85 results on '"Shi, Fu-Dong"'
Search Results
2. Interleukin-1β Protection Against Experimental Sepsis in Mice.
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Guo, Hai-lei, Shi, Fu-dong, Zhou, Qi, Liu, Qing-yang, Wang, Yue-xin, Song, Yang, Wu, Zong-sheng, Shi, Yu-hao, Zhang, Liu, Xu, Kai-zhi, and Song, Guo-dong
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ESCHERICHIA coli diseases , *SEPSIS , *BONE marrow cells , *LIVER cells , *ENZYME-linked immunosorbent assay - Abstract
The inflammatory response involving interleukin-1β (IL-1β) has been thought to play an important role in the development of late-phase sepsis. However, in this study, we wanted to explore the possibility of using IL-1β to improve the prognosis of sepsis by triggering local differentiation of bone marrow cells (BMCs) into regulatory dendritic cells (DCs) in vivo, thereby reversing the immune paralysis in late-phase sepsis. Sepsis mouse models were induced by cecal ligation and puncture (CLP) and lethal Escherichia coli O18 infection. Mice were injected intraperitoneally with IL-1β after CLP and after the lethal infection. Septic BMCs and liver immune cells were isolated at 0, 3, 6, 9, and 14 days post-CLP. BMCs and liver cells isolated from septic mice treated with IL-1β were adoptively transferred into CLP mice. GFP+-C57BL/6 parabiosis models were established. Serum IL-1β levels were determined by enzyme-linked immunosorbent assay (ELISA) kit, and the number, ratio, and phenotype of immune cells were observed by flow cytometry. IL-1β treatment improved the survival of sepsis and increased the numbers of BMCs and liver immune cells in septic mice. Moreover, IL-1β stimulation increased the number and the percentage of CD11c−CD45RBhigh DCs in septic BM and liver. Adoptive transfer of septic BMCs, liver immune cells, and CD11c−CD45RBhigh DCs treated with IL-1β into CLP mice attenuated sepsis. IL-1β triggered the redistribution of CD11c−CD45RBhigh DCs as well as BMCs in parabiosis models. IL-1β protects against sepsis by stimulating local proliferation and differentiation of BMCs into CD11c−CD45RBhigh DCs at immune organs and non-immune organs. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Cortical Microhemorrhage Presentation of Small Vessel Primary Angiitis of the Central Nervous System.
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Guo, Ai, Zhang, Zhe, Dong, Ge‐Hong, Su, Lei, Gao, Chenyang, Zhang, Mengting, Shi, Xiaoyu, Wang, Huabing, Zhang, Xinghu, Lu, De‐Hong, Fu, Ying, Jing, Jing, Shi, Fu‐Dong, and Tian, De‐Cai
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CENTRAL nervous system , *VASCULITIS , *MAGNETIC resonance imaging , *CEREBRAL atrophy , *SPINAL cord , *TAKAYASU arteritis , *CEREBRAL amyloid angiopathy - Abstract
Objective: Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV‐PACNS) using 7 T magnetic resonance imaging (MRI). Methods: This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1‐weighted magnetization‐prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility‐weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis. Results: We included 21 patients with SV‐PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral‐like sign." The onset age of patients with coral‐like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral‐like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV‐PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral‐like sign was not observed in patients with large vessel CNS vasculitis. Interpretation: The key characteristics of the coral‐like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV‐PACNS. ANN NEUROL 2024;96:194–203 [ABSTRACT FROM AUTHOR]
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- 2024
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4. Nicotinic Receptor β2 Determines NK Cell-Dependent Metastasis in a Murine Model of Metastatic Lung Cancer.
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Hao, Junwei, Shi, Fu-Dong, Abdelwahab, Mohammed, Shi, Samuel X., Simard, Alain, Whiteaker, Paul, Lukas, Ronald, and Zhou, Qinghua
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NICOTINIC receptors , *KILLER cells , *METASTASIS , *LABORATORY mice , *LUNG cancer , *CANCER research , *NICOTINIC acetylcholine receptors - Abstract
Cigarette smoke exposure markedly compromises the ability of the immune system to protect against invading pathogens and tumorigenesis. Nicotine is a psychoactive component of tobacco products that acts as does the natural neurotransmitter, acetylcholine, on nicotinic receptors (nAChRs). Here we demonstrate that natural killer (NK) cells strongly express nAChR β2. Nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2. This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine. Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies. [ABSTRACT FROM AUTHOR]
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- 2013
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5. Organ-specific features of natural killer cells.
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Shi, Fu-Dong, Ljunggren, Hans-Gustaf, La Cava, Antonio, and Van Kaer, Luc
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KILLER cells , *AUTOIMMUNITY , *CELL communication , *PATHOLOGICAL physiology , *CHEMOKINES - Abstract
Natural killer (NK) cells can be swiftly mobilized by danger signals and are among the earliest arrivals at target organs of disease. However, the role of NK cells in mounting inflammatory responses is often complex and sometimes paradoxical. Here, we examine the divergent phenotypic and functional features of NK cells, as deduced largely from experimental mouse models of pathophysiological responses in the liver, mucosal tissues, uterus, pancreas, joints and brain. Moreover, we discuss how organ-specific factors, the local microenvironment and unique cellular interactions may influence the organ-specific properties of NK cells. [ABSTRACT FROM AUTHOR]
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- 2011
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6. Overexpression of the IGF2-mRNA binding protein p62 in transgenic mice induces a steatotic phenotype
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Tybl, Elisabeth, Shi, Fu-Dong, Kessler, Sonja M., Tierling, Sascha, Walter, Jörn, Bohle, Rainer M., Wieland, Stefan, Zhang, Jianying, Tan, Eng M., and Kiemer, Alexandra K.
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GENE expression , *LIVER cancer , *FATTY degeneration , *INSULIN-like growth factor-binding proteins , *MESSENGER RNA , *TRANSGENIC mice , *CHRONIC active hepatitis - Abstract
Background & Aims: The insulin-like growth-factor 2 (IGF2) mRNA binding protein p62 is highly expressed in hepatocellular carcinoma tissue. Still, its potential role in liver disease is largely unknown. In this study, we investigated pathophysiological implications of p62 overexpression in mice. Methods: We generated mice overexpressing p62 under a LAP-promotor. mRNA expression levels and stability were examined by real-time RT-PCR. Allele-specific expression of Igf2 and H19 was assessed after crossing mice with SD7 animals. The Igf2 downstream mediators pAKT and PTEN were determined by Western blot. Results: Hepatic p62 overexpression neither induced inflammatory processes nor liver damage. However, 2.5week old transgenic animals displayed a steatotic phenotype and improved glucose tolerance. p62 overexpression induced the expression of the imprinted genes Igf2 and H19 and their transcriptional regulator Aire (autoimmune regulator). Neither monoallelic expression nor mRNA stability of Igf2 and H19 was affected. Investigating Igf2 downstream signalling pathways showed increased AKT activation and attenuated PTEN expression. Conclusions: The induction of a steatotic phenotype implies that p62 plays a role in hepatic pathophysiology. [Copyright &y& Elsevier]
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- 2011
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7. Natural killer cells as indispensable players and therapeutic targets in autoimmunity.
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Shi, Fu-Dong and Zhou, Qinghua
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KILLER cells , *CYTOLOGY , *AUTOIMMUNITY , *MULTIPLE sclerosis , *NATURAL immunity , *CYTOKINES , *IMMUNE response - Abstract
Natural killer (NK) cells of the innate immune system are equipped with a cytolytic machinery and produce cytokines, which enable these cells to profoundly modify adaptive immune responses to foreign invaders, as well as to self-antigens. Here we discuss the recent advances in understanding how NK cells can proactively influence sequential pathogenic steps that are instrumental for the initiation and progression of autoimmune diseases in human and experimental disease models. We also discuss the possible use of NK cells as a surrogate marker for disease activity and responsiveness to immune therapy. Finally, we present results on NK cell-based therapies in inflammatory and autoimmune disorders with a focus on existing challenges and current promises for the development of more effective therapies. [ABSTRACT FROM AUTHOR]
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- 2011
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8. Autoimmune response to anti-apoptotic protein survivin and its association with antibodies to p53 and c-myc in cancer detection
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Megliorino, Roxanne, Shi, Fu-Dong, Peng, Xuan-Xian, Wang, Xiao, Chan, Edward K.L., Tan, Eng M., and Zhang, Jian-Ying
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PROTEOMICS , *APOPTOSIS , *CANCER , *IMMUNOGLOBULINS , *P53 antioncogene - Abstract
Abstract: Survivin, an inhibitor of apoptotic protein, is over-expressed in many cancers but not in normal differentiated adult tissues. Recently, antibodies to survivin have been demonstrated in patients with lung and colorectal cancer. Whether antibodies to survivin can be used as a marker for the diagnosis of cancer, and how antibody to survivin is related to antibodies against tumor suppressor protein p53 and oncoprotein c-myc remains to be evaluated. In the present study, the full-length recombinant proteins survivin, p53 and c-myc, were expressed and used as antigens in enzyme-linked immunosorbent assay (ELISA) and Western blot for the detection of antibodies to these three proteins. Sera from 1137 patients with 11 different types of cancer were analyzed. Antibodies to survivin were detected in 8.4% (96/1137), with a significant difference from the control groups consisting of normal individuals and autoimmune disease patients (p <0.05). Of 1137 cancer sera, 546 were also tested for the presence of antibodies to p53 and c-myc. Frequencies of antibodies to p53 and c-myc were 11.5 and 12.3%, respectively. Although antibodies to either one of three antigens do not reach levels of sensitivity, which could become routinely useful in diagnosis, it appears that there are different patterns of antibody frequency in individual cancer type. The results also indicated that when the presence of antibody to any one of these three antigens was considered, the cumulative frequency was increased to 27.3% (149/546) for the total group of cancer patients. It became apparent from our data that the combination of antibodies might acquire higher sensitivity. [Copyright &y& Elsevier]
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- 2005
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9. Natural killer cells determine the outcome of B cell?mediated autoimmunity.
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Shi, Fu-Dong, Wang, Hua-Bing, Li, Hulun, Hong, Seokmann, Taniguchi, Masaru, Link, Hans, Kaer, Luc Van, and Ljunggren, Hans-Gustaf
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KILLER cells , *AUTOIMMUNITY , *AUTOIMMUNE diseases , *B cells - Abstract
Natural killer (NK) cells can affect the outcome of adaptive immune responses. NK cells, but not NK1.1+ T cells, were found to participate in the development of myasthenia gravis (a T cell?dependent, B cell? and antibody-mediated autoimmune disease) in C57BL/6 mice. The requirement for NK cells was reflected by the lack of a type 1 helper T cell response and antibodies to the acetylcholine receptor in both NK1.1+ cell?depleted and NK cell?deficient IL-18-/- mice. These findings establish a previously unrecognized link between NK cells and autoreactive T and B cells. [ABSTRACT FROM AUTHOR]
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- 2000
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10. Enhancing natural killer cells is beneficial in multiple sclerosis – No.
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Liu, Qiang and Shi, Fu-Dong
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KILLER cells , *MULTIPLE sclerosis , *INTERLEUKIN-7 , *NATALIZUMAB , *GROWTH factors - Abstract
The article discuss the role of enhancing natural killer (NK) cells in multiple sclerosis (MS). Topics discussed include the role of NK cells to act as early responder of immune system to viral infections and promote cytolytic activity and cytokine secretion; clinical trials with Daclizumab, a humanized monoclonal antibody preventing formation of high-affinity IL-2 receptor; and neurological deficits in experimental autoimmune encephalomyelitis after NK cell depletion.
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- 2019
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11. Multiplex proteomics identifies inflammation-related plasma biomarkers for aging and cardio-metabolic disorders.
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Wu, Siting, Li, Yulin, Zhao, Xue, Shi, Fu-Dong, and Chen, Jingshan
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PROTEOMICS , *OLDER people , *AGING , *DISEASE risk factors , *BIOMARKERS , *BLOOD proteins - Abstract
Background: Cardio-metabolic disorders (CMDs) are common in aging people and are pivotal risk factors for cardiovascular diseases (CVDs). Inflammation is involved in the pathogenesis of CVDs and aging, but the underlying inflammatory molecular phenotypes in CMDs and aging are still unknown. Method: We utilized multiple proteomics to detect 368 inflammatory proteins in the plasma of 30 subjects, including healthy young individuals, healthy elderly individuals, and elderly individuals with CMDs, by Proximity Extension Assay technology (PEA, O-link). Protein-protein interaction (PPI) network and functional modules were constructed to explore hub proteins in differentially expressed proteins (DEPs). The correlation between proteins and clinical traits of CMDs was analyzed and diagnostic value for CMDs of proteins was evaluated by ROC curve analysis. Result: Our results revealed that there were 161 DEPs (adjusted p < 0.05) in normal aging and EGF was the most differentially expressed hub protein in normal aging. Twenty-eight DEPs were found in elderly individuals with CMDs and MMP1 was the most differentially expressed hub protein in CMDs. After the intersection of DEPs in aging and CMDs, there were 10 overlapping proteins: SHMT1, MVK, EGLN1, SLC39A5, NCF2, CXCL6, IRAK4, REG4, PTPN6, and PRDX5. These proteins were significantly correlated with the level of HDL-C, TG, or FPG in plasma. They were verified to have good diagnostic value for CMDs in aging with an AUC > 0.7. Among these, EGLN1, NCF2, REG4, and SLC39A2 were prominently increased both in normal aging and aging with CMDs. Conclusion: Our results could reveal molecular markers for normal aging and CMDs, which need to be further expanded the sample size and to be further investigated to predict their significance for CVDs. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Bruton's tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder.
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Liu, Ye, Huang, Zhenning, Zhang, Tian-Xiang, Han, Bin, Yang, Guili, Jia, Dongmei, Yang, Li, Liu, Qiang, Lau, Alexander Y. L., Paul, Friedemann, Verkhratsky, Alexei, Shi, Fu-Dong, and Zhang, Chao
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BRUTON tyrosine kinase , *B cells , *NEUROMYELITIS optica , *INTERLEUKIN-21 , *CENTRAL nervous system diseases , *MICROGLIA , *TRANSMISSION electron microscopes , *CELL adhesion molecules - Abstract
Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte–microglia interaction, which both contribute to evolution of NMOSD lesions. Main body: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes–microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. Conclusions: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3): Rationale and design of a multicenter randomized placebo-controlled trial.
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Wang, Yongjun, Li, Jiejie, Johnston, S Claiborne, Hankey, Graeme J, Easton, J Donald, Meng, Xia, Shi, Fu-Dong, Wang, Yilong, Zhao, Xingquan, Li, Zixiao, Liu, Liping, Gu, Hongqiu, Jiang, Yong, Wang, Anxin, Pan, Yuesong, Jing, Jing, Niu, Siying, and Li, Hao
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TRANSIENT ischemic attack , *STROKE patients , *ISCHEMIC stroke , *COLCHICINE , *CARDIAC patients , *CORONARY disease - Abstract
Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease. Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1–3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat. Trial registry name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356. [ABSTRACT FROM AUTHOR]
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- 2023
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14. DNA Vaccination With Hsp70 Protects Against Systemic Lupus Erythematosus in (NZB × NZW)F1 Mice.
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Liu, Aijing, Ferretti, Concetta, Shi, Fu‐Dong, Cohen, Irun R., Quintana, Francisco J., and La Cava, Antonio
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THERAPEUTIC use of proteins , *ANIMAL experimentation , *AUTOANTIBODIES , *CELL physiology , *CELL surface antigens , *COMPARATIVE studies , *CYTOKINES , *ENZYME-linked immunosorbent assay , *FLOW cytometry , *IMMUNITY , *IMMUNODIAGNOSIS , *MICE , *SYSTEMIC lupus erythematosus , *DESCRIPTIVE statistics - Abstract
Objective: To address whether a targeted modulation of the abnormal expression of Hsp70 and autoantibodies against this molecule in systemic lupus erythematosus can influence disease. Methods: Lupus‐prone (NZB × NZW)F1 mice that had been DNA‐vaccinated with plasmids encoding Hsp70 and controls were monitored for lupus disease parameters including anti–double stranded DNA (anti‐dsDNA) autoantibodies and cytokines using enzyme‐linked immunosorbent assay, and for kidney function and pathology. The phenotypic and numerical changes in relevant immune cells were evaluated by flow cytometry, and cell function was assessed. Results: Mice that had been DNA‐vaccinated with Hsp70 displayed marked suppression of anti‐dsDNA antibody production, reduced renal disease, and antiinflammatory responses that are associated with a significantly extended survival, compared to controls. These protective effects in Hsp70‐vaccinated mice were associated with an induction of tolerogenic immune responses and an expansion of functional Treg cells. Conclusion: DNA vaccination with Hsp70 suppresses murine lupus by inducing tolerogenic immune responses and antiinflammatory immune responses associated with reduced disease manifestations and increased mouse survival. [ABSTRACT FROM AUTHOR]
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- 2020
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15. Reference intervals for plasma amyloid-β, total tau, and phosphorylated tau181 in healthy elderly Chinese individuals without cognitive impairment.
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Chen, Jingshan, Zhao, Xue, Zhang, Wenyan, Zhang, Tianxiang, Wu, Siting, Shao, Jinghao, and Shi, Fu-Dong
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TAU proteins , *OLDER people , *COGNITION disorders , *ALZHEIMER'S disease , *MILD cognitive impairment , *NEURODEGENERATION - Abstract
Background: Plasma amyloid-β (Aβ) peptides and tau proteins are promising biomarkers of Alzheimer's disease (AD), not only for predicting Aβ and tau pathology but also for differentiating AD from other neurodegenerative diseases. However, reference intervals for plasma biomarkers of AD in healthy elderly Chinese individuals have not yet been established. Methods: Biomarkers of AD were measured using single-molecule array (Simoa) assays in plasma samples from 193 healthy, cognitively unimpaired Chinese individuals aged 50–89 years. The 95% reference intervals for plasma Aβ42, Aβ40, t-tau, p-tau181, and derived ratios were calculated by using log-transformed parametric methods. Results: Plasma Aβ42, Aβ40, and p-tau181 levels were positively correlated with age, while the Aβ42/Aβ40 ratio was negatively correlated with age. The 95% reference intervals for plasma Aβ42 and Aβ40 were 2.72–11.09 pg/mL and 61.4–303.9 pg/mL, respectively, and the 95% reference intervals for plasma t-tau and p-tau181 were 0.20–3.12 pg/mL and 0.49–3.29 pg/mL, respectively. The 95% reference intervals for the Aβ42/Aβ40 ratio, p-tau181/t-tau ratio, and p-tau181/Aβ42 ratio were 0.022–0.064, 0.38–6.34, and 0.05–0.55, respectively. Conclusion: Reference intervals for plasma biomarkers of AD may assist clinicians in making accurate clinical decisions. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.
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Tian, De‐Cai, Shi, Kaibin, Zhu, Zilong, Yao, Jia, Yang, Xiaoxia, Su, Lei, Zhang, Sheng, Zhang, Meixia, Gonzales, Rayna J., Liu, Qiang, Huang, DeRen, Waters, Michael F., Sheth, Kevin N., Ducruet, Andrew F., Fu, Ying, Lou, Min, Shi, Fu‐Dong, Tian, De-Cai, and Shi, Fu-Dong
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STROKE treatment , *THROMBOLYTIC therapy , *FINGOLIMOD , *ALTEPLASE , *DRUG efficacy - Abstract
Objective: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.Methods: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow.Results: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation.Interpretation: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736. [ABSTRACT FROM AUTHOR]- Published
- 2018
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17. Suramin is a novel competitive antagonist selective to α1β2γ2 GABAA over ρ1 GABAC receptors.
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Luo, Hui, Wood, Kristofer, Shi, Fu-Dong, Gao, Fenfei, and Chang, Yongchang
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SURAMIN , *BICUCULLINE , *PROTEIN expression , *MOLECULAR weights , *GABA receptors - Abstract
Abstract GABA A and GABA C receptors are both GABA-gated chloride channels with distinct pharmacological properties, mainly in their sensitivity to bicuculline and gabazine. In this study, we found that suramin, a purinergic receptor antagonist, is a novel competitive antagonist selective to GABA A over GABA C receptors. Specifically, suramin antagonized the GABA-induced current and the spontaneous opening current of the wild type α1β2γ2 GABA A receptor with high-level expression in Xenopus oocytes. The antagonism was concentration dependent with an IC 50 that varied depending on the concentration of GABA, and with the lowest IC 50 of 0.43 μM when antagonizing the spontaneous current. Thus, its potency is slightly higher than bicuculline on the same GABA A receptor. Suramin also antagonized the mouse native brain GABA receptors micro-transplanted into the Xenopus oocytes with its potency depending on the GABA concentration. In addition, in the presence of two fixed concentrations of suramin, the GABA concentration response of the receptor was shifted to the right without reduction of the maximum current. Thus, our results are consistent with that suramin is a competitive antagonist for the α1β2γ2 GABA A receptor. Interestingly, the rank order of maximum allosteric inhibition (efficacy) of spontaneous current of the GABA A receptor by three competitive antagonists was suramin > bicuculline > gabazine, similar to the rank order of their molecular weight. In contrast, similar to bicuculline, suramin has much lower potency in antagonizing the GABA-induced current of the ρ1 GABA C receptor. In conclusion, we have identified a novel GABA A receptor competitive antagonist, which is selective to the α1β2γ2 over ρ1 GABA receptors. Highlights • Suramin antagonized the GABA-induced current of the α1β2γ2 GABA A receptor. • The IC 50 of suramin inhibition was GABA concentration-depended. • Suramin shifted GABA concentration-response to right without reducing the maximum. • Suramin had much lower potency on the wild type ρ1 GABA receptor. [ABSTRACT FROM AUTHOR]
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- 2018
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18. Engineered agrin attenuates the severity of experimental autoimmune myasthenia gravis.
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Li, Zhiguo, Li, Minshu, Wood, Kristofer, Hettwer, Steffan, Muley, Suraj A., Shi, Fu‐Dong, Liu, Qiang, Ladha, Shafeeq S., and Shi, Fu-Dong
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PROTEIN metabolism , *CHOLINERGIC receptors , *ACTION potentials , *ANIMAL experimentation , *AUTOANTIBODIES , *BIOLOGICAL models , *COMPARATIVE studies , *DOSE-effect relationship in pharmacology , *ELECTROMYOGRAPHY , *GENES , *IMMUNIZATION , *RESEARCH methodology , *MEDICAL cooperation , *MUSCULAR atrophy , *MYONEURAL junction , *NERVE tissue proteins , *PEPTIDES , *RATS , *RESEARCH , *SOLUTION (Chemistry) , *EVALUATION research , *SKELETAL muscle , *MEMBRANE glycoproteins , *THERAPEUTICS - Abstract
Introduction: Agrin is essential for the formation and maintenance of neuromuscular junctions (NMJs). NT-1654 is a C-terminal fragment of mouse neural agrin. In this study, we determined the effects of NT-1654 on the severity of experimental autoimmune myasthenia gravis (EAMG).Methods: EAMG was induced in female Lewis rats by immunization with the Torpedo acetylcholine receptor (tAChR) and complete Freund's adjuvant (CFA). NT-1654 was dissolved in phosphate-buffered saline (PBS) and injected daily subcutaneously into tAChR immunized rats during the first 10 days after immunization, and then every other day for the following 20 days.Results: We showed that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats.Discussion: We demonstrated that NT-1654 attenuated clinical severity, effectively promoted the clustering of AChRs at NMJs, and alleviated the impairment of NMJ transmission and the reduction of muscle-specific kinase (MuSK) in EAMG rats. Muscle Nerve 57: 814-820, 2018. [ABSTRACT FROM AUTHOR]- Published
- 2018
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19. Functional Improvement Among Intracerebral Hemorrhage (ICH) Survivors up to 12 Months Post-injury.
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Sreekrishnan, Anirudh, Leasure, Audrey, Shi, Fu-Dong, Hwang, David, Schindler, Joseph, Petersen, Nils, Gilmore, Emily, Kamel, Hooman, Sansing, Lauren, Greer, David, Sheth, Kevin, Leasure, Audrey C, Hwang, David Y, Schindler, Joseph L, Petersen, Nils H, Gilmore, Emily J, Sansing, Lauren H, Greer, David M, and Sheth, Kevin N
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HEMORRHAGE , *BARTHEL Index , *CLINICAL trials , *HOSPITAL admission & discharge , *MEDICAL care , *CEREBRAL hemorrhage , *LONGITUDINAL method , *HEALTH outcome assessment , *PROGNOSIS , *SEVERITY of illness index , *DIAGNOSIS - Abstract
Background and Purpose: As survival rates have increased for intracerebral hemorrhage (ICH) patients, there is limited information regarding recovery beyond 3-6 months. This study was conducted to examine recovery curves using the modified Rankin Scale (mRS) and Barthel Index (BI) up to 12 months post-injury.Methods: We prospectively enrolled 173 patients admitted with ICH who were subsequently evaluated using the mRS and BI at discharge as well as 3, 6, and 12 months. Repeated measures nonparametric testing was conducted to assess functional trajectories across time.Results: The mRS scores showed significant improvement between discharge (median 4) and 3 (median 4), 6 (median 4), and 12 months (median 3) (p values <0.001). However, the mRS scores did not differ between follow-up time-points (i.e., 3-6, 6-12 months). There was significant improvement in scores using the BI (p values <0.001), showing improvement between discharge (mean 43.0) and 3 (mean 73.0), 6 (mean 78.2), and 12 months (mean 83.4). Additionally, there were differences in the BI between 3 and 12 months (p = 0.013), as well as between 6 and 12 months (p = 0.025).Conclusions: The BI may be a more sensitive measure of long-term recovery post-injury than the mRS, which shows minimal improvement for some survivors after 3 months. BI scores indicate survivors continually improve till 12 months post-injury. These results may have implications for the prognostication of ICH and design of clinical trial outcome measures. [ABSTRACT FROM AUTHOR]- Published
- 2017
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20. Targeting CCL5 signaling attenuates neuroinflammation after seizure.
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Zhang, Zhuoran, Li, Yan, Jiang, Shihe, Shi, Fu‐Dong, Shi, Kaibin, and Jin, Wei‐Na
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CHEMOKINE receptors , *SEIZURES (Medicine) , *NEUROINFLAMMATION , *NEUROLOGICAL disorders , *NEURODEGENERATION - Abstract
Background: Epilepsy is a neurological condition that causes unprovoked, recurrent seizures. Accumulating evidence from clinical and experimental studies indicates that neuroinflammation exacerbates seizure activity. Methods: We investigated the transcriptional changes occurring in specific brain domains of a seizure mouse model, using 10× Genomics spatial transcriptomics. Differential gene expression and pathway analysis were applied to investigate potential signaling targets for seizure, including CCL5/CCR5 pathway. Maraviroc, an FDA‐approved C‐C chemokine receptor 5 (CCR5) antagonist, was used to verify the impact of CCL5/CCR5 signaling in seizure mice. Results: We found distinguished regional transcriptome features in the hippocampus of seizure mice. The hippocampus exhibited unique inflammatory gene signatures, including glia activation, apoptosis, and immune response in seizure mice. Especially, we observed notable expression of C‐C chemokine ligand 5 (CCL5) throughout the entire seizure hippocampus. Blockade of CCL5/CCR5 signaling via maraviroc prevented microglia activation and neuron degeneration in seizure mice. Conclusions: This study supports the potential of CCL5/CCR5 signaling for targeting neuroinflammation after seizure. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Brain-derived programmed death-ligand 1 mediates immunosuppression post intracerebral hemorrhage.
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Cheng, Nuo, Wang, Hong, Zou, Ming, Jin, Wei-Na, Shi, Fu-Dong, and Shi, Kaibin
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Immunosuppression commonly occurs after a stroke, which is believed to be associated with the increased risk of infectious comorbidities of stroke patients, while the mechanisms underlying post-stroke immunosuppression is yet to be elucidated. In the brains of intracerebral hemorrhage (ICH) patients and murine ICH models, we identified that neuron-derived programmed death-ligand 1 (PD-L1) is reduced in the perihematomal area, associating increased soluble PD-L1 level in the peripheral blood. ICH induced a significant decrease of T and natural killer (NK) cell numbers in the periphery with an upregulation of programed death-1 (PD-1) in these cells. Blocking PD-1 pathway with an anti-PD1 monoclonal antibody prevented the T and NK cell compartment contraction and spleen atrophy post-ICH, with reduced pulmonary bacterial burden and improved neurological outcome. Thus, we here identified that brain-derived PD-L1 as a new mechanism driving post-stroke immunosuppression, and anti-PD1 treatment could be potentially developed to reducing the risk of post-stroke infections. [ABSTRACT FROM AUTHOR]
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- 2022
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22. The difference of the retinal structural and microvascular characteristics in patients with MOGAD-ON and AQP4-ON.
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Yao, Yajun, Li, Xindi, Xu, Yun, Liang, Xiaofang, Yang, Liu, Shi, Fu-Dong, Zhang, Xinghu, Tian, De-Cai, and Zhang, Xuxiang
- Abstract
Background: Antibodies against myelin-oligodendrocyte-glycoprotein (MOG-Abs) associated disease (MOGAD) has been recognized as a disease entity. Optic neuritis (ON) is the most common symptom in MOGAD. To demonstrate the differences in retinal microvascular characteristics between patients with MOGAD-ON and aquaporin-4 antibody (AQP4-Ab) positive ON.Methods: In a prospective study, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) were used to measure retinal and microvascular parameters.Results: Twenty-six MOGAD-ON eyes, 40 AQP4-ON eyes, and 60 control eyes were included in the study. The thickness of RNFL and GCC in MOGAD-ON eyes was significantly lower than that of HC (p < 0.001, respectively), but comparable to AQP4-ON eyes. The vessel density in retina capillary plexus (RCP) was reduced significantly in MOGAD-ON than that in AQP4-ON (p < 0.05, respectively). The visual accuracy was positively correlated with vessel density of superficial RCP in MOG-ON (p = 0.001) and positively correlated with the thickness of the inner retina layer in AQP4-ON (p < 0.001).Conclusion: The retinal neuro-axonal damages between MOGAD-ON and AQP4-ON were comparable. Unlike AQP4-ON eyes, microvascular densities were significantly reduced in MOGAD-ON and were positively correlated with the deterioration of visual acuity in MOGAD-ON.Trial Registration: Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE, NCT: 04106830). [ABSTRACT FROM AUTHOR]- Published
- 2022
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23. Organ-specific features of natural killer cells.
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Shi, Fu-Dong, Ljunggren, Hans-Gustaf, La Cava, Antonio, and Van Kaer, Luc
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KILLER cells - Abstract
A correction to the article "Organ-specific features of natural killer cells," by Fu-Dong Shi and colleagues is presented.
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- 2011
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24. OR.29. Monocyte Chemoattractant Protein 1 (MCP-1)/CCL2 Influences the Autoantibody Response and Severity of Experimental Autoimmune Myasthenia Gravis
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Shi, Fu-Dong, Liu, Ruolan, Huang, Deren, La Cava, Antonio, Vollmer, Timothy, and Ransohoff, Richard
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- 2006
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25. Activation of P2X4 receptor exacerbates acute brain injury after intracerebral hemorrhage.
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Wu, Si‐Ting, Han, Jin‐Rui, Yao, Nan, Li, Yu‐Lin, Zhang, Fang, Shi, Yao, Shi, Fu‐Dong, and Li, Zhi‐Guo
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BRAIN injuries , *CEREBRAL hemorrhage , *PURINERGIC receptors , *CEREBRAL edema , *BLOOD-brain barrier - Abstract
Introduction: Intracerebral hemorrhage (ICH) accounts for 10%–15% of all strokes and culminates in high mortality and disability. After ICH, brain injury is initiated by the mass effect of hematoma, followed by secondary cytotoxic injury from dying brain cells, hematoma disintegration, and cascading brain immune response. However, the molecular mechanism of secondary cytotoxic brain injury in ICH is not completely understood. The sensitive purinergic receptor, P2X4 receptor (P2X4R), was known to recognize extracellular free ATP released by dying cells during tissue injury. Aims: In this study, we aim to understand the role of P2X4R in acute brain injury triggered by ICH. Results: In this study, we found that the sensitive purinergic receptor, P2X4R, was upregulated in the brain of patients with ICH as well as in a mouse model of ICH induced by collagenase injection. P2X4R blockage with the specific inhibitor 5‐BDBD attenuated brain injury in ICH mice by significantly reducing brain edema, blood–brain barrier leakage, neural death, and ultimately acute neurodeficits. Further study indicated that the protective effect of P2X4R inhibition is related to decreased pro‐inflammatory activity of microglia and recruitment of peripheral immune cells into the hemorrhagic brain. Conclusions: These results suggest that the P2X4 receptor is activated by ICH stimuli which worsen brain injury following ICH. [ABSTRACT FROM AUTHOR]
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- 2022
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26. Brain structural and functional alterations in MOG antibody disease.
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Zhuo, Zhizheng, Duan, Yunyun, Tian, Decai, Wang, Xinli, Gao, Chenyang, Ding, Jinli, Zheng, Fenglian, Zhang, Tian, Zhang, Xinghu, Barkhof, Frederik, Shi, Fu-Dong, and Liu, Yaou
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NEUROMYELITIS optica , *MYELIN oligodendrocyte glycoprotein , *CORPUS callosum , *GRAY matter (Nerve tissue) , *INSULAR cortex , *TEMPORAL lobe - Abstract
Background: The impact of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) on brain structure and function is unknown. Objectives: The aim of this study was to study the multimodal brain MRI alterations in MOGAD and to investigate their clinical significance. Methods: A total of 17 MOGAD, 20 aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4 + NMOSD), and 28 healthy controls (HC) were prospectively recruited. Voxel-wise gray matter (GM) volume, fractional anisotropy (FA), mean diffusivity (MD), and degree centrality (DC) were compared between groups. Clinical associations and differential diagnosis were determined using partial correlation and stepwise logistic regression. Results: In comparison with HC, MOGAD had GM atrophy in frontal and temporal lobe, insula, thalamus, and hippocampus, and WM fiber disruption in optic radiation and anterior/posterior corona radiata; DC decreased in cerebellum and increased in temporal lobe. Compared to AQP4 + NMOSD, MOGAD presented lower GM volume in postcentral gyrus and decreased DC in cerebellum. Hippocampus/parahippocampus atrophy associated with Expanded Disability Status Scale (R = −0.55, p = 0.04) and California Verbal Learning Test (R = 0.62, p = 0.031). The differentiation of MOGAD from AQP4 + NMOSD achieved an accuracy of 95% using FA in splenium of corpus callosum and DC in occipital gyrus. Conclusion: Distinct structural and functional alterations were identified in MOGAD. Hippocampus/parahippocampus atrophy associated with clinical disability and cognitive impairment. [ABSTRACT FROM AUTHOR]
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- 2021
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27. IL-10-Producing Lymphocytes in Inflammatory Disease.
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Yao, Yang, Simard, Alain R., Shi, Fu-Dong, and Hao, Junwei
- Abstract
IL-10 is an anti-inflammatory cytokine that plays a significant role in controlling inflammation and modulating adaptive immune responses that cause tissue damage. IL-10-producing lymphocytes contribute to the delicate balance between inflammation and immunoregulation, and are thus regarded as a kind of 'regulatory cells.' Dysregulation of these cells is linked with susceptibility to numerous inflammatory diseases. In this review, we summarized what is known about the regulatory effects of IL-10 produced by lymphocytes, including T cells, B cells and natural killer cells, in inflammatory diseases. We hope to augment immune responses or prevent immunopathology through making some small changes in the levels of IL-10 produced by lymphocytes, or in the cellular location where it is produced. [ABSTRACT FROM AUTHOR]
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- 2013
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28. Tolerance induced by anti-DNA Ig peptide in (NZB×NZW)F1 lupus mice impinges on the resistance of effector T cells to suppression by regulatory T cells
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Yu, Yiyun, Liu, Yaoyang, Shi, Fu-Dong, Zou, Hejian, Hahn, Bevra H., and La Cava, Antonio
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DNA antibodies , *SYSTEMIC lupus erythematosus , *LABORATORY mice , *T cells , *IMMUNOLOGICAL tolerance , *AUTOANTIBODIES , *GLOMERULONEPHRITIS - Abstract
Abstract: We have previously shown that immune tolerance induced by the anti-DNA Ig peptide pCons in (NZB×NZW)F1 (NZB/W) lupus mice prolonged survival of treated animals and delayed the appearance of autoantibodies and glomerulonephritis. Part of the protection conferred by pCons could be ascribed to the induction of regulatory T cells (TReg) that suppressed the production of anti-DNA antibodies in a p38 MAPK-dependent fashion. Here we show that another effect of pCons in the induction of immune tolerance in NZB/W lupus mice is the facilitation of effector T cell suppression by TReg. These new findings indicate that pCons exerts protective effects in NZB/W lupus mice by differentially modulating the activity of different T cell subsets, implying new considerations in the design of TReg–based approaches to modulate T cell autoreactivity in SLE. [Copyright &y& Elsevier]
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- 2012
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29. Natural killer cells in human autoimmunity
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Flodström-Tullberg, Malin, Bryceson, Yenan T, Shi, Fu-Dong, Höglund, Petter, and Ljunggren, Hans-Gustaf
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KILLER cells , *AUTOIMMUNITY , *NATURAL immunity , *MEDICAL statistics , *CELL communication , *CELLULAR control mechanisms , *INFECTION - Abstract
Natural killer (NK) cells are innate immune cells. Although NK cells are best characterized for their ability to control tumors and infections, recent data have indicated that they also are important regulatory cells by virtue of interactions with many types of immune and nonimmune cells. Thereby, they can affect the outcome of adaptive immune responses and maintain immune homeostasis. Thus, NK cells can either exacerbate or limit immune responses, including those to autoantigens. Here, we discuss current insights into the role of NK cells in human autoimmunity. [Copyright &y& Elsevier]
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- 2009
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30. miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling.
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Feng, Yan, Li, Yan, Zhang, Ying, Zhang, Bo-Hao, Zhao, Hui, Zhao, Xin, Shi, Fu-Dong, Jin, Wei-Na, and Zhang, Xiao-An
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KILLER cells , *TRANSCRIPTION factor Sp1 , *ISCHEMIC stroke , *CEREBRAL ischemia , *ARTERIAL occlusions - Abstract
Background: Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke.Methods: Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.Results: We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.Conclusions: These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain. [ABSTRACT FROM AUTHOR]- Published
- 2021
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31. Microglia-derived CCL20 deteriorates neurogenesis following intraventricular hemorrhage.
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Yao, Nan, Li, Yulin, Han, Jinrui, Wu, Siting, Liu, Xin, Wang, Qiuyu, Li, Zhiguo, and Shi, Fu-Dong
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MACROPHAGE colony-stimulating factor , *INTRAVENTRICULAR hemorrhage , *CHEMOKINES , *PROTEIN kinase B , *NEUROGENESIS - Abstract
Intraventricular hemorrhage (IVH) commonly occurs as an extension of intracerebral hemorrhage (ICH) into the brain ventricular system, leading to worse outcomes without effective management. Using a mouse model of IVH, we found that impaired neurogenesis is evident in the subventricular zone (SVZ), along with persistent microglia activation, leukocyte infiltration and cell death. Pharmacological depletion of microglia using PLX3397, an inhibitor of colony stimulating factor 1 receptor (CSF1R), promotes neurogenesis, and alleviated delayed functional impairments in IVH mice. Meanwhile, an elevated level of microglia-derived CC chemokine ligand 20 (CCL20) is observed in the SVZ following IVH, which can induce the upregulation of pro-inflammatory factors in microglia and impair the proliferation and survival of neural stem cells (NSCs) in vitro. Blocking CCL20 in microglia leads to downregulation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/the nuclear factor-κB (NF-κB) signaling pathway, which may contribute to CCL20-dependent pro-inflammatory responses and neural injury. These findings demonstrate a detrimental role of microglia in the neurogenesis and neurorepair after IVH in which CCL20 likely plays a role. • The impaired neurogenesis was observed in the subventricular zone (SVZ) following IVH. • Persistent neuroinflammation, especially microglial activation within the SVZ, exacerbated neurogenesis impairment and neurodeficits in IVH mice. • The upregulation of CCL20 in microglia facilitated the secretion of pro-inflammatory cytokines and disrupted the proliferation and survival of NSCs. • Blocking CCL20 in the cultured microglia leads to downregulation of Akt/mTOR /NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Immunotherapy choice and maintenance for generalized myasthenia gravis in China.
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Zhang, Chao, Bu, Bitao, Yang, Huan, Wang, Lihua, Liu, Weibin, Duan, Rui‐Sheng, Zhang, Meini, Zeng, Pei, Du, Chen, Yang, Li, and Shi, Fu‐Dong
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MYASTHENIA gravis , *DISEASE relapse , *CORTICOSTEROIDS , *PROBABILITY measures , *DRUG efficacy , *IMMUNOTHERAPY - Abstract
Aims: To compare long‐term efficacy and safety of immunotherapeutic strategies as maintenance to prevent disease relapses of generalized myasthenia gravis (MG) in real‐world settings. Methods: This is a retrospective cohort study on generalized MG conducted in seven major neurological centers across China. Eligible participants were patients with generalized MG who were under minimal manifestation status or better. Main outcome measures were probability of patients free of relapses and causes of drug discontinuation. Results: Among 1064 patients enrolled, the median (interquartile range) age was 50.3 (37.0‐62.5) years and 641 (60.2%) were women. Disease relapse was significantly lower for rituximab (6.1%) compared with all the other monotherapies (hazard ratio [HR] = 0.18, 95% confidence interval [CI] 0.06 to 0.56, P =.0030). As combination therapies, tacrolimus in combination with corticosteroids reduced risk of disease relapses compared with azathioprine with corticosteroids (HR = 0.45, 95% CI 0.25 to 0.81, P =.0077) or mycophenolate mofetil with corticosteroids (HR = 0.32, 95% CI 0.15 to 0.67, P =.0020). Otherwise, lower‐dose corticosteroids or azathioprine as monotherapy significantly increased risk of disease relapses (HR = 2.78, 95% CI 1.94 to 3.99, P <.0001; HR = 2.14, 95% CI 1.42 to 3.23, P =.0003, respectively). The proportion of discontinuation was lowest in patients with rituximab (20.4%) as monotherapy and tacrolimus with corticosteroids (23.6%). Overall, combination treatment of immunosuppressants with corticosteroids had a lower rate of discontinuation compared with corresponding monotherapy (HR = 0.51, 95% CI 0.36 to 0.71, P <.0001). Conclusions: Rituximab as monotherapy and tacrolimus with corticosteroids displayed better clinical efficacy as well as drug maintenance to prevent disease relapses in patients with generalized MG. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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33. State of the Art and Future Challenges in Multiple Sclerosis Research and Medical Management: An Insight into the 5th International Porto Congress of Multiple Sclerosis.
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Sá, María José, Soares dos Reis, Ricardo, Altintas, Ayse, Celius, Elisabeth Gulowsen, Chien, Claudia, Comi, Giancarlo, Graus, Francesc, Hillert, Jan, Hobart, Jeremy, Khan, Gulfaraz, Kissani, Najib, Langdon, Dawn, Leite, Maria Isabel, Okuda, Darin T., Palace, Jacqueline, Papais-Alvarenga, Regina María, Mendes-Pinto, Inês, and Shi, Fu-Dong
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MULTIPLE sclerosis , *CONFERENCES & conventions , *MEDICAL research , *DEMYELINATION - Abstract
The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes—including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)—led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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34. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.
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Zhang, Chao, Zhang, Meini, Qiu, Wei, Ma, Hongshan, Zhang, Xinghu, Zhu, Zilong, Yang, Chun-Sheng, Jia, Dongmei, Zhang, Tian-Xiang, Yuan, Meng, Feng, Yan, Yang, Li, Lu, Wenli, Yu, Chunshui, Bennett, Jeffrey L, Shi, Fu-Dong, and TANGO Study Investigators
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THERAPEUTIC use of monoclonal antibodies , *RESEARCH , *AZATHIOPRINE , *RESEARCH methodology , *MONOCLONAL antibodies , *EVALUATION research , *MEDICAL cooperation , *TREATMENT effectiveness , *COMPARATIVE studies , *RANDOMIZED controlled trials , *RESEARCH funding , *IMMUNOSUPPRESSIVE agents , *STATISTICAL sampling , *NEUROMYELITIS optica - Abstract
Background: Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD.Methods: We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633.Findings: Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107-0·518]; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076-0·463]; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related.Interpretation: Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD.Funding: Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China. [ABSTRACT FROM AUTHOR]- Published
- 2020
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35. Temporal and Spatial Dynamics of Astroglial Reaction and Immune Response in Cuprizone-Induced Demyelination.
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An, Jun, Yin, Jun-Jun, He, Yan, Sui, Ruo-Xuan, Miao, Qiang, Wang, Qing, Yu, Jie-Zhong, Yu, Jing-Wen, Shi, Fu-Dong, Ma, Cun-Gen, and Xiao, Bao-Guo
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IMMUNE response , *OLIGODENDROGLIA , *CORPUS callosum , *MYELIN sheath , *TIGHT junctions , *DEMYELINATION , *SCHWANN cells - Abstract
The cuprizone (CPZ)-induced demyelination is a relatively reproducible animal model and has been extremely useful for identifying the specific cellular and molecular signals that regulate oligodendrocyte survival and efficiency of oligodendrogenesis and remyelination. Here, we reported the temporal and spatial dynamics of astroglial reaction and immune response in CPZ-induced demyelinating model. CPZ did not induce significant microglia and astrocyte reaction after 2 weeks of feeding. After 4–6 weeks of CPZ feeding, microglia and astrocytes were markedly migrated and accumulated in myelin sheath. Simultaneously, the expression of tight junction protein ZO-1 was declined and the infiltration of CD4+IFNγ+ and CD4+IL-17+ T cells was increased in the brain, accompanied by increased production of IFN-γ and IL-17 in the extract of brain. However, the levels of IFN-γ and IL-17 were reduced, while IL-6 and TNF-α were elevated in the supernatant of splenocytes. At the 4th and 6th weeks of feeding, CPZ caused astrocyte activation and upregulated the expression of BDNF, CNTF, and IGF-II, providing a neurotrophic microenvironment in the brain. At this stage, NG2+ and PDGF-Rα+ oligodendroglia progenitor cells were enhanced in the corpus callosum, but the myelin sheath is still severely lost. Therefore, targeting microglia to improve the inflammatory microenvironment should contribute to the remyelination. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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36. Global brain inflammation in stroke.
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Shi, Kaibin, Tian, De-Cai, Li, Zhi-Guo, Ducruet, Andrew F, Lawton, Michael T, and Shi, Fu-Dong
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ENCEPHALITIS , *STROKE , *BLOOD-brain barrier , *BRAIN injuries , *CELL death - Abstract
Stroke, including acute ischaemic stroke and intracerebral haemorrhage, results in neuronal cell death and the release of factors such as damage-associated molecular patterns (DAMPs) that elicit localised inflammation in the injured brain region. Such focal brain inflammation aggravates secondary brain injury by exacerbating blood-brain barrier damage, microvascular failure, brain oedema, oxidative stress, and by directly inducing neuronal cell death. In addition to inflammation localised to the injured brain region, a growing body of evidence suggests that inflammatory responses after a stroke occur and persist throughout the entire brain. Global brain inflammation might continuously shape the evolving pathology after a stroke and affect the patients' long-term neurological outcome. Future efforts towards understanding the mechanisms governing the emergence of so-called global brain inflammation would facilitate modulation of this inflammation as a potential therapeutic strategy for stroke. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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37. Colivelin Rescues Ischemic Neuron and Axons Involving JAK/STAT3 Signaling Pathway.
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Zhao, Hui, Feng, Yan, Wei, Changjuan, Li, Yan, Ma, Hongshan, Wang, Xuejiao, Cui, Zhigang, Jin, Wei-Na, and Shi, Fu-Dong
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TRANSIENT ischemic attack , *CEREBRAL ischemia , *AXONS , *BRAIN death , *NEURONS , *CHONDROITIN sulfate proteoglycan , *CATHELICIDINS - Abstract
Colivelin is a neuroprotective humanin family peptide with potent long-term capacity against Aβ deposition, neuronal apoptosis, and synaptic plasticity deficits in neurodegenerative disease. We seek to investigate whether this effect of Colivelin also govern ischemic brain injury, and potential mechanism underlying the Colivelin-mediated action on ischemic neurons. We adopted 60 min induction of transient focal cerebral ischemia and reperfusion in mice. We found that relative to mice receiving vehicle, Colivelin administration decreased the neurological deficits and infarct lesion induced by brain ischemia. Colivelin inhibited axonal damage and neuronal death in brain tissue, which was associated with elevated anti-apoptotic gene expression in ischemic neurons as well as increased axonal growth up until two-weeks post-stroke. Moreover, Colivelin activated STAT3 signaling, which may partially contribute to its beneficial effect against neuronal death and axon growth. In conclusion, Colivelin induce anti-apoptotic genes up-regulation, and activate JAK/STAT3 signaling after ischemic stroke, which may contribute to its effects of rescuing ischemic neuronal death and axonal remodeling. This study may justify further works to examine Colivelin as a single or adjunct therapy in ischemic stroke. • Colivelin decreased neurological deficits and infarct lesion after brain ischemia. • Colivelin inhibited axonal damage and neuronal death after ischemic stroke. • Colivelin increased anti-apoptotic genes level via JAK/STAT3. • Colivelin may serve as a single or adjunct therapy in ischemic stroke. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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38. CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage.
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Ren, Honglei, Pan, Yan, Wang, Danni, Hao, Hongying, Han, Ranran, Qi, Caiyun, Zhang, Wenjun, He, Wenyan, Shi, Fu-Dong, and Liu, Qiang
- Subjects
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MICROGLIA , *CEREBRAL hemorrhage , *MACROPHAGE colony-stimulating factor , *BLOCKADE , *NEUROINFLAMMATION , *MOLECULAR switches - Abstract
Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2023
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39. Weak space charge effects in laser multiphoton ionization of a rarefied gas beam of heavy species.
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Zhou, Wen-Chang, Zhao, Dong-Mei, Qian, Dong-Bin, Li, Yu-Fan, Yang, Jie, Shi, Fu-Dong, Zhu, Yu-Hao, Zhang, Shao-Feng, Zhu, Xiao-Long, Wu, Yong, and Ma, Xin-Wen
- Subjects
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SPACE charge , *MULTIPHOTON ionization , *IONIZATION of gases , *KINETIC energy , *MASS spectrometers , *LASERS - Abstract
Graphical abstract A typical image of C 60 + photoionsmeasured by a high-resolution velocity-map-imaging spectrometer. The photoion energy distribution in the transverse dimension (along the X-axis) can be extracted from the image, indicating that our apparatus has sufficiently high energy resolution to quantify the influence of weak space charge effects on the photoion kinetic energy distribution in a low charge-density regime (107 ions / cm3). Highlights • Proposing an approach to explore the space charge effects involving a low charge densities. • Presenting quantitative information on the space charge effects in the order of 0.1 meV. • Providing a benchmark for estimating the space charge effects in high precision measurements. Abstract We experimentally explore weak space charge effects (SCEs) in multiphoton ionization (MPI) experiments using C 60 as an example of heavy species. The laser-induced delayed ionization of C 60 was used to prepare a photoion pulse with a decreasing initial charge density distribution from a start value that is one order of magnitude smaller than the density limit (3☓108 ions/cm3) proposed previously to assume that the SCEs can be negligible. The photoion spectra at different time slices of the photoion pulse were measured using a velocity map imaging spectrometry. This allows us to quantify the SCEs on the photoion spectra in such low-density and heavy-species regime. The weak SCEs explored here can help us to understand and improve the temporal-spatial resolutions in those high-precision measurements. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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40. Altered neurovascular coupling in neuromyelitis optica.
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Guo, Xi, Zhu, Jiajia, Zhang, Ningnannan, Zhang, Linjie, Qi, Yuan, Cai, Huanhuan, Zhang, Xue, Sun, Jie, Wang, Qiuhui, Yang, Li, Shi, Fu‐Dong, and Yu, Chunshui
- Abstract
Neurovascular coupling reflects the close relationship between neuronal activity and cerebral blood flow (CBF), providing a new mechanistic insight into health and disease. Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system and shows cognitive decline‐related brain gray matter abnormalities besides the damage of optic nerve and spinal cord. We aimed to investigate neurovascular coupling alteration and its clinical significance in NMO by using regional homogeneity (ReHo) to measure neuronal activity and CBF to measure vascular response. ReHo was calculated from functional MRI and CBF was computed from arterial spin labeling (ASL) in 56 patients with NMO and 63 healthy controls. Global neurovascular coupling was assessed by across‐voxel CBF‐ReHo correlations and regional neurovascular coupling was evaluated by CBF/ReHo ratio. Correlations between CBF/ReHo ratio and clinical variables were explored in patients with NMO. Global CBF‐ReHo coupling was decreased in patients with NMO relative to healthy controls (p = .009). Patients with NMO showed decreased CBF/ReHo ratio (10.9%–17.3% reduction) in the parietal and occipital regions and increased CBF/ReHo ratio (8.0%–13.3% increase) in the insular, sensorimotor, temporal and prefrontal regions. Some of these abnormalities cannot be identified by a single CBF or ReHo analysis. Both abnormally decreased and increased CBF/ReHo ratios were correlated with more severe clinical impairments and cognitive decline in patients with NMO. These findings suggested that patients with NMO show abnormal neurovascular coupling, which is associated with disease severity and cognitive impairments. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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41. Bidirectional degeneration in the visual pathway in neuromyelitis optica spectrum disorder (NMOSD).
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Tian, De-Cai, Su, Lei, Fan, Moli, Yang, Jian, Zhang, Rui, Wen, Peng, Han, Yujuan, Yu, Changlu, Zhang, Chao, Ren, Honglei, Shi, Kaibin, Zhu, Zilong, Dong, Yinhua, Liu, Yaou, and Shi, Fu-Dong
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NEUROMYELITIS optica , *OPTIC neuritis , *NEURODEGENERATION , *VISUAL pathways , *MAGNETIC resonance imaging - Abstract
Objective: This study aims to investigate whether bidirectional degeneration occurs within the visual pathway and, if so, the extent of such changes in neuromyelitis optica spectrum disorder (NMOSD). Methods: In total, 36 NMOSD and 24 healthy controls (HCs) were enrolled. Three-dimensional T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging were used to analyze damage to the posterior visual pathway. Damage to the anterior visual pathway was measured by optical coherence tomography. Results: In total, 24 NMOSD with prior optic neuritis (NMOON) patients showed significant reduction of peripapillary retinal nerve fiber layer, inner and outer retinal thickness, lateral geniculate nucleus volume, primary visual cortex volume, and decreased integrity of optic radiations, compared with 12 NMOSD without prior optic neuritis (NMONON) patients and 24 HCs. In NMONON, only the inner retinal thickness and the integrity of optic radiations were significantly reduced in comparison with HCs. Moreover, patients with optic neuritis showed severe bidirectional degeneration, the loss of the RNFL was greater than the atrophy of V1. Conclusion: Our study indicated the presence of trans-synaptic degeneration in NMOSD. Damage to the inner retina and optic radiations can be observed even in NMONON. After an episode of optic neuritis, the anterior visual pathway damage is greater than the posterior visual pathway damage. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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42. Multimodal characterization of gray matter alterations in neuromyelitis optica.
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Liu, Yaou, Jiang, Xueyan, Butzkueven, Helmut, Duan, Yunyun, Huang, Jing, Ren, Zhuoqiong, Dong, Huiqing, Shi, Fu-Dong, Barkhof, Frederik, Li, Kuncheng, and Wang, Jinhui
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NEUROMYELITIS optica , *MAGNETIC resonance imaging , *GRAY matter (Nerve tissue) , *DIFFUSION tensor imaging , *ANISOTROPY - Abstract
Objective: To investigate structural and functional alterations of gray matter (GM) and examine their clinical relevance in neuromyelitis optica (NMO) using multimodal magnetic resonance imaging (MRI) techniques. Methods: A total of 35 NMO and 36 healthy controls (HC) were recruited in this study. Cortical lesions were investigated by double inversion recovery technique. Five voxel-wise MRI measurements were obtained for each participant in the GM including gray matter volume (GMV), fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF), and weighted functional connectivity strength (wFCS). Between-group differences, cross-modality relationships, and MRI-clinical correlations were examined. Results: No cortical lesions were found in NMO. Compared to HC, NMO patients exhibited significantly decreased GMV in deep GM and cortical regions involving visual function and cognition. Diffusion GM abnormalities were widespread in the patients. Decreased ALFF and wFCS were observed in the patients in sensorimotor, visual, cognition, and cerebellar sites. GM structural alterations were correlated with cognitive but not physical disability scores of the patients. Conclusion: Despite the lack of focal cortical lesions, patients with NMO exhibit both structural and functional alterations of GM in cerebrum and cerebellum that predominantly involve deep GM, visual, motor, and cognitive regions. GM alterations are associated with cognitive impairment but not physical disability. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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43. Anti-Rituximab antibody in patients with NMOSDs treated with low dose Rituximab.
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Li, Ting, Zhang, Lin-Jie, Zhang, Qiu-Xia, Yang, Chun-Sheng, Zhang, Chao, Li, Yu-jing, Shi, Fu-Dong, and Yang, Li
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NEUROMYELITIS optica , *THERAPEUTIC use of immunoglobulins , *ENZYME-linked immunosorbent assay , *B cells , *THERAPEUTIC use of monoclonal antibodies , *THERAPEUTICS - Abstract
Background Rituximab is a mouse-human chimeric anti-CD20 monoclonal antibody and has been increasingly used for preventing relapses in NMOSDs. The clinical relevance of Anti-Rituximab antibodies (ARA) against Rituximab in NMOSDs is unknown. Methods Nineteen NMOSDs patients receiving repeated 100 mg Rituximab treatment were recruited. The ARA was quantitatively analyzed by enzyme linked immunoassay. Annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) were analyzed concurrently. Results ARR was reduced markedly since starting Rituximab therapy in the majority (78.9%) of NMOSDs patients. 36.9% (7/19) patients were ARA positive. There was no significant difference in the improvement of ARR and EDSS after treatment with Rituximab in either ARA positive or negative groups. The frequency of Rituximab reinfusion was higher in patients with ARA, suggesting that the presence of ARA led to an increased frequency of Rituximab reinfusion to maintain B cell depletion. Conclusion The majority of (78.9%) patients with NMOSDs were responsive to low dose Rituximab. The presence of ARA is associated with the requirement for increased frequency of Rituximab reinfusion to maintain treatment response in NMOSDs. In patients with ARA it might be necessary to detect ARA levels and monitor B cell depletion closely, or even attempt other treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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44. Organ‐ and cell‐specific immune responses are associated with the outcomes of intracerebral hemorrhage.
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Zhang, Jing, Shi, Kaibin, Li, Zhiguo, Li, Minshu, Han, Yujuan, Wang, Lei, Zhang, Zhecheng, Yu, Changlu, Zhang, Fang, Song, Lijuan, Dong, Jing‐Fei, Cava, Antonio La, Sheth, Kevin N., and Shi, Fu‐Dong
- Abstract
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post‐ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus‐pituitary‐adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.—Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang,Z.,Yu,C.,Zhang,F.,Song,L.,Dong,J.‐F.,LaCava,A.,Sheth,K.N.,Shi,F.‐D.Organ‐andcell‐specificimmune responses are associated with the outcomes of intracerebral hemorrhage. FASEB J. 32,220‐229 (2018). www.fasebj.org [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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45. Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.
- Author
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Liu, Yaou, Duan, Yunyun, Huang, Jing, Ren, Zhuoqiong, Liu, Zheng, Dong, Huiqing, Weiler, Florian, Hahn, Horst K., Shi, Fu-Dong, Butzkueven, Helmut, Barkhof, Frederik, and Li, Kuncheng
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BRAIN , *SPINAL cord , *NEUROMYELITIS optica , *MULTIPLE sclerosis , *DISABILITIES - Abstract
Objective: To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression.Patients and Methods: We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS.Results: MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO.Conclusion: Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS.Key Points: • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS. [ABSTRACT FROM AUTHOR]- Published
- 2018
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46. Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.
- Author
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Wang, Zhen, Guo, Wen, Liu, Yuanchu, Gong, Ye, Ding, Xiaoli, Shi, Kaibin, Thome, Rodolfo, Zhang, Guang-Xian, Shi, Fu-Dong, and Yan, Yaping
- Subjects
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AUTOANTIBODIES , *NEUROMYELITIS optica , *AUTOANTIGENS , *CD59 antigen , *DEMYELINATION , *THERAPEUTICS - Abstract
Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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47. Neurological picture. Multiple intracranial arteritis and hypothyroidism secondary to Streptococcus anginosus infection.
- Author
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Zhang, Chao, Xie, Bingdi, Shi, Fu-Dong, and Hao, Junwei
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BRAIN , *HYPOTHYROIDISM , *STREPTOCOCCAL diseases , *INTRACRANIAL arterial diseases , *STREPTOCOCCUS , *DISEASE complications - Published
- 2015
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48. Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage.
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Grunwald, Zachary, Beslow, Lauren, Urday, Sebastian, Vashkevich, Anastasia, Ayres, Alison, Greenberg, Steven, Goldstein, Joshua, Leasure, Audrey, Shi, Fu-Dong, Kahle, Kristopher, Battey, Thomas, Simard, J., Rosand, Jonathan, Kimberly, W., Sheth, Kevin, Beslow, Lauren A, Greenberg, Steven M, Goldstein, Joshua N, Kahle, Kristopher T, and Battey, Thomas W K
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CEREBRAL edema , *INTRACEREBRAL hematoma , *COMPUTED tomography , *BIOMARKERS , *DEATH rate , *DIAGNOSIS , *THERAPEUTICS , *CEREBRAL hemorrhage treatment , *CEREBRAL hemorrhage , *LONGITUDINAL method , *HEALTH outcome assessment , *RESEARCH funding , *RETROSPECTIVE studies - Abstract
Background: Perihematomal edema (PHE) expansion rate may predict functional outcome following spontaneous intracerebral hemorrhage (ICH). We hypothesized that the effect of PHE expansion rate on outcome is greater for deep versus lobar ICH.Methods: Subjects (n = 115) were retrospectively identified from a prospective ICH cohort enrolled from 2000 to 2013. Inclusion criteria were age ≥ 18 years, spontaneous supratentorial ICH, and known onset time. Exclusion criteria were primary intraventricular hemorrhage (IVH), trauma, subsequent surgery, or warfarin-related ICH. ICH and PHE volumes were measured from CT scans and used to calculate expansion rates. Logistic regression assessed the association between PHE expansion rates and 90-day mortality or poor functional outcome (modified Rankin Scale > 2). Odds ratios are per 0.04 mL/h.Results: PHE expansion rate from baseline to 24 h (PHE24) was associated with mortality for deep (p = 0.03, OR 1.13[1.02-1.26]) and lobar ICH (p = 0.02, OR 1.03[1.00-1.06]) in unadjusted regression and in models adjusted for age (deep p = 0.02, OR 1.15[1.02-1.28]; lobar p = 0.03, OR 1.03[1.00-1.06]), Glasgow Coma Scale (deep p = 0.03, OR 1.13[1.01-1.27]; lobar p = 0.02, OR 1.03[1.01-1.06]), or time to baseline CT (deep p = 0.046, OR 1.12[1.00-1.25]; lobar p = 0.047, OR 1.03[1.00-1.06]). PHE expansion rate from baseline to 72 h (PHE72) was associated with mRS > 2 for deep ICH in models that were unadjusted (p = 0.02, OR 4.04[1.25-13.04]) or adjusted for ICH volume (p = 0.02, OR 4.3[1.25-14.98]), age (p = 0.03, OR 5.4[1.21-24.11]), GCS (p = 0.02, OR 4.19[1.2-14.55]), or time to first CT (p = 0.03, OR 4.02[1.19-13.56]).Conclusions: PHE72 was associated with poor functional outcomes after deep ICH, whereas PHE24 was associated with mortality for deep and lobar ICH. [ABSTRACT FROM AUTHOR]- Published
- 2017
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49. Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations.
- Author
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Liu, Qiang, Jin, Wei-Na, Liu, Yaou, Shi, Kaibin, Sun, Haoran, Zhang, Fang, Zhang, Chao, Gonzales, Rayna J., Sheth, Kevin N., La Cava, Antonio, and Shi, Fu-Dong
- Subjects
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CEREBRAL ischemia , *BRAIN immunology , *PERIPHERAL nervous system , *INNERVATION of the brain , *KILLER cells , *HYPOTHALAMIC-pituitary-adrenal axis , *CELLULAR immunity , *LABORATORY mice - Abstract
Summary Brain ischemia inhibits immune function systemically, with resulting infectious complications. Whether in stroke different immune alterations occur in brain and periphery and whether analogous mechanisms operate in these compartments remains unclear. Here we show that in patients with ischemic stroke and in mice subjected to middle cerebral artery occlusion, natural killer (NK) cells display remarkably distinct temporal and transcriptome profiles in the brain as compared to the periphery. The activation of catecholaminergic and hypothalamic-pituitary-adrenal axis leads to splenic atrophy and contraction of NK cell numbers in the periphery through a modulated expression of SOCS3, whereas cholinergic innervation-mediated suppression of NK cell responses in the brain involves RUNX3. Importantly, pharmacological or genetic ablation of innervation preserved NK cell function and restrained post-stroke infection. Thus, brain ischemia compromises NK cell-mediated immune defenses through mechanisms that differ in the brain versus the periphery, and targeted inhibition of neurogenic innervation limits post-stroke infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
50. Intracerebral Hemorrhage Location and Functional Outcomes of Patients: A Systematic Literature Review and Meta-Analysis.
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Sreekrishnan, Anirudh, Dearborn, Jennifer, Greer, David, Shi, Fu-Dong, Hwang, David, Leasure, Audrey, Zhou, Sonya, Gilmore, Emily, Matouk, Charles, Petersen, Nils, Sansing, Lauren, Sheth, Kevin, Dearborn, Jennifer L, Greer, David M, Hwang, David Y, Leasure, Audrey C, Zhou, Sonya E, Gilmore, Emily J, Matouk, Charles C, and Petersen, Nils H
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CEREBRAL hemorrhage , *COGNITIVE ability , *ACTIVITIES of daily living , *MEDICAL care , *SYSTEMATIC reviews , *PATIENTS - Abstract
Background and Purpose: Intracerebral hemorrhage (ICH) has the highest mortality rate among all strokes. While ICH location, lobar versus non-lobar, has been established as a predictor of mortality, less is known regarding the relationship between more specific ICH locations and functional outcome. This review summarizes current work studying how ICH location affects outcome, with an emphasis on how studies designate regions of interest.Methods: A systematic search of the OVID database for relevant studies was conducted during August 2015. Studies containing an analysis of functional outcome by ICH location or laterality were included. As permitted, the effect size of individual studies was standardized within a meta-analysis.Results: Thirty-seven studies met the inclusion criteria, the majority of which followed outcome at 3 months. Most studies found better outcomes on the Modified Rankin Scale (mRS) or Glasgow Outcome Score (GOS) with lobar compared to deep ICHs. While most aggregated deep structures for analysis, some studies found poorer outcomes for thalamic ICH in particular. Over half of the studies did not have specific methodological considerations for location designations, including blinding or validation.Conclusions: Multiple studies have examined motor-centric outcomes, with few studies examining quality of life (QoL) or cognition. Better functional outcomes have been suggested for lobar versus non-lobar ICH; few studies attempted finer topographic comparisons. This study highlights the need for improved reporting in ICH outcomes research, including a detailed description of hemorrhage location, reporting of the full range of functional outcome scales, and inclusion of cognitive and QoL outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
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