Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,n...Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.展开更多
Aquaporin-4 （AQP-4）, a water-channel protein,is highly expressed in the brain, which is important ele- ments in the formation of brain edema and plays an important role in the rapid transmembrane transport. AQP-4 ex...Aquaporin-4 （AQP-4）, a water-channel protein,is highly expressed in the brain, which is important ele- ments in the formation of brain edema and plays an important role in the rapid transmembrane transport. AQP-4 ex- pression up-regulates after ischemia-reperfusion injury in rats, making the astrocytic endfeet swelling, with the con- sequence of the injury of blood-brain barrier（BBB） , increasing the permeability of BBB, render too much water in the blood flow to the brain parenchyma, which results in cytotoxic edema, disordering the stability of the central nervous system. In addintion, the increased permeability of BBB is one of the important reasons for the cerebral stroke, therefore, it is essential that research the relationship between AQP-4 with BBB further and restore the blood-brain barrier injury be a new strategy for the prevention and treatment of stroke, worthy of further research.展开更多
Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which ...Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-（N,N-dimethylaminoethyl）-ginkgolide B methanesulfonate （XQ-1H） , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion （MCAO） modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide （LPS） incubation with rat brain microvessel endothelial cells （rBMECs） was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.展开更多
OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectom...OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine(TCM) diagnostic classification of MDD.METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation(LQS,n=30) and Heart and Spleen Deficiency(HSD,n=20) subtypes according to TCM diagnosis.Healthy volunteers(n=28) were included as controls.Gas chromatography-mass spectrometry(GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity,respectively.RESULTS In metabolomic analysis,28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples.While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls,the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters.Several metabolites are differentially associated with the two subtypes.In connectomic analysis,The LQS subtype showed significant differences in multiple network metrics of the angular gyrus,middle occipital gyrus,calcarine sulcus,and Heschl′ s gyrus when compared to the other two groups.The HSD subtype had markedly greater regional connectivity of the insula,parahippocampal gyrus,and posterior cingulate gyrus than the other two groups,and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole.The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity.CONCLUSION The LQS subtype may represent an MDD subpopulation mainly characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters,closer associations with stress-related pathophysiology,and aberrant connectivity of the audiovisual perception-related temporal-occipital network,whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbicparalimbic network.Certain metabolomic and connectomic variables are potential biomarkers for TCM diagnostic subtypes which is perhaps an alternative classification for depressive disorders.展开更多
To investigate the effects of aluminium （Al） exposure on amino acid neurotransmitters, the chickens with different levels of subchronic Al poisoning were estabolished by continuous peritoneal injection of fixed volu...To investigate the effects of aluminium （Al） exposure on amino acid neurotransmitters, the chickens with different levels of subchronic Al poisoning were estabolished by continuous peritoneal injection of fixed volume and different concentrations of gradient of aluminium trichloride （AlCl3）. The levels of amino acid neurotransmitters in chicken brains were determined by high performance liquid chromatography （HPLC） after being exposed of Al for 60 days, and Al levels in serum and brain tissue were determined by atomic absorption spectrophotometry （AAS）. The results showed that Glu levels increased with the increase of Al, but there was no significant difference compared with the control. The levels of Al, Asp, Gly, GABA and Tau were significantly higher in Al-treated groups than those in the control. The results indicated that Al intoxication led to excitatory neurotoxicity.展开更多
Nowadays, the vein based recognition system becomes an emerging and facilitating biometric technology in the recognition system. Vein recognition exploits the different modalities such as finger, palm and hand image f...Nowadays, the vein based recognition system becomes an emerging and facilitating biometric technology in the recognition system. Vein recognition exploits the different modalities such as finger, palm and hand image for the person identification. In this work, the fuzzy least brain storm optimization and Euclidean distance(EED) are proposed for the vein based recognition system. Initially, the input image is fed into the region of interest(ROI) extraction which obtains the appropriate image for the subsequent step. Then, features or vein pattern is extracted by the image enlightening, circular averaging filter and holoentropy based thresholding. After the features are obtained, the entropy based Euclidean distance is proposed to fuse the features by the score level fusion with the weight score value. Finally, the optimal matching score is computed iteratively by the newly developed fuzzy least brain storm optimization(FLBSO) algorithm. The novel algorithm is developed by the least mean square(LMS) algorithm and fuzzy brain storm optimization(FBSO). Thus, the experimental results are evaluated and the performance is compared with the existing systems using false acceptance rate(FAR), false rejection rate(FRR) and accuracy. The performance outcome of the proposed algorithm attains the higher accuracy of 89.9% which ensures the better recognition rate.展开更多
Epidemiological studies have shown that there is a link between asthma and brain damage,but toxicological studies have not fully confirmed yet,especially the effects of asthma on the brain. In this study,at first,we e...Epidemiological studies have shown that there is a link between asthma and brain damage,but toxicological studies have not fully confirmed yet,especially the effects of asthma on the brain. In this study,at first,we explore the effects of asthma on the brain through the establishment of an allergic asthma model. Then PM_(2.5),a typical outdoor air pollutant and formaldehyde,a typical indoor air pollutant were selected to be closer to the true environment and find whether there is any synergism between them. In this study,an ovalbumin( OVA)-sensitized mice asthma model was established. 30 male Balb/c mice were randomly divided into 5 groups:( 1) saline control group,( 2) OVA-sensitized group,( 3) OVA-combined with formaldehyde exposure group,( 4) OVA-combined with PM_(2.5) exposure group,( 5) Combination of OVA,formaldehyde and PM_(2.5) exposure group. The mice were inhaled with formaldehyde or/and instilled with PM_(2.5) from day 1 to 18. The mice asthma model was developed by OVA sensitization and challenge. The mice were sensitized with OVA+Al( OH)3( 5 mg OVA and 175 mg Al( OH)3 in 30 m L saline each time) or saline( 30 m L saline each time) by intraperitoneal injection on day 1,7 and 14.This was then followed by an aerosol challenge in 1% OVA( 30 min·d^(-1)) from day 19 to 25( 7 times) using an ultrasonic nebulizer. On the 26 th day,the organ coefficient of mice brain was counted,then the contents of oxidative stress of mice brain were measured,including reactive oxygen species( ROS),glutathione( GSH) and malondialdehyde( MDA),and the concentrations of NF-κB and interleukin-1β( IL-1β) were detected by using ELISA kits.Detection of interleukin-6( IL-6) was made with immunohistochemical method. Histological assay for brain was also conducted. In our results,all the OVA treated groups showed a significant increase of ROS and a significant decrease of GSH contents when compared with the control group. Except OVA-sensitized group,other OVA treated groups also showed a significant increase of MDA contents when compared with the control group,and MDA contents of OVA-sensitized group showed significant change when compared to the combined exposure group. In ROS and GSH,combined exposure showed some joint effect compared with single exposure. When OVA was applied in combination with formaldehyde and PM_(2.5),NF-κB was activated. And all the OVA treated groups showed increased levels of IL-1β and IL-6 compared with the control group. And the combined exposure showed an aggravated effect when compared with OVA-sensitized group. Histopathological observation of the hippocampus in mice brain clearly showed the difference of eosin( EO) stained neurons in the combined exposure group compared with the control group and OVA-sensitized group. The pyramidal neurons of the mice with allergic asthma exposed to formaldehyde and/or PM_(2.5) had been reduced in number,the cells were swollen and the dendrites had disappeared. Allergic asthma can cause damage to the brain through oxidative stress. Exposure to formaldehyde and PM_(2.5) will increase the damage caused by allergic asthma to the brain,which may be mediated by oxidative stress and NF-κB activation.This promotes the release of the inflammatory factors,resulting in increased inflammation.展开更多
OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was ...OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was applied to the rightcerebral ventricle immediately after transient middle cerebral artery occlusion.Brain water content,Evans blue leakage and the expression of aquaporin-4(AQP-4),matrix metalloproteinase-9(MMP-9),zonula occludens-1(ZO-1)and occludin were measured.RESULTS After treatment with antiCKLF1 antibody,brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24 h after reperfusion,but not changed in contralateral hemisphere.Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9,and upregulated the expression of ZO-1 and Occludin.These results suggest that CKLF1 is involved in BBB disruption after reperfusion.CONCLUSION Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity,possibly via inhibiting the expression of AQP-4 and MMP-9,and increasing the expression of tight junction protein.展开更多
To overcome the deficiencies of high computational complexity and low convergence speed in traditional neural networks, a novel bio-inspired machine learning algorithm named brain emotional learning （BEL） is introdu...To overcome the deficiencies of high computational complexity and low convergence speed in traditional neural networks, a novel bio-inspired machine learning algorithm named brain emotional learning （BEL） is introduced. BEL mimics the emotional learning mechanism in brain which has the superior features of fast learning and quick reacting. To further improve the performance of BEL in data analysis, genetic algorithm （GA） is adopted for optimally tuning the weights and biases of amygdala and orbitofrontal cortex in BEL neural network. The integrated algorithm named GA-BEL combines the advantages of the fast learning of BEL, and the global optimum solution of GA. GA-BEL has been tested on a real-world chaotic time series of geomagnetic activity index for prediction, eight benchmark datasets of university California at Irvine （UCI） and a functional magnetic resonance imaging （fMRI） dataset for classifications. The comparisons of experimental results have shown that the proposed GA-BEL algorithm is more accurate than the original BEL in prediction, and more effective when dealing with large-scale classification problems. Further, it outperforms most other traditional algorithms in terms of accuracy and execution speed in both prediction and classification applications.展开更多
OBJECTIVE To evaluate the effects of Tong-Qiao-Huo-Xue decoction(TQHXD)on the bloodbrain barrier(BBB)permeability and the expressions of related proteins on the rats;and to analyse the constituents in the cerebrospina...OBJECTIVE To evaluate the effects of Tong-Qiao-Huo-Xue decoction(TQHXD)on the bloodbrain barrier(BBB)permeability and the expressions of related proteins on the rats;and to analyse the constituents in the cerebrospinal fluid on the rats with cerebral ischemic injury.METHODS Cerebral ischemia rats were induced by middle cerebral artery occlusion(MCAO).Adult male sprague-dawley(SD)rats were randomly divided into seven groups:sham-group;model group;nimodipine(NMP)-treated group and nao mai tai(NMT)-treated group were set as positive drug control groups;TQHXD-treated group(3,6 and 12g·kg-1body weight);The neurological function of rats was estimated by neurological defect scoring after the 1,7and 15 dafter administration.Histological structure of the brain in rats were observed by hematoxylin and eosin(H&E)staining.Ultramicrostructural features of hippocampus neurons and the opening of tight junction(TJ)of BBB in rats were observed by transmission electron microscope(TEM).Western blotting was performed to detect the expression of ZO-1,occludin,claudin-5,AQP-4 and MMP-9 in BBB after cerebral ischemia injury.Component analysis experiments:adult male SD rats were randomly divided into four groups:Distilled water was administered intragastrically sham-operated rats;Distilled water was administered intragastrically model rats by MCAO;TQHXD was administered intragatrically to rats in sham-operated group;TQHXD was administered intragestrically to rats in model group by MCAO.GC and HPLC was used to detect three compounds,namely,muscone,ligustilide and hydroxysafflor yellow A,in rats cerebrospinal fluid(CSF)after oral administration of TQHXD.Finally,samples of cerebrospinal fluid of rats in each group were compared with single medicine so as to explicit the three compounds come from which herb.RESULTS TQHXD significantly reduced the neurological defect scores.Histological examination indicated that dense neuropil and largely surviving neurons had been seen in TQHXD-treated rats.TEM observation revealed that TQHXD could significantly inhibit the damage of hippocampal neurons and reduce the opening of TJ.The decreased protein expression levels of claudin-5,occludin,ZO-1 and the increased protein expression levels of AQP-4 and MMP-9in cerebral ischemia tissue were significantly prevented by treatment of TQHXD.Analysis of experimental results showed that muscone,ligustilide and hydroxysafflor yellow A could penetrate the BBB into the CSF,and the content of the model group was lower than that of sham group after intragastric administration of TQHXD.CONCLUSION These results demonstrated that TQHXD may act as a potential neuroprotective agent against BBB damage for cerebral ischemia through protecting of hippocampus neurons,reducing the opening of TJ and decreasing the permeability of BBB by up-regulating ZO-1,occludin,claudin-5 expressions,down-regulating AQP-4 and MMP-9 expressions.The effect of TQHXD on the decrease of the opening of TJ also reduced the content of muscone,ligustilide and hydroxysafflor yellow A in cerebrospinal fluid.展开更多
The purpose of this study was to develop a quantitative structure–property relationship(QSPR) model based on the enhanced replacement method(ERM) and support vector machine(SVM) to predict the blood-to-brain barrier ...The purpose of this study was to develop a quantitative structure–property relationship(QSPR) model based on the enhanced replacement method(ERM) and support vector machine(SVM) to predict the blood-to-brain barrier partitioning behavior(log BB) of various drugs and organic compounds. Different molecular descriptors were calculated using a dragon package to represent the molecular structures of the compounds studied. The enhanced replacement method(ERM) was used to select the variables and construct the SVM model. The correlation coefficient, R^2, between experimental results and predicted log BB was 0.878 and 0.986, respectively. The results obtained demonstrated that, for all compounds, the log BB values estimated by SVM agreed with the experimental data, demonstrating that SVM is an effective method for model development, and can be used as a powerful chemometric tool in QSPR studies.展开更多
OBJECTIVE To establish Idiopathic basal ganglia calcification(IBGC′s)disease model in mouse,and investigate the effect of Chinese herbal medicine formula SYM to prevent brain calcification caused by SLC20A2 mutations...OBJECTIVE To establish Idiopathic basal ganglia calcification(IBGC′s)disease model in mouse,and investigate the effect of Chinese herbal medicine formula SYM to prevent brain calcification caused by SLC20A2 mutations.METHODS In order to apply the IBGC model in mice,we introduced S602 W point mutation into the mouse Slc20a2.Mice(3months old)with homozygous mutation developed brain calcification as similar as IBGC in human.The SYM decoction was diluted and added into the drinking water of 2-week-old homozygous Slc20a2 KI mice for 5months.Another group of homozygous Slc20a2 KI mice were set as control and received no treatment.After 5months,to analyze the effect of the SYM decoction on brain calcification,pathological sections with the brain of Slc20a2 KI mice were made and stained.RESULTS Calcified nodules were not seen in the brain of Slc20a2 KI mice that received SYM decoction treatment,while the control group developed multiple calcifications in the thalamus region.CONCLUSION SYM decoction produced preventive effect on the formation of calcified nodules in IBGC model mice,which might be useful for the treatment of IBGC caused by SLC20A2 mutations.展开更多
OBJECTIVE The receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile.In the present study,we investigate the potential role of endothelial ErbB4 receptor signaling...OBJECTIVE The receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile.In the present study,we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. METHODS ErbB4 conditional KO mice were generated by a lox P/Cre strategy. The experimenter conducting the experimentsand scoring the behavior was blinded to the genotype of the mice. Open field test,Y-maze and novel-object exploration test,novel object recognition task,step-through passive avoidance task,Morris water maze and memory reconsolidation task were carried out in WT and Cdh5-Cre; ErbB4^(loxP/loxP)mice. A high-resolution micro PET/CT scanner was used for brain metabolism imaging. RESULTS Here,we show that Cdh5Cre; ErbB4^(f/f) mice have lower levels ofexploration activity as measured by these particular behavior tests. However,our data indicate that conditional knockout of ErbB4 in endothelial cells did not impair working memory,memory acquisition,retrieval,and reconsolidation in mice. Furthermore,^(18)F-FDG-uptake was reduced in the Cdh5Cre; ErbB4^(f/f) mice as revealed by the significantly decreased SUVs in compared with the WT mice. Consistently,the immunoblot data demonstrate the downregulation of brain Glut1,phosphoULK1(Ser555) and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively,the endothelial ErbB4 deletion induced impairment in exploratory activity in adult mice,which may be due to the decreased brain energy metabolism. CONCLUSION Our study provides insight into the potential pathophysiological mechanisms of endothelial ErbB 4 and therapeutic strategies for neurological disorders.展开更多
OBJECTIVE To investigate the protective effects and mechanisms of costunolide against mousebrain slice injury induced by oxygen-glucose deprivation/reoxygenation(OGD/R).METHODS Mouse brain slice injury was induced by ...OBJECTIVE To investigate the protective effects and mechanisms of costunolide against mousebrain slice injury induced by oxygen-glucose deprivation/reoxygenation(OGD/R).METHODS Mouse brain slice injury was induced by OGD/R in vitro,and the degree ofinjury was evaluated by measuring the release of lactate dehydrogenase(LDH)and 2,3,5-triphenyltetrazolium chloride(TTC)staining.Western blotting was used to analyze the expression of Bax,Bcl-2,Cyt-c,caspase-9,caspase-7 and caspase-3.RESULTS Compared with OGD/R,1,5,and 10μmol·L^-1 costu⁃nolide decreased the LDH levels,increased the TTC staining intensity,inhibited Bax,Cyt-c,caspase-9,caspase-7,caspase-3 expression levels,and enhanced Bcl-2 expression level.CONCLUSION Costunolide has latent neuroprotective activi⁃ties by the regulation of apoptosis via the mitochondrial apoptosis pathway.展开更多
OBJECTIVE Brain inflammation plays an important role in the pathophysiology of brain ischemicstroke,psychiatric and neurological diseases.During brain inflammation,microglia cells are activated and show pro-inflammato...OBJECTIVE Brain inflammation plays an important role in the pathophysiology of brain ischemicstroke,psychiatric and neurological diseases.During brain inflammation,microglia cells are activated and show pro-inflammatory M1 and anti-inflammatory M2 phenotypes,producing neurotoxic molecules and neurotrophic factors,respectively.We have previously discovered a novel natural product compound 3c exhibiting antiinflammatory effects in microglia cells,but the underlying mechanisms and its beneficial effects on brain inflammation and brain ischemia are unknown.METHODS The gene expression of M1 markers and M2 markers was measured by RT-PCR.The AMPK phosphorylation level and M2 marker CD206 protein expression were determined by Western blotting.TNFαrelease was measured by ELISA.The gene knowdown was performed by the si RNA transfection experiment.The LPS-induced brain inflammation mouse model and transient middle cerebral artery occlusion(t MCAO)stroke model were used.RESULTS We found that compound 3c inhibited M1polarization and promoted M2 polarization in LPS-stimulated BV2 and primary microglia cells,and these effects are mediated by Ca MKKβ/AMPK/JNK signaling pathway.Furthermore,compound 3c prevented M1 gene expression and enhanced M2 gene expression in a mouse model of LPS-induced neuroinflammation,and reduced the LPS-induced sickness behavior.In addition,compound 3c significantly reduced infarct volume,improved the neurological deficit,and reduced neuroinflammation in rats with acute focal cerebral ischemia.CONCLUSION Our results indicate that natural product compound 3c suppresses microglia activation by promoting M2 polarization and may provide a novel therapeutic approach to treat brain ischemic stroke associated with enhanced brain inflammation.展开更多
Aim Adipose tissue releases adipokines that play important roles in metabolic and cardiocerebro- vascu- lar homeostasis. This study was to discover novel adipokines using caloric restriction model. Methods Adipokine c...Aim Adipose tissue releases adipokines that play important roles in metabolic and cardiocerebro- vascu- lar homeostasis. This study was to discover novel adipokines using caloric restriction model. Methods Adipokine candidates were captured by gene array and bioinformatics analysis and verified by preparation of recombinant pro- tein and antibody. Results We established a potential secreted protein database containing 208 genes and identi- fied a novel adipokine, Subfatin, that was the highest expressed in subcutaneous fat of both rodents and humans a- mong 15 detected tissues. The secreted mammalian Subfatin was a glycosylated protein. Subfatin was located dif- fusely throughout the adipose tissue except lipid droplets, with comparable expression between adipocytes and stro- real cells, but much lower expression in macrophages than adipocytes. Subfatin was downregulated in white adipose tissue of caloric restriction rats, whereas dramatically upregulated during white adipocyte differentiation as well as in white adipose tissue of diet-induced obese mice. Subfatin was annotated as Meteorin-like （Metrnl） in public data- bases, a similar transcript of Meteorin （Metrn, also known as glial cell differentiation regulator）. Meteorin dis- played a brain-specific expression and was scarce in various adipose tissues, in contrast to the tissue expression pat- terns of Subfatin. Conclusions Subfatin is a novel adipokine regulated by adipogenesis and obesity, with tissue distribution different from its homologue Meteorin.展开更多
文摘Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.
文摘Aquaporin-4 （AQP-4）, a water-channel protein,is highly expressed in the brain, which is important ele- ments in the formation of brain edema and plays an important role in the rapid transmembrane transport. AQP-4 ex- pression up-regulates after ischemia-reperfusion injury in rats, making the astrocytic endfeet swelling, with the con- sequence of the injury of blood-brain barrier（BBB） , increasing the permeability of BBB, render too much water in the blood flow to the brain parenchyma, which results in cytotoxic edema, disordering the stability of the central nervous system. In addintion, the increased permeability of BBB is one of the important reasons for the cerebral stroke, therefore, it is essential that research the relationship between AQP-4 with BBB further and restore the blood-brain barrier injury be a new strategy for the prevention and treatment of stroke, worthy of further research.
文摘Following ischemic stroke, blood-brain barrier （BBB） is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-（N,N-dimethylaminoethyl）-ginkgolide B methanesulfonate （XQ-1H） , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion （MCAO） modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide （LPS） incubation with rat brain microvessel endothelial cells （rBMECs） was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.
基金National Natural Science Foundation of China(81403502)General Research Fund ofResearch Grants Council of Hong Kong (17124418).
文摘OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine(TCM) diagnostic classification of MDD.METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation(LQS,n=30) and Heart and Spleen Deficiency(HSD,n=20) subtypes according to TCM diagnosis.Healthy volunteers(n=28) were included as controls.Gas chromatography-mass spectrometry(GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity,respectively.RESULTS In metabolomic analysis,28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples.While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls,the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters.Several metabolites are differentially associated with the two subtypes.In connectomic analysis,The LQS subtype showed significant differences in multiple network metrics of the angular gyrus,middle occipital gyrus,calcarine sulcus,and Heschl′ s gyrus when compared to the other two groups.The HSD subtype had markedly greater regional connectivity of the insula,parahippocampal gyrus,and posterior cingulate gyrus than the other two groups,and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole.The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity.CONCLUSION The LQS subtype may represent an MDD subpopulation mainly characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters,closer associations with stress-related pathophysiology,and aberrant connectivity of the audiovisual perception-related temporal-occipital network,whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbicparalimbic network.Certain metabolomic and connectomic variables are potential biomarkers for TCM diagnostic subtypes which is perhaps an alternative classification for depressive disorders.
基金Supported by the Science and Technology Program of Helongjiang Educational Bureau (12511028)the Postgraduate Innovative Scientific Research Foundation of Heilongjiang Province (YJSCX2012-026HLJ)
文摘To investigate the effects of aluminium （Al） exposure on amino acid neurotransmitters, the chickens with different levels of subchronic Al poisoning were estabolished by continuous peritoneal injection of fixed volume and different concentrations of gradient of aluminium trichloride （AlCl3）. The levels of amino acid neurotransmitters in chicken brains were determined by high performance liquid chromatography （HPLC） after being exposed of Al for 60 days, and Al levels in serum and brain tissue were determined by atomic absorption spectrophotometry （AAS）. The results showed that Glu levels increased with the increase of Al, but there was no significant difference compared with the control. The levels of Al, Asp, Gly, GABA and Tau were significantly higher in Al-treated groups than those in the control. The results indicated that Al intoxication led to excitatory neurotoxicity.
文摘Nowadays, the vein based recognition system becomes an emerging and facilitating biometric technology in the recognition system. Vein recognition exploits the different modalities such as finger, palm and hand image for the person identification. In this work, the fuzzy least brain storm optimization and Euclidean distance(EED) are proposed for the vein based recognition system. Initially, the input image is fed into the region of interest(ROI) extraction which obtains the appropriate image for the subsequent step. Then, features or vein pattern is extracted by the image enlightening, circular averaging filter and holoentropy based thresholding. After the features are obtained, the entropy based Euclidean distance is proposed to fuse the features by the score level fusion with the weight score value. Finally, the optimal matching score is computed iteratively by the newly developed fuzzy least brain storm optimization(FLBSO) algorithm. The novel algorithm is developed by the least mean square(LMS) algorithm and fuzzy brain storm optimization(FBSO). Thus, the experimental results are evaluated and the performance is compared with the existing systems using false acceptance rate(FAR), false rejection rate(FRR) and accuracy. The performance outcome of the proposed algorithm attains the higher accuracy of 89.9% which ensures the better recognition rate.
基金National Natural Science Foundation of China (No: 21577045).
文摘Epidemiological studies have shown that there is a link between asthma and brain damage,but toxicological studies have not fully confirmed yet,especially the effects of asthma on the brain. In this study,at first,we explore the effects of asthma on the brain through the establishment of an allergic asthma model. Then PM_(2.5),a typical outdoor air pollutant and formaldehyde,a typical indoor air pollutant were selected to be closer to the true environment and find whether there is any synergism between them. In this study,an ovalbumin( OVA)-sensitized mice asthma model was established. 30 male Balb/c mice were randomly divided into 5 groups:( 1) saline control group,( 2) OVA-sensitized group,( 3) OVA-combined with formaldehyde exposure group,( 4) OVA-combined with PM_(2.5) exposure group,( 5) Combination of OVA,formaldehyde and PM_(2.5) exposure group. The mice were inhaled with formaldehyde or/and instilled with PM_(2.5) from day 1 to 18. The mice asthma model was developed by OVA sensitization and challenge. The mice were sensitized with OVA+Al( OH)3( 5 mg OVA and 175 mg Al( OH)3 in 30 m L saline each time) or saline( 30 m L saline each time) by intraperitoneal injection on day 1,7 and 14.This was then followed by an aerosol challenge in 1% OVA( 30 min·d^(-1)) from day 19 to 25( 7 times) using an ultrasonic nebulizer. On the 26 th day,the organ coefficient of mice brain was counted,then the contents of oxidative stress of mice brain were measured,including reactive oxygen species( ROS),glutathione( GSH) and malondialdehyde( MDA),and the concentrations of NF-κB and interleukin-1β( IL-1β) were detected by using ELISA kits.Detection of interleukin-6( IL-6) was made with immunohistochemical method. Histological assay for brain was also conducted. In our results,all the OVA treated groups showed a significant increase of ROS and a significant decrease of GSH contents when compared with the control group. Except OVA-sensitized group,other OVA treated groups also showed a significant increase of MDA contents when compared with the control group,and MDA contents of OVA-sensitized group showed significant change when compared to the combined exposure group. In ROS and GSH,combined exposure showed some joint effect compared with single exposure. When OVA was applied in combination with formaldehyde and PM_(2.5),NF-κB was activated. And all the OVA treated groups showed increased levels of IL-1β and IL-6 compared with the control group. And the combined exposure showed an aggravated effect when compared with OVA-sensitized group. Histopathological observation of the hippocampus in mice brain clearly showed the difference of eosin( EO) stained neurons in the combined exposure group compared with the control group and OVA-sensitized group. The pyramidal neurons of the mice with allergic asthma exposed to formaldehyde and/or PM_(2.5) had been reduced in number,the cells were swollen and the dendrites had disappeared. Allergic asthma can cause damage to the brain through oxidative stress. Exposure to formaldehyde and PM_(2.5) will increase the damage caused by allergic asthma to the brain,which may be mediated by oxidative stress and NF-κB activation.This promotes the release of the inflammatory factors,resulting in increased inflammation.
基金The project supported by National Natural Science Foundation of China(81302760)the Chinese Postdoctoral Science Foundation Project(2013M542510)
文摘OBJECTIVE To investigate the role of chemokine-like factor 1(CKLF1),a novel C-C chemokine,on brain-blood barrier(BBB)integrity in rat focal cerebral ischemia and reperfusion model.METHODS Antibodies against CKLF1 was applied to the rightcerebral ventricle immediately after transient middle cerebral artery occlusion.Brain water content,Evans blue leakage and the expression of aquaporin-4(AQP-4),matrix metalloproteinase-9(MMP-9),zonula occludens-1(ZO-1)and occludin were measured.RESULTS After treatment with antiCKLF1 antibody,brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24 h after reperfusion,but not changed in contralateral hemisphere.Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9,and upregulated the expression of ZO-1 and Occludin.These results suggest that CKLF1 is involved in BBB disruption after reperfusion.CONCLUSION Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity,possibly via inhibiting the expression of AQP-4 and MMP-9,and increasing the expression of tight junction protein.
基金Project(61403422)supported by the National Natural Science Foundation of ChinaProject(17C1084)supported by Hunan Education Department Science Foundation of ChinaProject(17ZD02)supported by Hunan University of Arts and Science,China
文摘To overcome the deficiencies of high computational complexity and low convergence speed in traditional neural networks, a novel bio-inspired machine learning algorithm named brain emotional learning （BEL） is introduced. BEL mimics the emotional learning mechanism in brain which has the superior features of fast learning and quick reacting. To further improve the performance of BEL in data analysis, genetic algorithm （GA） is adopted for optimally tuning the weights and biases of amygdala and orbitofrontal cortex in BEL neural network. The integrated algorithm named GA-BEL combines the advantages of the fast learning of BEL, and the global optimum solution of GA. GA-BEL has been tested on a real-world chaotic time series of geomagnetic activity index for prediction, eight benchmark datasets of university California at Irvine （UCI） and a functional magnetic resonance imaging （fMRI） dataset for classifications. The comparisons of experimental results have shown that the proposed GA-BEL algorithm is more accurate than the original BEL in prediction, and more effective when dealing with large-scale classification problems. Further, it outperforms most other traditional algorithms in terms of accuracy and execution speed in both prediction and classification applications.
基金The project supported by National Natural Science Foundation of China(81374005)″Twelfth Five Year″National Science and Technology Support Program(2012BAI26B03)
文摘OBJECTIVE To evaluate the effects of Tong-Qiao-Huo-Xue decoction(TQHXD)on the bloodbrain barrier(BBB)permeability and the expressions of related proteins on the rats;and to analyse the constituents in the cerebrospinal fluid on the rats with cerebral ischemic injury.METHODS Cerebral ischemia rats were induced by middle cerebral artery occlusion(MCAO).Adult male sprague-dawley(SD)rats were randomly divided into seven groups:sham-group;model group;nimodipine(NMP)-treated group and nao mai tai(NMT)-treated group were set as positive drug control groups;TQHXD-treated group(3,6 and 12g·kg-1body weight);The neurological function of rats was estimated by neurological defect scoring after the 1,7and 15 dafter administration.Histological structure of the brain in rats were observed by hematoxylin and eosin(H&E)staining.Ultramicrostructural features of hippocampus neurons and the opening of tight junction(TJ)of BBB in rats were observed by transmission electron microscope(TEM).Western blotting was performed to detect the expression of ZO-1,occludin,claudin-5,AQP-4 and MMP-9 in BBB after cerebral ischemia injury.Component analysis experiments:adult male SD rats were randomly divided into four groups:Distilled water was administered intragastrically sham-operated rats;Distilled water was administered intragastrically model rats by MCAO;TQHXD was administered intragatrically to rats in sham-operated group;TQHXD was administered intragestrically to rats in model group by MCAO.GC and HPLC was used to detect three compounds,namely,muscone,ligustilide and hydroxysafflor yellow A,in rats cerebrospinal fluid(CSF)after oral administration of TQHXD.Finally,samples of cerebrospinal fluid of rats in each group were compared with single medicine so as to explicit the three compounds come from which herb.RESULTS TQHXD significantly reduced the neurological defect scores.Histological examination indicated that dense neuropil and largely surviving neurons had been seen in TQHXD-treated rats.TEM observation revealed that TQHXD could significantly inhibit the damage of hippocampal neurons and reduce the opening of TJ.The decreased protein expression levels of claudin-5,occludin,ZO-1 and the increased protein expression levels of AQP-4 and MMP-9in cerebral ischemia tissue were significantly prevented by treatment of TQHXD.Analysis of experimental results showed that muscone,ligustilide and hydroxysafflor yellow A could penetrate the BBB into the CSF,and the content of the model group was lower than that of sham group after intragastric administration of TQHXD.CONCLUSION These results demonstrated that TQHXD may act as a potential neuroprotective agent against BBB damage for cerebral ischemia through protecting of hippocampus neurons,reducing the opening of TJ and decreasing the permeability of BBB by up-regulating ZO-1,occludin,claudin-5 expressions,down-regulating AQP-4 and MMP-9 expressions.The effect of TQHXD on the decrease of the opening of TJ also reduced the content of muscone,ligustilide and hydroxysafflor yellow A in cerebrospinal fluid.
文摘The purpose of this study was to develop a quantitative structure–property relationship(QSPR) model based on the enhanced replacement method(ERM) and support vector machine(SVM) to predict the blood-to-brain barrier partitioning behavior(log BB) of various drugs and organic compounds. Different molecular descriptors were calculated using a dragon package to represent the molecular structures of the compounds studied. The enhanced replacement method(ERM) was used to select the variables and construct the SVM model. The correlation coefficient, R^2, between experimental results and predicted log BB was 0.878 and 0.986, respectively. The results obtained demonstrated that, for all compounds, the log BB values estimated by SVM agreed with the experimental data, demonstrating that SVM is an effective method for model development, and can be used as a powerful chemometric tool in QSPR studies.
基金The project supported by National Natural Science Foundation of China grants(31230045and 81271252)the National Science&Technology Pillar Program duringthe 12th Five-year Plan Period(2012BAI09B04)
文摘OBJECTIVE To establish Idiopathic basal ganglia calcification(IBGC′s)disease model in mouse,and investigate the effect of Chinese herbal medicine formula SYM to prevent brain calcification caused by SLC20A2 mutations.METHODS In order to apply the IBGC model in mice,we introduced S602 W point mutation into the mouse Slc20a2.Mice(3months old)with homozygous mutation developed brain calcification as similar as IBGC in human.The SYM decoction was diluted and added into the drinking water of 2-week-old homozygous Slc20a2 KI mice for 5months.Another group of homozygous Slc20a2 KI mice were set as control and received no treatment.After 5months,to analyze the effect of the SYM decoction on brain calcification,pathological sections with the brain of Slc20a2 KI mice were made and stained.RESULTS Calcified nodules were not seen in the brain of Slc20a2 KI mice that received SYM decoction treatment,while the control group developed multiple calcifications in the thalamus region.CONCLUSION SYM decoction produced preventive effect on the formation of calcified nodules in IBGC model mice,which might be useful for the treatment of IBGC caused by SLC20A2 mutations.
文摘OBJECTIVE The receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile.In the present study,we investigate the potential role of endothelial ErbB4 receptor signaling in the brain. METHODS ErbB4 conditional KO mice were generated by a lox P/Cre strategy. The experimenter conducting the experimentsand scoring the behavior was blinded to the genotype of the mice. Open field test,Y-maze and novel-object exploration test,novel object recognition task,step-through passive avoidance task,Morris water maze and memory reconsolidation task were carried out in WT and Cdh5-Cre; ErbB4^(loxP/loxP)mice. A high-resolution micro PET/CT scanner was used for brain metabolism imaging. RESULTS Here,we show that Cdh5Cre; ErbB4^(f/f) mice have lower levels ofexploration activity as measured by these particular behavior tests. However,our data indicate that conditional knockout of ErbB4 in endothelial cells did not impair working memory,memory acquisition,retrieval,and reconsolidation in mice. Furthermore,^(18)F-FDG-uptake was reduced in the Cdh5Cre; ErbB4^(f/f) mice as revealed by the significantly decreased SUVs in compared with the WT mice. Consistently,the immunoblot data demonstrate the downregulation of brain Glut1,phosphoULK1(Ser555) and TIGAR in the endothelial ErbB4 conditional knockout mice. Collectively,the endothelial ErbB4 deletion induced impairment in exploratory activity in adult mice,which may be due to the decreased brain energy metabolism. CONCLUSION Our study provides insight into the potential pathophysiological mechanisms of endothelial ErbB 4 and therapeutic strategies for neurological disorders.
基金National Natural Science Foundation of China(8166070081260679)Ningxia College FirstClass Discipline Construction Project(Chinese Medicine)Funded Project(NXYLXK2017A06)
文摘OBJECTIVE To investigate the protective effects and mechanisms of costunolide against mousebrain slice injury induced by oxygen-glucose deprivation/reoxygenation(OGD/R).METHODS Mouse brain slice injury was induced by OGD/R in vitro,and the degree ofinjury was evaluated by measuring the release of lactate dehydrogenase(LDH)and 2,3,5-triphenyltetrazolium chloride(TTC)staining.Western blotting was used to analyze the expression of Bax,Bcl-2,Cyt-c,caspase-9,caspase-7 and caspase-3.RESULTS Compared with OGD/R,1,5,and 10μmol·L^-1 costu⁃nolide decreased the LDH levels,increased the TTC staining intensity,inhibited Bax,Cyt-c,caspase-9,caspase-7,caspase-3 expression levels,and enhanced Bcl-2 expression level.CONCLUSION Costunolide has latent neuroprotective activi⁃ties by the regulation of apoptosis via the mitochondrial apoptosis pathway.
文摘OBJECTIVE Brain inflammation plays an important role in the pathophysiology of brain ischemicstroke,psychiatric and neurological diseases.During brain inflammation,microglia cells are activated and show pro-inflammatory M1 and anti-inflammatory M2 phenotypes,producing neurotoxic molecules and neurotrophic factors,respectively.We have previously discovered a novel natural product compound 3c exhibiting antiinflammatory effects in microglia cells,but the underlying mechanisms and its beneficial effects on brain inflammation and brain ischemia are unknown.METHODS The gene expression of M1 markers and M2 markers was measured by RT-PCR.The AMPK phosphorylation level and M2 marker CD206 protein expression were determined by Western blotting.TNFαrelease was measured by ELISA.The gene knowdown was performed by the si RNA transfection experiment.The LPS-induced brain inflammation mouse model and transient middle cerebral artery occlusion(t MCAO)stroke model were used.RESULTS We found that compound 3c inhibited M1polarization and promoted M2 polarization in LPS-stimulated BV2 and primary microglia cells,and these effects are mediated by Ca MKKβ/AMPK/JNK signaling pathway.Furthermore,compound 3c prevented M1 gene expression and enhanced M2 gene expression in a mouse model of LPS-induced neuroinflammation,and reduced the LPS-induced sickness behavior.In addition,compound 3c significantly reduced infarct volume,improved the neurological deficit,and reduced neuroinflammation in rats with acute focal cerebral ischemia.CONCLUSION Our results indicate that natural product compound 3c suppresses microglia activation by promoting M2 polarization and may provide a novel therapeutic approach to treat brain ischemic stroke associated with enhanced brain inflammation.
文摘Aim Adipose tissue releases adipokines that play important roles in metabolic and cardiocerebro- vascu- lar homeostasis. This study was to discover novel adipokines using caloric restriction model. Methods Adipokine candidates were captured by gene array and bioinformatics analysis and verified by preparation of recombinant pro- tein and antibody. Results We established a potential secreted protein database containing 208 genes and identi- fied a novel adipokine, Subfatin, that was the highest expressed in subcutaneous fat of both rodents and humans a- mong 15 detected tissues. The secreted mammalian Subfatin was a glycosylated protein. Subfatin was located dif- fusely throughout the adipose tissue except lipid droplets, with comparable expression between adipocytes and stro- real cells, but much lower expression in macrophages than adipocytes. Subfatin was downregulated in white adipose tissue of caloric restriction rats, whereas dramatically upregulated during white adipocyte differentiation as well as in white adipose tissue of diet-induced obese mice. Subfatin was annotated as Meteorin-like （Metrnl） in public data- bases, a similar transcript of Meteorin （Metrn, also known as glial cell differentiation regulator）. Meteorin dis- played a brain-specific expression and was scarce in various adipose tissues, in contrast to the tissue expression pat- terns of Subfatin. Conclusions Subfatin is a novel adipokine regulated by adipogenesis and obesity, with tissue distribution different from its homologue Meteorin.
