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| 1 | Amino acid transporter SLC7A11/ xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer显示文摘Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs,and to maintain redox homeostasis.One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT).SLC7A11 promotes cystine uptake and glutathione biosynthesis,resulting in protection from oxidative stress and ferroptotic cell death.Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells.This review discusses the roles of SLC7A11 in regulating the anti-oxidant response and nutrient dependency of cancer cells,explores our current understanding of SLC7A11 regulation in cancer metabolism,and highlights key open questions for future studies in this emerging research area.A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment. | Pranavi Koppula Yilei Zhang Li Zhuang Boyi Gan | 2018 | Cancer Communications2018，38，1： | 77 |
| 2 | Neurodegeneration:An early event of diabetic retinopathy显示文摘Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia.However,retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination.In other words,retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR.Therefore,the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR.Elevated levels of glutamate and the overexpression of the renin-angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina.Among neuroprotective factors,pigment epithelial derived factor,somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review.Nevertheless,it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye.New strategies,based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors,are currently being tested in experimental models and in clinical pilot studies.Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research. | Marta Villarroel Andreea Ciudin Cristina Hernández Rafael Simó | 2010 | World Journal of Diabetes2010，1，2： | 41 |
| 3 | Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion显示文摘Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region.The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged.Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion,but had no effect on Synapsin I levels.Besides,we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus.This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats,and suggests that these positive effects occur via the upregulation of the postsynaptic membrane a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018. | Bei-Yao Gao Dong-Sheng Xu Pei-Le Liu Ce Li Liang Du Yan Hua Jian Hu Jia-Yun Hou Yu-Long Bai | 2020 | Neural Regeneration Research2020，15，6： | 19 |
| 4 | Ferrostatin-1 protects HT-22 cells from oxidative toxicity显示文摘Ferroptosis is a type of programmed cell death dependent on iron.It is different from other forms of cell death such as apoptosis,classic necrosis and autophagy.Ferroptosis is involved in many neurodegenerative diseases.The role of ferroptosis in glutamate-induced neuronal toxicity is not fully understood.To test its toxicity,glutamate(1.25–20 mM)was applied to HT-22 cells for 12 to 48 hours.The optimal experimental conditions occurred at 12 hours after incubation with 5 mM glutamate.Cells were cultured with 3–12μM ferrostatin-1,an inhibitor of ferroptosis,for 12 hours before exposure to glutamate.The cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Autophagy was determined by monodansylcadaverine staining and apoptosis by caspase 3 activity.Damage to cell structures was observed under light and by transmission electron microscopy.The release of lactate dehydrogenase was detected by the commercial kit.Reactive oxygen species were measured by flow cytometry.Glutathione peroxidase activity,superoxide dismutase activity and malondialdehyde level were detected by the appropriate commercial kit.Prostaglandin peroxidase synthase 2 and glutathione peroxidase 4 gene expression was detected by real-time quantitative polymerase chain reaction.Glutathione peroxidase 4 and nuclear factor erythroid-derived-like 2 protein expression was detected by western blot analysis.Results showed that ferrostatin-1 can significantly counter the effects of glutamate on HT-22 cells,improving the survival rate,reducing the release of lactate dehydrogenase and reducing the damage to mitochondrial ultrastructure.However,it did not affect the caspase-3 expression and monodansylcadaverine-positive staining in glutamate-injured HT-22 cells.Ferrostatin-1 reduced the levels of reactive oxygen species and malondialdehyde and enhanced superoxide dismutase activity.It decreased gene expression of prostaglandin peroxidase synthase 2 and increased gene expression of glutathione peroxidase 4 and protein expressions of glutathione peroxidase 4 and nuclear factor(erythroid-derived)-like 2 in glutamate-injured HT-22 cells.Treatment of cultured cells with the apoptosis inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone(2–8μM),autophagy inhibitor 3-methyladenine(100–400μM)or necrosis inhibitor necrostatin-1(10–40μM)had no effect on glutamate induced cell damage.However,the iron chelator deferoxamine mesylate salt inhibited glutamate induced cell death.Thus,the results suggested that ferroptosis is caused by glutamate-induced toxicity and that ferrostatin-1 protects HT-22 cells from glutamate-induced oxidative toxicity by inhibiting the oxidative stress. | Jun Chu Chen-Xu Liu Rui Song Qing-Lin Li | 2020 | Neural Regeneration Research2020，15，3： | 16 |
| 5 | Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease显示文摘Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17, 2015(approval No. AEEI-2015-182). | Ning Li Yang Li Li-Juan Li Ke Zhu Yan Zheng Xiao-Min Wang | 2019 | Neural Regeneration Research2019，14，6： | 14 |
| 6 | Nerve growth factor pretreatment against glutamate-induced hippocampal neuronal injury Action mechanism of phosphatase and tensin homologue deleted on chromosome 10显示文摘BACKGROUND: Nerve growth factor (NGF) attenuates glutamate-induced injury to hippocampal neurons, and the human tumor suppressor gene phosphatase and tensin homologue deleted on chromosome 10 (PTEN) promotes neuronal apoptosis. However, effects of PTEN in NGF-mediated neuroprotection against glutamate excitotoxicity remain poorly understood. OBJECTIVE: To investigate the relationship between NGF inhibition of glutamate-induced injury and PTEN. DESIGN, TIME AND SETTING: The randomized, controlled, in vitro study was performed at the Department of Pathophysiology, Medical School of Nantong University, China from October 2007 to March 2008. MATERIALS: Glutamate, NGF, 4, 6-diamidino-2-phenyl-indolediacetate, 3-[4, 5-dimethylthiazol-2-yl]- 2, 5-diphenyl tetrazoliumbromide (MTT), and lactate dehydrogenase kit (Sigma, USA), fluorescence microscope and inverted phase contrast microscope (Olympus, Japan) were used in this study. METHODS: Hippocampal neurons were obtained from newborn (< 24 hours) Sprague Dawley rats and cultured for 7 days. The control group was not treated with any intervention factor, the glutamate group was treated with glutamate (0.2 mmol/L), and NGF groups were treated with NGF (10, 50, 100, and 200 μg/L, respectively) prior to glutamate treatment. MAIN OUTCOME MEASURES: The MTT and lactate dehydrogenase assays were applied to evaluate viability of hippocampal neurons. Morphological changes in hippocampal neurons were observed using an inverted phase-contrast microscope, and neuronal apoptosis was detected by 4, 6-diamidino-2-phenyl-indolediacetate staining. PTEN mRNA and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot analysis, respectively. RESULTS: Glutamate (0.2 mmol/L) induced significantly decreased neuronal viability and greater lactate dehydrogenase efflux compared with the control group (P < 0.01). However, compared with the glutamate group, cell viability significantly increased and lactate dehydrogenase efflux decreased in the NGF group with increasing NGF concentrations (P < 0.05 or P < 0.01). The apoptotic ratio and PTEN mRNA and protein expression decreased in the NGF group compared with the glutamate group (P < 0.01). CONCLUSION: Pretreatment with NGF exerted neuroprotective effects against glutamate-induced injury, partially through inhibition of PTEN expression and neuronal apoptosis. | Yae Hu Jiahui Mao Yan Zhu Ailing Zhou | 2010 | Neural Regeneration Research2010，5，1： | 12 |
| 7 | EFFECT OF RADIX SALVIAE MILTIORRHIZAE ON EAA AND IAA DURING CEREBRAL ISCHEMIA IN GERBILS: A MICRODIALYSIS STUDY显示文摘The concentrations of amino acids (AA), stroke index and infarct area were determined in 26 gerbils which were divided into 3 groups: RSM-treated (n = 8), Saline-treated (n = 10) and sham-operated (n = 8). The levels of AA were measured with microdialysis technique in cerebral cortex. The concentrations of neurotransmitter AA, as Glu and GABA and Asp, were significantly increased during the first 60 min after CCA ligation, while the concentra-tions of non-neurotransmitter AA, as Thr and Ser, had no significant changes. In RSM-treated gerbils, the level of Glu was significantly lower than that of the saline-treated, but the GABA in RSM-treated was significantly higher than that of the sa-line-treated. The ratio of Glu/ GABA was significantly decreased after ischemia. The RSM could improve the reduction of ratio of Glu / GABA during 0-30 min and 91-120 min after cerebral ischemia. There were statistically significant decrease in terms of stroke index in RSM-treated group when compared with saline-treated group at 24 h and 16 h after CCA ligation respectively. The RSM has a tendency to decrease the size of infarct area, but no statistical difference. The results suggest that the neurotransmitter AA involve in the pathophysiological procedures of cerebral ischemia and the RSM can attenuate dysfunctions of EAA and IAA. Furthermore, the results also imply that there may be an alternate way to treat cerebral ischemia by inhibiting the presynaptic releasing of Glu and stimulating the releasing of GABA. | 匡培根 向敬 | 1994 | Journal of Traditional Chinese Medicine1994，14，1： | 10 |
| 8 | Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders显示文摘Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the presynaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter(EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders. | Georgia M Parkin Madhara Udawela Andrew Gibbons Brian Dean | 2018 | World Journal of Psychiatry2018，8，2： | 9 |
| 9 | Glutamate and aspartate alleviate testicular/epididymal oxidative stress by supporting antioxidant enzymes and immune defense systems in boars显示文摘Several potential oxidative agents have damaging effects on mammalian reproductive systems.This study was conducted to investigate the effects of glutamate(Glu)and aspartate(Asp)supplementation on antioxidant enzymes and immune defense systems in the outer scrotum of boars injected with H2O2.A total of 24 healthy boars were randomly divided into 4 treatment groups:control(basal diet,saline-treated),H2O2(basal diet,H2O2-challenged outer scrotum(1 m L kg^–1 BW)),Glu(basal diet+2%Glu,H2O2-challenged),and Asp(basal diet+2%Asp,H2O2-challenged).Our results showed that both Glu and Asp supplementation improved testicular morphology and decreased the genital index in the H2O2-treated boars.Glu and Asp administration increased the antioxidant enzyme activities and affected the testicular inflammatory cytokine secretion but had no effect on sex hormone levels.Furthermore,the m RNA expression of CAT,Cu Zn SOD,and GPx4 was altered in the testes and epididymis of boars treated with Asp and Glu.Glu and Asp supplementation also modulated the expression of TGF-β1,IL-10,TNF-α,IL-6 and IL-1βin the testis and epididymis.These results indicate that dietary Glu and Asp supplementation might enhance antioxidant capacity and regulate the secretion and expression of inflammatory cytokines to protect the testes and epididymis of boars against oxidative stress. | Wenjie Tang Jian Wu Shunshun Jin Liuqin He Qinlu Lin Feijun Luo Xingguo He Yanzhong Feng Binsheng He Pingping Bing Tiejun Li Yulong Yin | 2020 | Science China(Life Sciences)2020，63，1： | 9 |
| 10 | Glutamate reduces experimental intestinal hyperpermeability and facilitates glutamine support of gut integrity显示文摘AIM:To assess whether glutamate plays a similar role to glutamine in preserving gut wall integrity.METHODS:The effects of glutamine and glutamate on induced hyperpermeability in intestinal cell lines were studied.Paracellular hyperpermeability was induced in Caco2.BBE and HT-29CL.19A cell lines by adding phorbol-12,13-dibutyrate(PDB) apically,after which the effects of glutamine and glutamate on horseradish peroxidase(HRP) diffusion were studied.An inhibitor of glutamate transport(L-trans-pyrrolidine-2,4-dicarboxylic acid:trans-PDC) and an irreversible blocker(acivicin) of the extracellular glutamine to glutamate converting enzyme,γ-glutamyltransferase,were used.RESULTS:Apical to basolateral HRP flux increased significantly compared to controls not exposed to PDB (n=30,P<0.001).Glutamine application reduced hyperpermeability by 19%and 39%in the respective cell lines.Glutamate application reduced hyperpermeability by 30%and 20%,respectively.Incubation of HT29CL.19A cells with acivicin and subsequent PDB and glutamine addition increased permeability levels.Incubation of Caco2.BBE cells with trans-PDC followed by PDB and glutamate addition also resulted in high permeability levels.CONCLUSION:Apical glutamate-similar to glutaminecan decrease induced paracellular hyperpermeability.Extracellular conversion of glutamine to glutamate and subsequent uptake of glutamate could be a pivotal step in the mechanism underlying the protective effect of glutamine. | Mechteld AR Vermeulen Jeffrey de Jong Mathijs J Vaessen Paul AM van Leeuwen Alexander PJ Houdijk | 2011 | World Journal of Gastroenterology2011，17，12： | 9 |
| 11 | Paired associated magnetic stimulation promotes neural repair in the rat middle cerebral artery occlusion model of stroke显示文摘Paired associative stimulation has been used in stroke patients as an innovative recovery treatment.However,the mechanisms underlying the therapeutic effectiveness of paired associative stimulation on neurological function remain unclear.In this study,rats were randomly divided into middle cerebral occlusion model(MCAO)and paired associated magnetic stimulation(PAMS)groups.The MCAO rat model was produced by middle cerebral artery embolization.The PAMS group received PAMS on days 3 to 20 post MCAO.The MCAO group received sham stimulation,three times every week.Within 18 days after ischemia,rats were subjected to behavioral experiments—the foot-fault test,the balance beam walking test,and the ladder walking test.Balance ability was improved on days 15 and 17,and the footfault rate was less in their affected limb on day 15 in the PAMS group compared with the MCAO group.Western blot assay showed that the expression levels of brain derived neurotrophic factor,glutamate receptor 2/3,postsynaptic density protein 95 and synapsin-1 were significantly increased in the PAMS group compared with the MCAO group in the ipsilateral sensorimotor cortex on day 21.Resting-state functional magnetic resonance imaging revealed that regional brain activities in the sensorimotor cortex were increased in the ipsilateral hemisphere,but decreased in the contralateral hemisphere on day 20.By finite element simulation,the electric field distribution showed a higher intensity,of approximately 0.4 A/m^2,in the ischemic cortex compared with the contralateral cortex in the template.Together,our findings show that PAMS upregulates neuroplasticity-related proteins,increases regional brain activity,and promotes functional recovery in the affected sensorimotor cortex in the rat MCAO model.The experiments were approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018. | Bei-Yao Gao Cheng-Cheng Sun Guo-Hua Xia Shao-Ting Zhou Ye Zhang Ye-Ran Mao Pei-Le Liu Ya Zheng Dan Zhao Xu-Tong Li Janie Xu Dong-Sheng Xu Yu-Long Bai | 2020 | Neural Regeneration Research2020，15，11： | 8 |
| 12 | Effects of primary microglia and astrocytes on neural stem cells in in vitro and in vivo models of ischemic stroke显示文摘Transplantation of neural stem cells(NSCs) can protect neurons in animal stroke models;however, their low rates of survival and neuronal differentiation limit their clinical application. Glial niches, an important location of neural stem cells, regulate survival, proliferation and differentiation of neural stem cells. However, the effects of activated glial cells on neural stem cells remain unclear. In the present study, we explored the effects of activated astrocytes and microglia on neural stem cells in vitro stroke models. We also investigated the effects of combined transplantation of neural stem cells and glial cells after stroke in rats. In a Transwell co-culture system, primary cultured astrocytes, microglia or mixed glial cells were exposed to glutamate or H_2O_2 and then seeded in the upper inserts, while primary neural stem cells were seeded in the lower uncoated wells and cultured for 7 days. Our results showed that microglia were conducive to neurosphere formation and had no effects on apoptosis within neurospheres, while astrocytes and mixed glial cells were conducive to neurosphere differentiation and reduced apoptosis within neurospheres, regardless of their pretreatment. In contrast, microglia and astrocytes induced neuronal differentiation of neural stem cells in differentiation medium, regardless of their pretreatment, with an exception of astrocytes pretreated with H_2O_2. Rat models of ischemic stroke were established by occlusion of the middle cerebral artery. Three days later, 5 × 10~5 neural stem cells with microglia or astrocytes were injected into the right lateral ventricle. Neural stem cell/astrocyte-treated rats displayed better improvement of neurological deficits than neural stem cell only-treated rats at 4 days after cell transplantation. Moreover, neural stem cell/microglia-, and neural stem cell/astrocyte-treated rats showed a significant decrease in ischemic volume compared with neural stem celltreated rats. These findings indicate that microglia and astrocytes exert different effects on neural stem cells, and that co-transplantation of neural stem cells and astrocytes is more conducive to the recovery of neurological impairment in rats with ischemic stroke. The study was approved by the Animal Ethics Committee of Tongji University School of Medicine, China(approval No. 2010-TJAA08220401) in 2010. | Sheng-Jun Wen Xi-Min Zheng Li-Fen Liu Na-Na Li Hai-An Mao Liang Huang Qiong-Lan Yuan | 2021 | Neural Regeneration Research2021，16，9： | 7 |
| 13 | Acute drivers of neuroinflammation in traumatic brain injury显示文摘Neuroinflammation is initiated as a result of traumatic brain injury and can exacerbate evolving tissue pathology.Immune cells respond to acute signals from damaged cells,initiate neuroinflammation,and drive the pathological consequences over time.Importantly,the mechanism(s)of injury,the location of the immune cells within the brain,and the animal species all contribute to immune cell behavior following traumatic brain injury.Understanding the signals that initiate neuroinflammation and the context in which they appear may be critical for understanding immune cell contributions to pathology and regeneration.Within this paper,we review a number of factors that could affect immune cell behavior acutely following traumatic brain injury. | Kathryn L.Wofford David J.Loane D.Kacy Cullen | 2019 | Neural Regeneration Research2019，14，9： | 7 |
| 14 | Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor显示文摘The effects of glutamate and its agonists and antagonists on the swelling of cultured astrocytes were studied. Swelling of astrocytes was measured by [3H]-O-methyl-D-glucose uptake. Glutamate at 0.5, 1 and 10mmol/L and irons-l-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), a metabotropic glutamate receptor (mGluR) agonist, at 1 mmol/L caused a significant increase in astrocytic volume, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) was not effective. L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist of mGluR, blocked the astrocytic swelling induced by trans-ACPD or glutamate. In Ca2+-free condition, glutamate was no longer effective. Swelling of astrocytes induced by glutamate was not blocked by CdCl2 at 20 μmol/L, but significantly reduced by CdCl2 at 300 μmol/L and dantrolene at 30 μmol/L. These findings indicate that mGluR activation results in astrocytic swelling and both extracellular calcium and internal calcium stores play important roles in the | 袁芳 王天佑 | 1996 | Science China(Life Sciences)1996，39，5： | 7 |
| 15 | Molecular mechanisms of protein induced hyperinsulinaemic hypoglycaemia显示文摘The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors(such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase(GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism. | Suresh Chandran Fabian Yap Khalid Hussain | 2014 | World Journal of Diabetes2014，5，5： | 6 |
| 16 | Increased L-arginine Production by Site-directed Mutagenesis of N-acetyl-L-glutamate Kinase and pro B Gene Deletion in Corynebacterium crenatum显示文摘Objective In Corynebacterium crenatum,the adjacent D311 and D312 of N-acetyl-L-glutamate kinase(NAGK),as a key rate-limiting enzyme of L-arginine biosynthesis under substrate regulatory control by arginine,were initially replaced with two arginine residues to investigate the L-arginine feedback inhibition for NAGK.Methods NAGK enzyme expression was evaluated using a plasmid-based method.Homologous recombination was employed to eliminate the pro B.Results The IC50 and enzyme activity of NAGK M4,in which the D311 R and D312 R amino acid substitutions were combined with the previously reported E19 R and H26 E substitutions,were 3.7-fold and 14.6% higher,respectively,than those of the wild-type NAGK.NAGK M4 was successfully introduced into the C.crenatum MT genome without any genetic markers;the L-arginine yield of C.crenatum MT-M4 was 26.2% higher than that of C.crenatum MT.To further improve upon the L-arginine yield,we constructed the mutant C.crenatum MT-M4 ?pro B.The optimum concentration of L-proline was also investigated in order to determine its contribution to L-arginine yield.After L-proline was added to the medium at 10 mmol/L,the L-arginine yield reached 16.5 g/L after 108 h of shake-flask fermentation,approximately 70.1% higher than the yield attained using C.crenatum MT.Conclusion Feedback inhibition of L-arginine on NAGK in C.crenatum is clearly alleviated by the M4 mutation of NAGK,and deletion of the pro B in C.crenatum from MT to M4 results in a significant increase in arginine production. | ZHANG Bin WAN Fang QIU Yu Lou CHEN Xue Lan TANG Li CHEN Jin Cong XIONG Yong Hua | 2015 | Biomedical and Environmental Sciences2015，28，12： | 5 |
| 17 | Glutamine and glutamate: Nonessential or essential amino acids?显示文摘Glutamine and glutamate are not considered essential amino acids but they play important roles in maintaining growth and health in both neonates and adults. Although glutamine and glutamate are highly abundant in most feedstuffs there is increasing evidence that they may be limiting during pregnancy, lactation and neonatal growth, particularly when relatively low protein diets are fed. Supplementation of diets with glutamine, glutamate or both at 0.5 to 1.0% to both suckling and recently weaned piglets improves intestinal and immune function and results in better growth. In addition such supplementation to the sow prevents some of the loss of lean body mass during lactation, and increases milk glutamine content. However, a number of important questions related to physiological condition,species under study and the form and amount of the supplements need to be addressed before the full benefits of glutamine and glutamate supplementation in domestic animal production can be realized. | Malcolm Watford | 2015 | Animal Nutrition2015，，3： | 5 |
| 18 | Systematic analyses of glutamine and glutamate metabolisms across different cancer types显示文摘Background: Glutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across different cancer types, whereas such knowledge could be critical for understanding the distinct characteristics of different cancer types. Our computational study aimed to examine the functional roles of glutamine and glutamate across different cancer types.Methods: We conducted a comparative analysis of gene expression data of cancer tissues versus normal control tissues of 11 cancer types to understand glutamine and glutamate metabolisms in cancer. Specifically, we developed a linear regression model to assess differential contributions by glutamine and/or glutamate to each of seven biological processes in cancer versus control tissues.Results: While our computational predictions were consistent with some of the previous observations, multiple novel predictions were made:(1) glutamine is generally not involved in purine synthesis in cancer except for breast cancer, and is similarly not involved in pyridine synthesis except for kidney cancer;(2) glutamine is generally not involved in ATP production in cancer;(3) glutamine's contribution to nucleotide synthesis is minimal if any in cancer;(4) glutamine is not involved in asparagine synthesis in cancer except for bladder and lung cancers; and(5) glutamate does not contribute to serine synthesis except for bladder cancer.Conclusions: We comprehensively predicted the roles of glutamine and glutamate metabolisms in selected metabolic pathways in cancer tissues versus control tissues, which may lead to novel approaches to therapeutic development targeted at glutamine and/or glutamate metabolism. However, our predictions need further functional validation. | Yuan Tian Wei Du Sha Cao Yue Wu Ning Dong Yan Wang Ying Xu | 2017 | Chinese Journal of Cancer2017，36，12： | 5 |
| 19 | Optogenetics-induced activation of glutamate receptors improves memory function in mice with Alzheimer’s disease显示文摘Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011. | Ke-Wei Wang Xiao-Lin Ye Ting Huang Xi-Fei Yang Liang-Yu Zou | 2019 | Neural Regeneration Research2019，14，12： | 5 |
| 20 | Methylene blue ameliorates brain edema in rats with experimental ischemic stroke via inhibiting aquaporin 4 expression显示文摘Brain edema is a common and serious complication of ischemic stroke with limited effective treatment.We previously reported that methylene blue(MB)attenuated ischemic brain edema in rats,but the underlying mechanisms remained unknown.Aquaporin 4(AQP4)in astrocytes plays a key role in brain edema.We also found that extracellular signal-regulated kinase 1/2(ERK1/2)activation was involved in the regulation of AQP4 expression in astrocytes.In the present study,we investigated whether AQP4 and ERK1/2 were involved in the protective effect of MB against cerebral edema.Rats were subjected to transient middle cerebral artery occlusion(tMCAO),MB(3 mg/kg,for 30 min)was infused intravenously through the tail vein started immediately after reperfusion and again at 3 h after ischemia(1.5 mg/kg,for 15 min).Brain edema was determined by MRI at 0.5,2.5,and 48 h after tMCAO.The decreases of apparent diffusion coefficient(ADC)values on diffusion-weighted MRI indicated cytotoxic brain edema,whereas the increase of T2 MRI values reflected vasogenic brain edema.We found that MB infusion significantly ameliorated cytotoxic brain edema at 2.5 and 48 h after tMCAO and decreased vasogenic brain edema at 48 h after tMCAO.In addition,MB infusion blocked the AQP4 increases and ERK1/2 activation in the cerebral cortex in ischemic penumbra at 48 h after tMCAO.In a cell swelling model established in cultured rat astrocyte exposed to glutamate(1 mM),we consistently found that MB(10μM)attenuated cell swelling,AQP4 increases and ERK1/2 activation.Moreover,the ERK1/2 inhibitor U0126(10μM)had the similar effects as MB.These results demonstrate that MB improves brain edema and astrocyte swelling,which may be mediated by the inhibition of AQP4 expression via ERK1/2 pathway,suggesting that MB may be a potential choice for the treatment of brain edema. | Zhong-fang Shi Qing Fang Ye Chen Li-xin Xu Min Wu Mei Jia Yi Lu Xiao-xuan Wang Yu-jiao Wang Xu Yan Li-ping Dong Fang Yuan | 2021 | Acta Pharmacologica Sinica2021，42，3： | 5 |
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