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Homer signaling pathways as effective therapeutic targets for ischemic and traumatic brain injuries and retinal lesions

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Neural Regeneration Research 2022年第7期17卷 1454-1461页

作者： Xiu-Quan Wu Ning Su Zhou Fei Fei Fei Department of Neurosurgery Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina Department of Radiation Oncology Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina Department of Ophthalmology Xijing Hospitalthe Fourth Military Medical UniversityXi’anShaanxi ProvinceChina

Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.

关键词： brain injury calcium signaling cerebral ischemia dendritic spine glutamate receptor Homer scaffolding protein neuron neuroprotection retinal ganglion cell review traumatic brain injury

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Monitored anesthesia care and asleep-awake-asleep techniques combined with multiple monitoring for resection of gliomas in eloquent brain areas:a retrospective analysis of 225 patients

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Chinese Neurosurgical Journal 2023年第2期9卷 88-97页

作者： San-Zhong Li Ning Su Shuang Wu Xiao-Wei Fei Xin He Jiu-Xiang Zhang Xiao-Hui Wang Hao-Peng Zhang Xiao-Guang Bai Guang Cheng Zhou Fei Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi’an 710032China Department of Radiotherapy Xijing HospitalFourth Military Medical UniversityXi’an 710032China Department of Anesthesiology Xijing HospitalFourth Military Medical UniversityXi’an 710032China

Background:Awake craniotomy(AC)has become gold standard in surgical resection of gliomas located in eloquent areas.The conscious sedation techniques in AC include both monitored anesthesia care(MAC)and asleep-awake-asleep(AAA).The choice of optimal anesthetic method depends on the preferences of the surgical team(mainly anesthesiologist and neurosurgeon).The aim of this study was to compare the difference in physiological and blood gas data,dosage of different drugs,the probability of switching to endotracheal intubation,and extent of tumor resection and dysfunction after operation between AAA and MAC anesthetic management for resection of gliomas in eloquent brain areas.Methods:Two-hundred and twenty-five patients with super-tentorial tumor located in eloquent areas underwent AC from 2009 to 2021 in Xijing Hospital.Forty-one patients underwent AAA technique,and the rest one-hundred eighty-four patients underwent MAC technique.Anesthetic management,dosage of different drugs,intraoperative complications,postoperative outcomes,adverse events,extent of resection and motor,and sensory and language dysfunction after operation were compared between MAC and AAA.Result:There was no significant difference in gender,KPS score,MMSE score,glioma grade,type,and growth site between the patients in the two groups,except the older age of patients in MAC group than that in AAA group.During the whole process of operation,there were greater pulse pressure difference(P=0.046),shorter operation time(P=0.039),less dosage of remifentanil(P=0.000),more dosage of dexmedetomidine(P=0.013),more use of antiemetics(81%,P=0.0067),lower use of vasoactive agent(45.1%,P=0.010),and lower probability of conversion to general anesthesia(GA,P=0.027)in MAC group than that in AAA group.Blood gas analysis showed that PetCO2(P=0.000),Glu concentration(P=0.000),and PaCO2(P=0.000)were higher,but SPO2(P=0.002)and PaO2(P=0.000)were lower in MAC group than that in AAA group.In the postoperative recovery stage,compared with that of AAA group,the probability o

关键词： Monitored anesthesia care(MAC) Asleep-awake-asleep(AAA) Retrospective analysis Eloquent areas Gliomas

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Brain Glycogen:An Angel or a Devil for Ischemic Stroke?

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Neuroscience Bulletin 2023年第4期39卷 690-694页

作者： Haiyun Guo Yumeng Li Wugang Hou Yanhui Cai Department of Anesthesiology and Perioperative Medicine Xijing HospitalFourth Military Medical UniversityXi’an710032China Department of Psychiatry Xijing HospitalFourth Military Medical UniversityXi’an710032China

Brain Glycogen Works as an Angel Under Physiological Condition Glycogen Metabolism in the Brain One of the unique characteristics of the brain is its diversity in neural cell types,and neurons and astrocytes exhibit different metabolic patterns[1].Glycogen mainly exists in astrocytes,not in neurons[2].Glycogen metabolism is conservative throughout the body.Similar to the liver and muscle,the astrocytic glycogen level is controlled by glycogenesis and glycogenolysis[3].

关键词： metabolism conservative Brain

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Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

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Journal of Pharmaceutical Analysis 2024年第1期14卷 86-99页

作者： Shengyou Li Xue Gao Yi Zheng Yujie Yang Jianbo Gao Dan Geng Lingli Guo Teng Ma Yiming Hao Bin Wei Liangliang Huang Yitao Wei Bing Xia Zhuojing Luo Jinghui Huang Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi'an710032China

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

关键词： Ferroptosis UBA52 Ferroportin Ubiquitination Hydralazine Peripheral nerve injury

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Stem cells:a promising candidate to treat neurological disorders

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Neural Regeneration Research 2018年第7期13卷 1294-1304页

作者： Chang-Geng Song Yi-Zhe Zhang Hai-Ning Wu Xiu-Li Cao Chen-Jun Guo Yong-Qiang Li Min-Hua Zheng Hua Han Department of medical Genetics and Developmental Biology Fourth Military Medical University Department of Biochemistry and Molecular Biology Fourth Military Medical University

Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous system.Therefore,based on the regenerative capacity of stem cells,transplantation therapies of various stem cells have been tested in basic research and preclinical trials,and some have shown great prospects.This manuscript overviews the cellular and molecular characteristics of embryonic stem cells,induced pluripotent stem cells,neural stem cells,retinal stem/progenitor cells,mesenchymal stem/stromal cells,and their derivatives in vivo and in vitro as sources for regenerative therapy.These cells have all been considered as candidates to treat several major neurological disorders and diseases,owing to their self-renewal capacity,multi-directional differentiation,neurotrophic properties,and immune modulation effects.We also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease,and age-related macular degeneration,as well as traumatic brain injury and glioblastoma.In spite of a few unsuccessful cases,risks of tumorigenicity,and ethical concerns,most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system disease.In summary,these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological disorders.Thus,stem cells are a promising candidate for the treatment of nervous system diseases.

关键词： nerve regeneration stem cells transplantation stem cell therapy nervous system neurodegenerative disease neurological disorders animal experiment clinical trial regenerative medicine neural regeneration

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Anti-fibrotic Effects and Mechanism of Shengmai Injection(生脉注射液)on Human Hepatic Stellate Cells LX-2

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Chinese Journal of Integrative Medicine 2019年第3期25卷 197-202页

作者： ZHANG Yi MA Li-tian LI Jie QIAO Yu LIU Jun-ye WANG Jin REN Qin-you HU Jin-tao ZHENG Jin Department of Traditional Chinese Medicine Tangdu Hospital The Fourth Military Medical University Department of Endocrinology The 986 Hospital of The People's Liberation Army Department of Anatomy and K.K. Leung Brain Research Center The Fourth Military Medical University Student Brigade The Fourth Military Medical University Department of Radiation Medicine The Fourth Military Medical University Department of Immunology The Fourth Military Medical University

Objective: To investigate the effects of Shengmai Injection(生脉注射液, SMI) on the proliferation, apoptosis and N-myc downstream-regulated gene 2(NDRG2, a tumour suppressor gene) expression in varying densities of human hepatic stellate cells LX-2. Methods: LX-2 cells were cultured in vitro. Then, cells were plated in 96-well plates at an approximate density of 2.5×10~4 cells/mL and cultured for 48, 72, 96 or 120 h followed by the application of different concentrations of SMI(0.6, 1.2, 2.4, 4.8 or 6 μL/mL). Cell proliferation was measured after an additional 24 or 48 h using the 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. The effects of SMI on different cell growth states(cultured for 48, 72, 96, or 120 h) were observed by light microscopy at 24 h after treatment. When the cells reached 80% confluence, apoptosis was detected by flow cytometry after 24 h. Lastly, LX-2 cells were treated with different concentrations of SMI and extracted with protein lysis buffer. The levels of NDRG2 were measured by Western blot. Results: When the LX-2 cells grew for 48, 72, 96 and 120 h, 4.8 and 6 μL/m L of SMI significantly inhibited cell proliferation at 24 and 48 h after treatment(P<0.05). And 2.4 μL/mL of SMI also inhibited cell proliferation at 24 h after treatment when cell growth for 48 h(P<0.05) and at 48 h after treatment when cell growth for 72, 96 and 120 h(P<0.05). The NDRG2 expression level in the LX-2 cell was significantly increased when treated with SMI at concentrations of 1.2, 2.4, 4.8 or 6 μL/mL(P<0.05). Conclusions: The inhibitory effects of SMI on the proliferation of LX-2 cells were related to not only concentration dependent but also cell density. In addition, SMI(2.4, 4.8 and 6 μL/mL) could accelerate apoptosis in LX-2 cells, and the mechanism might be associated with NDRG2 over-expression.

关键词： Shengmai injection liver fibrosis N-myc downstream-regulated gene 2 LX-2 cell proliferation apoptosis Chinese medicine

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Hydralazine Promotes Central Nervous System Recovery after Spinal Cord Injury by Suppressing Oxidative Stress and Inflammation through Macrophage Regulation

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当代医学科学(英文) 2023年第4期43卷 749-758页

作者： Xin QUAN Teng MA Kai GUO Huan WANG Cai-yong YU Chu-chu QI Bao-qiang SONG Department of Plastic Surgery Xijing Hospitalthe Fourth Military Medical UniversityXi'an 710032China Department of Orthopedics Xijing Hospitalthe Fourth Military Medical UniversityXi'an 710032China Department of Burns and Cutaneous Surgery Xijing Hospitalthe Fourth Military Medical UniversityXi'an 710032China Department of Respiratory Medicine Xi'an Hospital of Traditional MedicineXi'an 710000China Department of Neurobiology School of Basic Medicinethe Fourth Military Medical UniversityXi'an 710032China

Objective:This study aims to investigate the effects of hydralazine on inflammation induced by spinal cord injury(SCI)in the central nervous system(CNS)and its mechanism in promoting the structural and functional recovery of the injured CNS.Methods:A compressive SCI mouse model was utilized for this investigation.Immunofluorescence and quantitative real-time polymerase chain reaction were employed to examine the levels of acrolein,acrolein-induced inflammation-related factors,and macrophages at the injury site and within the CNS.Western blotting was used to evaluate the activity of the phosphoinositide 3-kinase(PI3K)/AKT pathway to study macrophage regulation.The neuropathic pain and motor function recovery were evaluated by glutamic acid decarboxylase 65/67(GAD65/67),vesicular glutamate transporter 1(VGLUT1),paw withdrawal response,and Basso Mouse Scale score.Nissl staining and Luxol Fast Blue(LFB)staining were performed to investigate the structural recovery of the injured CNS.Results:Hydralazine downregulated the levels of acrolein,IL-1β,and TNF-αin the spinal cord.The downregulation of acrolein induced by hydralazine promoted the activation of the PI3K/AKT pathway,leading to M2 macrophage polarization,which protected neurons against SCI-induced inflammation.Additionally,hydralazine promoted the structural recovery of the injured spinal cord area.Mitigating inflammation and oxidative stress by hydralazine in the animal model alleviated neuropathic pain and altered neurotransmitter expression.Furthermore,hydralazine facilitated motor function recovery following SCI.Nissl staining and LFB staining indicated that hydralazine promoted the structural recovery of the injured CNS.Conclusion:Hydralazine,an acrolein scavenger,significantly mitigated SCI-induced inflammation and oxidative stress in vivo,modulated macrophage activation,and consequently promoted the structural and functional recovery of the injured CNS.

关键词： spinal cord injury proinflammation oxidative stress macrophage acrolein scavenger

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Changes in early postoperative outcomes and complications observed in a single center during the 2022 COVID-19 pandemic wave in China:A single-center ambispective cohort study

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Chinese medical Journal 2023年第14期136卷 1708-1718页

作者： Lini Wang Ziyu Zheng Shouqiang Zhu Gang Luo Baobao Gao Yumei Ma Shuai Xu Hailong Dong Chong Lei Department of Anesthesiology and Perioperative Medicine Xijing HospitalFourth Military Medical UniversityXi’anShaanxi 710032China Anesthesia Clinical Research Center Xijing HospitalFourth Military Medical UniversityXi’anShaanxi 710032China

Background:Currently,the effect of the 2022 nationwide coronavirus disease 2019(COVID-19)wave on the perioperative prognosis of surgical patients in China is unclear.Thus,we aimed to explore its influence on postoperative morbidity and mortality in surgical patients.Methods:An ambispective cohort study was conducted at Xijing Hospital,China.We collected 10-day time-series data from December 29 until January 7 for the 2018-2022 period.The primary outcome was major postoperative complications(Clavien-Dindo class III-V).The association between COVID-19 exposure and postoperative prognosis was explored by comparing consecutive 5-year data at the population level and by comparing patients with and without COVID-19 exposure at the patient level.Results:The entire cohort consisted of 3350 patients(age:48.5±19.2 years),including 1759 females(52.5%).Overall,961(28.7%)underwent emergency surgery,and 553(16.5%)had COVID-19 exposure(from the 2022 cohort).At the population level,major postoperative complications occurred in 5.9%(42/707),5.7%(53/935),5.1%(46/901),9.4%(11/117),and 22.0%(152/690)patients in the 2018-2022 cohorts,respectively.After adjusting for potential confounding factors,the 2022 cohort(80%patients with COVID-19 history)had a significantly higher postoperative major complication risk than did the 2018 cohort(adjusted risk difference[aRD],14.9%(95%confidence interval[CI],11.5-18.4%);adjusted odds ratio[aOR],8.19(95%CI,5.24-12.81)).At the patient level,the incidence of major postoperative complications was significantly greater in patients with(24.6%,136/553)than that in patients without COVID-19 history(6.0%[168/2797];aRD,17.8%[95%CI,13.6-22.1%];aOR,7.89[95%CI,5.76-10.83]).Secondary outcomes of postoperative pulmonary complications were consistent with primary findings.These findings were verified through sensitivity analyses using time-series data projections and propensity score matching.Conclusion:Based on a single-center observation,patients with recent COVID-19 exposure were likely to have a high incidenc

关键词： COVID-19 Decision-making Surgery Omicron Postoperative complications

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Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

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Neuroscience Bulletin 2024年第1期40卷 35-49页

作者： Shuhui Dai Yuan Feng Chuanhao Lu Hongchen Zhang Wenke Ma Wenyu Xie Xiuquan Wu Peng Luo Lei Zhang Fei Fei Zhou Fei Xia Li Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi'an 710000China National Translational Science Center for Molecular Medicine and Department of Cell Biology Fourth Military Medical UniversityXi'an 710000China Department of Neurosurgery The Central Hospital of BaojiBaoji 721000China Department of Ophthalmology Xijing HospitalFourth Military Medical UniversityXi'an 710000China

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness.Autophagy plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains unknown.Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain,and is partially responsible for HH-induced oxidative stress,neuronal loss,and brain damage.The autophagic agonist rapamycin only promotes the initiation of autophagy.By proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic flux.Overexpression of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with rapamycin.Furthermore,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure.These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

关键词： Autophagy-Proteomics Oxidative stress Hypobaric hypoxia-Brain injury

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New era:prospects for managing cancer of unknown primary

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癌症生物学与医学:英文版 2023年第8期20卷 562-567页

作者： Yize Li Yinmiao Bai Hongchen Ji Zhihui Liu Hongmei Zhang Department of Clinical Oncology Xijing HospitalThe Fourth Military Medical UniversityXi’an 710032China

Cancer of unknown primary(CUP)is a highly heterogeneous tumor type that is confirmed to be metastatic through pathological examination;however,its primary lesion cannot be determined on the basis of detailed clinical information and diagnostic methods.The current guidelines have not changed the basic definition of CUP.Some studies have reported a decline in the incidence of CUP,to approximately 2%1,with the development of diagnostic techniques such as radiology,histopathology,and genetic testing.

关键词： Cancer clinical cancer

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