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Stroke & Vascular neurology 2019年第3期4卷 148-153页

作者： Shen Li Kai Liu Rui Zhang Yuan Gao Hui Fang Xinjing Liu Lulu Pei L-Ying Richard Chou Sheng Guan Xinbin Guo Haowen Xu Bo Song Yuming Xu Department of neurology First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Cardio-neurology clinic and clinical Proteomics Research Center and Neuroprotection Research Laboratory Massachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA

Background Lymphocyte to monocyte ratio(LMR)is associated with functional outcome in patients with stroke.But the relationship between the LMR value and the prognosis of cerebral venous sinus thrombosis(CVST)has not been investigated.Methods CVST patients,admitted to the First Affiliated Hospital of Zhengzhou University,were retrospectively identified from November 2010 to January 2017.Functional outcomes of patients were evaluated with the modified Rankin Scale(mRS).Patients were divided into good(mRS 0-2)and poor(mRS 3-6)outcomes groups.Univariate and multivariate Cox regression analyses were used to assess the relationship between LMR and the poor survival outcome.Results A total of 228 patients were included of which 41 had poor outcomes(18.0%).The duration of follow-up was 22 months(6-66 months).LMR(2.3±1.2 vs 3.2±1.8,p<0.01)was significantly lower in the poor outcome group.Multivariate Cox regression analysis showed that LMR(HR 0.726,95%CI 0.546 to 0.964,p=0.027)was a independent predictor of poor prognosis.Conclusions LMR may be a predictor of poor prognosis in CVST patients.

关键词： patients admitted cerebral

Insula and the Immune System:More than mere Co-existence?

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Neuroscience Bulletin 2022年第10期38卷 1271-1273页

作者： Panagiotis Kerezoudis Charles L.Howe Long-Jun Wu Brian N.Lundstrom Jamie J.Van Gompel Department of Neurologic Surgery Mayo ClinicRochesterMNUSA Department of neurology Mayo ClinicRochesterMNUSA

Does the Brain Regulate the Immune System?While long considered to be separate entities,increasing evidence has demonstrated that thebrain and theperipheral immune system interact through bidirectional feedback[1].The brain hosts a vibrant immune environment(e.***.microglia and perivascular macrophages)that is responsible for maintaining the integrity of the central nervous system[2].In addition,the brain is the central regulator of the rest of the body and its homeostasis.

关键词： Immune homeostasis Ins

Mitochondrial complex Ⅰ as a therapeutic target for Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2022年第2期12卷 483-495页

作者： Eugenia Trushina Sergey Trushin Md Fayad Hasan Department of neurology Mayo ClinicRochesterMN 55905USA Department of Molecular Pharmacology and Experimental Therapeutics Mayo ClinicRochesterMN 55905USA

Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data suggest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.

关键词： Mitochondria Mitochondria signaling ComplexⅠinhibitors Alzheimer’s disease Integrated stress response Neuroprotection Mitochondria targeted therapeutics Healthy aging

The proteome of distal nerves: implication in delayed repair and poor functional recovery

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Neural Regeneration Research 2022年第9期17卷 1998-2006页

作者： Song Guo Raymond M.Moore M.Cristine Charlesworth Kenneth L.Johnson Robert J.Spinner Anthony J.Windebank Huan Wang Department of Neurologic Surgery Mayo ClinicRochesterMNUSA Biomedical Statistics and Informatics Mayo ClinicRochesterMNUSA Proteomics Core Mayo ClinicRochesterMNUSA Department of neurology Mayo ClinicRochesterMNUSA

Chronic denervation is one of the key factors that affect nerve regeneration.Chronic axotomy deteriorates the distal nerve stump,causes protein changes,and renders the microenvironment less permissive for regeneration.Some of these factors/proteins have been individually studied.To better delineate the comprehensive protein expression profiles and identify proteins that contribute to or are associated with this detrimental effect,we carried out a proteomic analysis of the distal nerve using an established delayed rat sciatic nerve repair model.Four rats that received immediate repair after sciatic nerve transection served as control,whereas four rats in the experimental group(chronic denervation)had their sciatic nerve repaired after a 12-week delay.All the rats were sacrificed after 16 weeks to harvest the distal nerves for extracting proteins.Twenty-five micrograms of protein from each sample were fractionated in SDS-PAGE gels.NanoLC-MS/MS analysis was applied to the gels.Protein expression levels of nerves on the surgery side were compared to those on the contralateral side.Any protein with a P value of less than 0.05 and a fold change of 4 or higher was deemed differentially expressed.All the differentially expressed proteins in both groups were further stratified according to the biological processes.A PubMed search was also conducted to identify the differentially expressed proteins that have been reported to be either beneficial or detrimental to nerve regeneration.Ingenuity Pathway Analysis(IPA)software was used for pathway analysis.The results showed that 709 differentially expressed proteins were identified in the delayed repair group,with a bigger proportion of immune and inflammatory process-related proteins and a smaller proportion of proteins related to axon regeneration and lipid metabolism in comparison to the control group where 478 differentially expressed proteins were identified.The experimental group also had more beneficial proteins that were downregulated and more detrimental proteins that

关键词： chronic axotomy chronic denervation delayed repair distal nerve functional recovery nerve regeneration peripheral nerve prolonged denervation proteome sciatic nerve sciatic nerve transection

Getting a Sense of ATP in Real Time

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Neuroscience Bulletin 2022年第7期38卷 834-836页

作者： Anthony D.Umpierre Koichiro Haruwaka Long-Jun Wu Department of neurology Mayo ClinicRochesterMN55905USA Department of Neuroscience Mayo ClinicJacksonvilFL32224USA Department of Immunology Mayo ClinicRochesterMN55905USA

Adenosine 5'-triphosphate(ATP)is a purinergic signal that can be sensed by all major cell classes in the brain.ATP is a key signal released during periods of physical damage/injury,inflammation,and neurological events,such as seizures.Understanding ATP signaling in the living brain is complicated by its fast enzymatic degradation,its action at multiple receptors,and its somewhat elusive.

关键词： signal damage somewhat

A shape shifting organelle: unusual mitochondrial phenotype determined with three-dimensional electron microscopy reconstruction

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Neural Regeneration Research 2016年第6期11卷 900-901页

作者： Eugenia Trushina Department of neurology Mayo Clinic Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic

Mitochondria,the powerhouses of the cell,are dynamic organelles that constantly move and change their size and morphology to meet energetic demands of the cell（Wai and Langer,2016）.Recent studies demonstrated that energy production is dependent on the ability of mitochondria to undergo cycles of fission and fusion collectively termed“mitochondrial dynamics”（Youle and van der Bliek,2012）.

关键词： mitochondrial phenotype Langer constantly fission hippocampal neuronal unusual protective deprivation

Significance of age and sex in botulinum neurotoxin dosing for adductor spasmodic dysphonia

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2023年第2期9卷 168-173页

作者： Richard Heyes Charles H.Adler Nan Zhang David G.Lott Stephen F.Bansberg Department of Otorhinolaryngology-Head and Neck Surgery Mayo Clinic ArizonaPhoenixArizonaUSA Department of neurology Mayo Clinic ArizonaPhoenixArizonaUSA Department of Biostatistics and Bioinformatics Mayo Clinic ArizonaPhoenixArizonaUSA

Objectives: This study aims to analyze the impact of age and sex on botulinum neurotoxin (BoNT-A) dosing and outcomes in adductor spasmodic dysphonia (AdSD).Methods: A database review of all spasmodic dysphonia patients treated with BoNT from 1989 to 2018 at the Mayo clinic in Arizona was performed. Only patients who had received ≥4 injections of BoNT-A for AdSD were included. Patients were divided into two cohorts to analyze age, with an age of first treatment cutoff of 60 years. Patients were divided into male and female cohorts to analyze sex.Results: The final analysis included 398 patients. The mean dose of BoNT-A per treatment was significantly higher in the younger cohort (4.4 vs. 3.9 units,p = 0.048). The mean maximal benefit was similar (72% vs. 70%,p = 0.48);however, the mean length of benefit was significantly shorter in younger patients (3.0 vs. 3.6 months,p < 0.01). The mean BoNT-A dose was significantly higher in the female cohort (4.2 vs. 3.6 units,p = 0.02). The mean maximal benefit was similar (69% vs. 75%,p = 0.58), as was the mean length of benefit (3.2 vs. 3.5 months,p = 0.11).Conclusions: This study suggests that age and sex influence BoNT-A dosing and outcomes in AdSD.

关键词： adductor age gender outcomes sex spasmodic dysphonia

Microglial voltage-gated proton channel Hv1 in spinal cord injury

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Neural Regeneration Research 2022年第6期17卷 1183-1189页

作者： Jiaying Zheng Madhuvika Murugan Lingxiao Wang Long-Jun Wu Department of neurology Mayo ClinicRochesterMNUSA Department of Neurosurgery Rutgers Robert Wood Johnson Medical SchoolPiscatawayNJUSA Department of Neuroscience Mayo ClinicJacksonvilleFLUSA Department of Immunology Mayo ClinicRochesterMNUSA

After spinal cord injury,microglia as the first responders to the lesion display both beneficial and detrimental characteristics.Activated microglia phagocyte and eliminate cell debris,release cytokines to recruit peripheral immune cells to the injury site.Excessively activated microglia can aggravate the secondary damage by producing extravagant reactive oxygen species and pro-inflammatory cytokines.Recent studies demonstrated that the voltage-gated proton channel Hv1 is selectively expressed in microglia and regulates microglial activation upon injury.In mouse models of spinal cord injury,Hv1 deficiency ameliorates microglia activation,resulting in alleviated production of reactive oxygen species and pro-inflammatory cytokines.The reduced secondary damage subsequently decreases neuronal loss and correlates with improved locomotor recovery.This review provides a brief historical perspective of advances in investigating voltage-gated proton channel Hv1 and home in on microglial Hv1.We discuss recent studies on the roles of Hv1 activation in pathophysiological activities of microglia,such as production of NOX-dependent reactive oxygen species,microglia polarization,and tissue acidosis,particularly in the context of spinal cord injury.Further,we highlight the rationale for targeting Hv1 for the treatment of spinal cord injury and related disorders.

关键词： Hv1 proton channel ion channels microglia NADPH oxidase pH regulation reactive oxygen species spinal cord injury

Microglia Research in the 100th Year Since Its Discovery

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Neuroscience Bulletin 2020年第3期36卷 303-306页

作者： Anthony DUmpierre Long-Jun Wu Department of neurology Mayo ClinicRochesterMN 55905USA Department of Neuroscience Mayo ClinicJacksonvilleFL 32224USA Department of Immunology Mayo ClinicRochesterMN 55905USA

In 1919,Pio del Rio-Hortega first described a class of cells residing in the brain with a tiny soma and branched architecture distinguishable from astrocytes and neurons.These cells,called microglia or mesoglia,have come to be appreciated as resident immune cells in the central nervous system(CNS).In the year 2019,we review the three most recent advances in microglia research in this 100th year since their discovery(Fig.1).We first discuss their transcriptional diversity,which allows us to appreciate the heterogeneity of microglia across species,development,diseases,and brain regions.We also highlight recent stem cell-based approaches that allow us to study human microglia.

关键词： diseases glia appreciate

Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain

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Neuroscience Bulletin 2023年第3期39卷 368-378页

作者： Sebastian Parusel Min-Hee Yi Christine L.Hunt Long-Jun Wu Department of neurology Mayo ClinicRochesterMN 55905USA Faculty of Psychology and Neuroscience Maastricht UniversityMaastricht MD6200The Netherlands Department of Pain Medicine Mayo ClinicJacksonvilleFL 32224USA Department of Neuroscience Mayo ClinicJacksonvilleFL 32224USA Department of Immunology Mayo ClinicRochesterMN 55905USA

Chronic pain relief remains an unmet medical need.Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis.Particularly,microglia play a crucial role in the development of chronic pain.To better understand the microglial contribution to chronic pain,specific regional and temporal manipulations of microglia are necessary.Recently,two new approaches have emerged that meet these demands.Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs(DREADDs)specifically in microglia.Similarly,optogenetic tools allow for microglial manipulation via the activation of artificially expressed,light-sensitive proteins.Chemo-and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain.This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

关键词： Chronic pain Microglia Optogenetics Chemogenetics DREADDs ReaChR