota and microbial metabolites are involved in the development of *** these,short-chain fatty acids(SCFAs),the most abundant microbial metabolites,have been proven to play a key role in brain-gut *** this review,we analyze the role of SCFAs in the pathology of PD from multiple dimensions and summarize the alterations of SCFAs in PD patients as well as their correlation with motor and non-motor *** research should focus on further elucidating the role of SCFAs in neuroinflammation,as well as developing novel strategies employing SCFAs and their derivatives to treat PD.

关键词： Parkinson’s disease Short-chain fatty acids Microbial metabolites Brain-gut-microbiota axis

Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning

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Neural Regeneration research 2024年第6期19卷 1284-1290页

作者： Anran Huo Jiali Wang Qi Li Mengqi Li Yuwan Qi Qiao Yin Weifeng Luo Jijun Shi Qifei Cong clinical research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversityInstitute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric DiseasesSoochow UniversitySuzhouJiangsu ProvinceChina department of neurology and clinical research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina

Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural *** brain physiology,highly dynamic microglial processes are facilitated to sense the surrounding environment and *** the brain switches its functional states,microglia are recruited to specific sites to exert their immune functions,including the release of cytokines and phagocytosis of cellular *** crosstalk of microglia between neurons,neural stem cells,endothelial cells,oligodendrocytes,and astrocytes contributes to their functions in synapse pruning,neurogenesis,vascularization,myelination,and blood-brain barrier *** this review,we highlight the neuron-derived“find-me,”“eat-me,”and“don't eat-me”molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain *** review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease,thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

关键词： complement immune signals microglia molecular signal synapse elimination synapse formation synapse refinement synaptic pruning

Calculus bovis in hepatocellular carcinoma:Tumor molecular basis,Wnt/β-catenin pathway role,and protective mechanism

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World Journal of Gastroenterology 2024年第35期30卷 3959-3964页

作者： Khaled Mohamed Mohamed Koriem department of Medical Physiology Medical Research and Clinical Studies InstituteNational Research CentreGiza 12622Egypt

In this editorial,we comment on the recent article by Huang et *** editorial focuses specifically on the molecular mechanisms of hepatocellular carcinoma(HCC),mechanism of Wnt/β-catenin pathway in HCC,and protective mechanism of Calculus bovis(CB)in *** cancer is the fourth most common cause of cancer-related deaths *** most prevalent kind of primary liver cancer,HCC,is typically brought on by long-term viral infections(hepatitis B and C),non-alcoholic steatohepatitis,excessive alcohol consumption,and other conditions that can cause the liver to become chronically inflamed and *** is a wellknown traditional remedy in China and Japan and has been used extensively to treat a variety of diseases,such as high fever,convulsions,and *** in lipid metabolism,cholesterol metabolism,bile acid metabolism,alcohol metabolism,and xenobiotic detoxification lead to fatty liver disease and liver ***,which is a tricarboxylic acid cycle intermediate,is vital to energy production and mitochondrial *** is also thought to be a signaling molecule in metabolism and in the development and spread of liver *** Wnt/β-catenin pathway is made up of a group of proteins that are essential for both adult tissue homeostasis and embryonic *** is frequently caused by the dysregulation of the Wnt/β-catenin signaling *** HCC liver carcinogenesis,Wnt/β-catenin signaling is activated by the expression of downstream target *** between the liver and the gut exists via the portal vein,biliary tract,and systemic ***"gutliver axis"controls intestinal *** of the main factors contributing to the development,progression,and treatment resistance of HCC is the abnormal activation of the Wnt/β-Catenin signaling ***,understanding this pathway is essential to treating *** ingredients of CB,particularly oleanolic acid,ergosterol,and ursolic acid,have anti-p

关键词： Hepatocellular carcinoma MicroRNAs Wnt/β-catenin pathway Calculus bovis Apoptosis

Anti-EGFR antibody monotherapy for colorectal cancer with severe hyperbilirubinemia: A case report

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 557-562页

作者： Toshiaki Tsurui Yuya Hirasawa Yutaro Kubota Kiyoshi Yoshimura Takuya Tsunoda department of Medical Oncology Showa UniversityTokyo 1428555Japan department of clinical Immuno Oncology Clinical Research Institute of Clinical Pharmacology and TherapeuticsShowa UniversityTokyo 1578577Japan

BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,owing to the liver’s diffuse metastatic ***,an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently *** SUMMARY The patient,a man in his 50s,presented with progressive fatigue and severe *** tomography revealed multiple hepatic masses with thick-ened walls in the sigmoid colon,which was pathologically confirmed as a well-differentiated *** RAS or BRAF mutations were *** Eastern Cooperative Oncology Group(ECOG)performance status(PS)score was *** drainage was impossible due to the absence of a dilated bile duct,and panitumumab monotherapy was promptly ***,the bilirubin level decreased and then normalized,and the patient’s PS improved to zero ECOG score after four cycles of therapy without significant adverse *** Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.

关键词： Colorectal neoplasms Panitumumab Chemotherapy Hyperbilirubinemia Jaundice Case report

Hemorrhagic transformation in patients with large-artery atherosclerotic stroke is associated with the gut microbiota and lipopolysaccharide

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Neural Regeneration research 2024年第7期19卷 1532-1540页

作者： Qin Huang Minping Wei Xianjing Feng Yunfang Luo Yunhai Liu Jian Xia department of neurology Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina department of neurology Peking University People’s HospitalBeijingChina clinical research Center for Cerebrovascular Disease of Hunan Province Central South UniversityChangshaHunan ProvinceChina National clinical research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

Hemorrhagic transformation is a major complication of large-artery atheroscle rotic stroke(a major ischemic stro ke subtype)that wo rsens outcomes and increases *** of the gut microbiota is an important feature of stroke,and some specific bacteria and bacterial metabolites may contribute to hemorrhagic transformation *** aimed to investigate the relationship between the gut microbiota and hemorrhagic transformation in largearte ry atheroscle rotic stro *** observational retrospective study was *** May 2020 to September 2021,blood and fecal samples were obtained upon admission from 32 patients with first-ever acute ischemic stroke and not undergoing intravenous thrombolysis or endovascular thrombectomy,as well as 16 healthy *** with stro ke who developed hemorrhagic transfo rmation(n=15)were compared to those who did not develop hemorrhagic transformation(n=17)and with healthy *** gut microbiota was assessed through 16S ribosomal ribonucleic acid *** also examined key components of the lipopolysaccharide pathway:lipopolysaccharide,lipopolysaccharide-binding protein,and soluble *** observed that bacterial diversity was decreased in both the hemorrhagic transformation and non-hemorrhagic transfo rmation group compared with the healthy *** patients with ischemic stro ke who developed hemorrhagic transfo rmation exhibited altered gut micro biota composition,in particular an increase in the relative abundance and dive rsity of members belonging to the Enterobacteriaceae *** lipopolysaccharide and lipopolysaccharide-binding protein levels were higher in the hemorrhagic transformation group compared with the non-hemorrhagic transfo rmation ***,lipopolysaccharide-binding protein,and soluble CD14 concentrations were associated with increased abundance of Enterobacte ***,the role of the gut microbiota in hemorrhagic transformation was evaluated using

关键词： gut microbiota hemorrhagic transformation inflammation lipopolysaccharide stroke

Tenecteplase versus alteplase for acute ischaemic stroke:a meta-analysis of phaseⅢrandomised trials

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Stroke & Vascular neurology 2024年第4期9卷 360-366,I0001-I0021页

作者： Yunyun Xiong Liyuan Wang Guangshuo Li Kai-Xuan Yang Manjun Hao Shuya Li Yuesong Pan Yongjun Wang department of neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National clinical research Center for Neurological Diseases BeijingChina Chinese institute for Brain research BeijingChina Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease BeijingChina

Background Tenecteplase(TNK)was found non-inferior to alteplase in recent clinical *** aimed to elucidate the efficacy and safety of TNK versus alteplase for acute ischaemic stroke(AIS).Methods Systematic literature search and a meta-analysis of phaseⅢclinical trials in ischaemic stroke patients with TNK use were *** primary outcome was excellent functional outcome which was defined as modified Rankin Scale score of 0–1 at 90 days and safety outcomes included symptomatic intracerebral haemorrhage and death at 90 *** used random-effects model to estimate the pooled risk difference and 95%CI in R package‘Meta’.The included trials were adapted to the non-inferiority analysis with a margin of-4%.Results Three trials enrolling 4094 patients were identified by systematic *** trials included AIS patients within 4.5hours time ***-analysis indicated that 1089(53.0%)of 2056 patients in the TNK arm and 1016(50.5%)of 2012 in the alteplase arm had excellent functional outcome at 90 days(0.03(95%CI-0.00 to 0.06);I^(2)=0%),meeting the prespecified non-inferiority *** TNK thrombolysis was not correlated with increased risk of symptomatic intracerebral haemorrhage(0.00(95%CI-0.01 to 0.01);I^(2)=0%)or death(0.01(95%CI-0.01 to 0.02);I^(2)=0%)at 90 *** sensitivity analysis with the 0.25mg/kg trials exclusively showed similar results to the main *** TNK was non-inferior to alteplase for achieving excellent functional outcome at 90 days without increasing the safety concern in treating patients with *** findings suggest that TNK can be an alternative to alteplase.

关键词： analysis random phase