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central nervous system Involvement in 179 Chinese Children with Hemophagocytic Lymphohistiocytosis

Chinese Medical Journal 2018年第15期131卷 1786-1792页

作者： Yun-Ze Zhao Qing Zhang Zhi-Gang Li Li Zhang Hong-Yun Lian Hong-Hao Ma Dong Wang Xiao-Xi Zhao Tian-You Wang Rui Zhang Beijing Key Laboratory of Pediatric Hematology Oncology National Key Discipline of Pediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children Ministry of Education Hematology Oncology Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing 100045 China Hematology and Oncology Laboratory Beijing Pediatric Research Institute Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing Key Laboratory of Pediatric Hematology Oncology Key Laboratory of Major Diseases in Children Ministry of Education National Key Discipline of Pediatrics Ministry of Education Beijing 100045 China Yun-Ze Zhao and Qing Zhang contributed equally to this work

Background： central nervous system （CNS） involvement is found in many patients with hemophagocytic lymphohistiocytosis （HLH）. In this study, we mainly analyzed neurological symptoms, imaging findings, cerebrospinal fluid （CSF）, and their relationship with outcomes of HLH children. Methods： Related data of 179 Chinese pediatric patients with HLH admitted to our center from January 2010 to December 2015 were analyzed retrospectively. Diagnosis and treatment were based on the H LH-2004 protocol. Two-tailed Chi-squared test was used to compare between different groups, and Kaplan-Meier survival curves were used to analyze the overall survival （OS） of patients with HLH. Results： In the present study, 21.2% （38/179） of total patients had neurological symptoms including seizure, irritability, somnolence, and unconsciousness. There were 80 （50.0%, excluding 19 patients without imaging data） patients with cranial imaging abnormalities. There were 14.7% （17/116, excluding 63 patients who did not accept lumbar puncture） of patients with abnormal CSF results. CNS involvement is defined as abnormalities in one or more of CNS symptoms, radiological findings, and CSF. Thus, 60.3% of them had CNS involvement, As for the prognosis, the median follow-up time was 3.2 years （17 lost to follow-up）. The probable 3-year OS of children was higher without CNS involvement （86.0% ± 4.6%） than those with CNS involvement （68.9% ± 4.9%, hazard ratio [HR] = 2.286, P = 0.019）, Among them, the probable 3-year OS of children without CNS symptoms was 76.0% ± 3.8%, higher than with CNS symptoms （59.5% ± 8.1%, HR = 2.147, P ： 0.047）. The 3-year OS of children with abnormal CSF was 64.7% ± 11.6%, compared with normal CSF （85.1% ± 3.7%, HR = 0.255, P = 0.038）. Conclusions： HLH patients with CNS involvement might have worse outcomes compared with those without CNS involvement, and CNS symptoms and CSF changes are more important to access the prognosis than imaging abnormality.

关键词： central nervous system Cerebrospinal Fluid Hemophagocytic Lymphohistiocytosis

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central nervous system Involvement in Hemophagocytic Lymphohistiocytosis in Adults： A Retrospective Analysis of 96 Patients in a Single Center

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Chinese Medical Journal 2018年第7期131卷 776-783页

作者： Yue Song Rui-Jun Pei Yi-Ni Wang Jia Zhang Zhao Wang Department of Hematology Beijing Friendship Hospital Capital Medical University Beijing 100050 China

Background： Hemophagocytic lymphohistiocytosis （HLH） is a life-threatening clinical syndrome. central nervous system （CNS） involvement is a severe complication, which can lead to rapid disease development and higher morality. However, this has not been given enough attention in adult HLH. Therefore, we carried out this study to analyze the clinical features, laboratory findings, treatment outcomes, and other characteristics of adult HLH with CNS involvement. Methods： A retrospective analysis of 96 adult patients with HLH combined with CNS involvement between June 2003 and December 2016 was conducted. Clinical features, cerebrospinal fluid （CSF） features, image changes, and therapeutic outcomes were analyzed. Results： Among the 96 patients, 86 had various CNS symptoms and 33 （38.4%） had already presented symptoms before the HLH diagnosis was confirmed. A total of 59 patients received CSF examinations and showed abnormalities in 23 patients （39.0%）. Seventy patients received imaging examinations and the results showed fifty patients with imaging changes （71.4%）. Fifty-seven patients received multiple rounds of repeated intrathecal injection therapy and 35 patients improved （61.4%）. As for the multiple analyses of effective factors on survival time, the results showed that the effects of combined Epstein-Barr virus （EBV） infection （P = 0.026, Exp（B） 95% confidence interval [CI] [1.108, 4.823） and intrathecal injection therapy （P = 0.013, Exp（B） = 0.422, 95% CI [0.214, 0.831]） survival time of the CNS-HLH patients were significant. 2.309, on the Conclusions： Complication with EBV infection is a risk factor, and intrathecal injection is a protective factor. CNS involvement in HLH is not rare, which can result in a poor prognosis. Multiple rounds of repeated intrathecal injection therapy can improve the prognosis of CNS-HLH patients.

关键词： central nervous system Hemophagocytic Lymphohistiocytosis Neuroimaging Treatment

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central nervous system Toxicity of Sodium Nitroprusside in Treatment of Patients with Aortic Dissection

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第6期32卷 927-930页

作者：黄雪渊侯凌波唐家荣张艳梅陈复琼汪道文 Department of Cardiology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

This study examined the sodium nitroprusside (SNP) toxicity to central nervous system (CNS) in treatment of patients with aortic dissection (AD). The medical records of 191 AD patients who were admitted to Tongji Hospital, China, from Jan. 1998 to Feb. 2009 were retrospectively analyzed. There were 140 cases of hypertension (73.3%) and 13 cases of Marfan syndrome (6.8%) among the 191 AD patients. A total of 157 patients were given SNP treatment. The toxic reactions of CNS occurred in 18 subjects (11.5%). Most of the adverse reactions occurred on the fifth day following SNP injection. SNP infusion rate was significantly higher in patients who developed CNS toxicity. It was suggested that systemic hypertension is the most common predisposing factor for AD. The combination of SNP with a β-receptor blocker is a medical therapy commonly used in patients with AD. Cyanide and thio-cyanate toxicity from SNP treatment is always the consequence of prolonged drug infusion or relatively high dose administration.

关键词： sodium nitroprusside toxicity central nervous system aortic dissection

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The effects and potential of microglial polarization and crosstalk with other cells of the central nervous system in the treatment of Alzheimer’s disease

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Neural Regeneration Research 2023年第5期18卷 947-954页

作者： Yi-Ge Wu Li-Juan Song Li-Jun Yin Jun-Jun Yin Qing Wang Jie-Zhong Yu Bao-Guo Xiao Cun-Gen Ma The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology Shanxi University of Chinese MedicineJinzhongShanxi ProvinceChina Department of Physiology Shanxi Medical UniversityTaiyuanShanxi ProvinceChina Zhejiang Chinese Medical University HangzhouZhejiang ProvinceChina Institute of Brain Science/Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases/Medical School Shanxi Datong UniversityDatongShanxi ProvinceChina Institute of Neurology Huashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina

Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.

关键词： Alzheimer’s disease amyloid biomarker central nervous system cytokines diabetes inflammation microglia neuroinflammation phagocytosis tau

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The lymphatic system:a therapeutic target for central nervous system disorders

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Neural Regeneration Research 2023年第6期18卷 1249-1256页

作者： Jia-Qi Xu Qian-Qi Liu Sheng-Yuan Huang Chun-Yue Duan Hong-Bin Lu Yong Cao Jian-Zhong Hu Department of Spine Surgery and Orthopaedics Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Key Laboratory of Organ Injury Aging and Regenerative Medicine of Hunan ProvinceChangshaHunan ProvinceChina Mobile Health Ministry of Education-China Mobile Joint Laboratory ChangshaHunan ProvinceChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of Cardiovascular Surgery The Second Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of Sports Medicine Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.

关键词： central nervous system central nervous system injury glymphatic system lymphatic vessels meninges neurodegenerative disorders neuroinflammatory diseases vascular endothelial growth factor C

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Pentadecapeptide BPC 157 and the central nervous system

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Neural Regeneration Research 2022年第3期17卷 482-487页

作者： Jakša Vukojević Marija Milavić Darko Perović Spomenko Ilić Andrea ZembaČilić NatašaĐuran SanjaŠtrbe Zoran Zoričić Igor Filipčić Petrana Brečić Sven Seiverth Predrag Sikirić Department of Pharmacology Medical SchoolUniversity of ZagrebZagrebCroatia Department of Pathology Medical SchoolUniversity of ZagrebZagrebCroatia University Clinical Hospital Center“Zagreb” ZagrebCroatia University Psychiatric Hospital“Vrapče” ZagrebCroatia University Clinical Hospital Center“Sestre Milosrdnice” ZagrebCroatia Psychiatric Hospital“Sveti Ivan” ZagrebCroatia

We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157,three very recent demonstrations that may be essential in the gut-brain and braingut axis operation,and therapy application in the central nervous system disorders,in particular.Firstly,given in the reperfusion,BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke,sustained brain neuronal damages were resolved in rats as well as disturbed memory,locomotion,and coordination.This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats.Secondly,there are L-NG-nitro arginine methyl ester(L-NAME)-and haloperidol-induced catalepsy as well as the rat acute and chronic models of 'positivelike' schizophrenia symptoms,that BPC 157 counteracted,and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine(dopamine agents application),MK-801(non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration(to induce sensitivity).Thirdly,after rat spinal cord compression,there were advanced healing and functional recovery(counteracted tail paralysis).Likewise,in BPC 157 therapy,there is specific support for each of these topics:counteracted encephalopathies;alleviated vascular occlusion disturbances(stroke);counteracted dopamine disturbances(dopamine receptors blockade,receptors super sensitivity development,or receptor activation,over-release,nigrostriatal damage,vesicles depletion),and nitric oxide-system disturbances("L-NAME non-responsive,L-arginine responsive," and "L-NAME responsive,L-arginine responsive")(schizophrenia therapy);inflammation reduction,nerve recovery in addition to alleviated hemostasis and vessels function after compression(spinal cord injury therapy).Thus,these disturbances may be all resolved within the same agent's beneficial activity,i.e.,the stable gastric pentadecapeptide BPC 157.

关键词： BPC 157 central nervous system cytoprotection injury nitric oxide system peptide regeneration

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Neuroprotective agents effective against radiation damage of central nervous system

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Neural Regeneration Research 2022年第9期17卷 1885-1892页

作者： Mária Lalkovičová Laboratory of Radiation Biology Joint Institute for Nuclear ResearchDubnaRussia Slovak Academy of Sciences Institute of Experimental PhysicsKošiceSlovakia

Ionizing radiation caused by medical treatments,nuclear events or even space flights can irreversibly damage structure and function of brain cells.That can result in serious brain damage,with memory and behavior disorders,or even fatal oncologic or neurodegenerative illnesses.Currently used treatments and drugs are mostly targeting biochemical processes of cell apoptosis,radiation toxicity,neuroinflammation,and conditions such as cognitive-behavioral disturbances or others that result from the radiation insult.With most drugs,the side effects and potential toxicity are also to be considered.Therefore,many agents have not been approved for clinical use yet.In this review,we focus on the latest and most effective agents that have been used in animal and also in the human research,and clinical treatments.They could have the potential therapeutical use in cases of radiation damage of central nervous system,and also in prevention considering their radioprotecting effect of nervous tissue.

关键词： antioxidants biomedical neuroprotectants central nervous system ionizing radiation neuroprotection radiation injury radiomitigators radioprotectants radioprotection therapeutics

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Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

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Neural Regeneration Research 2022年第6期17卷 1172-1182页

作者： Bart Nieuwenhuis Richard Eva John van Geest Center for Brain Repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

关键词： axon cytoskeleton axon regeneration axon transport cell signaling central nervous system growth cone neuroprotection PI3-kinase PI3K PTEN trafficking transcription translation

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Commentary: A nearly forgotten class of anti-inflammatory lipid molecules in central nervous system

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药学学报:英文版 2023年第6期13卷 2809-2811页

作者： Nan Ru Wan-Yang Sun Hua-Jun Wang Yan-Ping Wu Xiao-Fei Zheng Rong-Rong He The First Affiliated Hospital/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE)/Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research Jinan UniversityGuangzhou 510632China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacaoChina

Lipids are the major components of cells in the central nervous system(CNS) and are essential for the brain development and homeostasis. Several studies have demonstrated that impaired lipid metabolism is closely related to neurological diseases among the elderly^(1). Lipidomics can serve us well in identifying and quantifying lipid molecules in cells, tissues, and organisms at the system level. However, finding out biologically meaningful lipids from the massive lipidomics data is not straightforward.

关键词： Lipidomics Aging 3-Sulfogalactosyl diacylglycerols Anti-inflammation central nervous system

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Exploring the role of interleukin-27 as a regulator of neuronal survival in central nervous system diseases

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Neural Regeneration Research 2022年第10期17卷 2149-2152页

作者： Andrea N.Nortey Kimberly N.Garces Abigail S.Hackam Bascom Palmer Eye Institute University of Miami Miller School of MedicineMiamiFLUSA

Interleukin-27 is a pleiotropic cytokine that is involved in tissue responses to infection,cell stress,neuronal disease,and tumors.Recent studies in various tissues indicate that interleukin-27 has complex activating and inhibitory properties in innate and acquired immunity.The availability of recombinant interleukin-27 protein and mice with genetic deletions of interleukin-27,its receptors and signaling mediators have helped define the role of interleukin-27 in neurodegenerative diseases.Interleukin-27 has been well-characterized as an important regulator of T cell activation and differentiation that enhances or suppresses T cell responses in autoimmune conditions in the central nervous system.Evidence is also accumulating that interleukin-27 has neuroprotective activities in the retina and brain.Interleukin-27 is secreted from and binds to infiltrating microglia,macrophage,astrocytes,and even neurons and it promotes neuronal survival by regulating pro-and anti-inflammatory cytokines,neuroinflammatory pathways,oxidative stress,apoptosis,autophagy,and epigenetic modifications.However,interleukin-27 can have the opposite effect and induce inflammation and cell death in certain situations.In this review,we describe the current understanding of regulatory activities of interleukin-27 on cell survival and inflammation and discuss its mechanisms of action in the brain,spinal cord,and retina.We also review evidence for and against the therapeutic potential of interleukin-27 for dampening harmful neuroinflammatory responses in central nervous system diseases.

关键词： central nervous system cytokine inflammatory interleukin-27 neuroprotection retina

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