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1.  Positive temperature coefficient thermistors based on carbon nanotube/polymer composites 
Scientific Reports  2014;4:6684.
In order to explore availability of carbon nanotube (CNT)-based positive temperature coefficient (PTC) thermistors in practical application, we prepared carbon nanotube (CNT) filled high density polyethylene (HDPE) composites by using conventional melt-mixing methods, and investigated their PTC effects in details. The CNT-based thermistors exhibit much larger hold current and higher hold voltage, increasing by 129% in comparison with the commercial carbon black (CB) filled HDPE thermistors. Such high current-bearing and voltage-bearing capacity for the CNT/HDPE thermistors is mainly attributed to high thermal conductivity and heat dissipation of entangled CNT networks. Moreover, the CNT/HDPE thermistors exhibit rapid electrical response to applied voltages, comparable to commercial CB-based thermistors. In light of their high current-bearing capacity and quick response, the CNT-based thermistors have great potential to be used as high-performance thermistors in practical application, especially in some critical circumstances of high temperature, large applied currents, and high applied voltages.
doi:10.1038/srep06684
PMCID: PMC4202205  PMID: 25327951
2.  Exercise facilitates the action of dietary DHA on functional recovery after brain trauma 
Neuroscience  2013;248:655-663.
The abilities of docosahexaenoic acid (DHA) and exercise to counteract cognitive decay after TBI is getting increasing recognition; however, the possibility that these actions can be complementary remains just as an intriguing possibility. Here we have examined the likelihood that the combination of diet and exercise has the added potential to facilitate functional recovery following TBI. Rats received mild fluid percussion injury (mFPI) or sham injury and then were maintained on a diet high in DHA (1.2% DHA) with or without voluntary exercise for 12 days. We found that FPI reduced DHA content in the brain, which was accompanied by increased levels of lipid peroxidation assessed using 4-HHE. FPI reduced the enzymes Acox1 and 17 -HSD4, and the calcium-independent phospholipases A2 (iPLA2), which are involved in metabolism of membrane phospholipids. FPI reduced levels of syntaxin-3 (STX-3), involved in the action of membrane DHA on synaptic membrane expansion, and also reduced BDNF signaling through its TrkB receptor. These effects of FPI were optimally counteracted by the combination of DHA and exercise. Our results support the possibility that the complementary action of exercise is exerted on restoring membrane homeostasis after TBI, which is necessary for supporting synaptic plasticity and cognition. It is our contention that strategies that take advantage of the combined applications of diet and exercise may have additional effects to the injured brain.
doi:10.1016/j.neuroscience.2013.06.041
PMCID: PMC3951948  PMID: 23811071
DHA; exercise; BDNF; omega-3 fatty acids; cognition
3.  Inherent Dynamics of Head Domain Correlates with ATP-Recognition of P2X4 Receptors: Insights Gained from Molecular Simulations 
PLoS ONE  2014;9(5):e97528.
P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139–146 and loop169–183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.
doi:10.1371/journal.pone.0097528
PMCID: PMC4039465  PMID: 24878662
4.  STAT3, p-STAT3 and HIF-1α are associated with vasculogenic mimicry and impact on survival in gastric adenocarcinoma 
Oncology Letters  2014;8(1):431-437.
Vasculogenic mimicry (VM) formation is important for invasion and metastasis of tumor cells in gastric adenocarcinoma (GAC). The present study aimed to investigate the association between signal transducer and activator of transcription-3 (STAT3), phosphor-STAT3 (p-STAT3), hypoxia-inducible factor-1α (HIF-1α) and VM formation in GAC, and discuss their clinical significance and correlation with the prognosis of patients with GAC. The expression levels of STAT3, p-STAT3, HIF-1α and VM were assessed in 60 cases of patients with GAC and 20 cases of patients with gastritis on tissue microarrays by immunohistochemical methods. The expression levels of STAT3, p-STAT3, HIF-1α and VM were higher in patients with GAC (particularly in poorly differentiated GAC) than in those with gastritis (P<0.05). The expression levels of STAT3, p-STAT3 and HIF-1α were higher in VM tissues compared with non-VM tissues (P<0.05). Positive correlations existed between STAT3, p-STAT3, HIF-1α and VM expression (P<0.05). The expression levels of STAT3, p-STAT3 and HIF-1α, VM, status of lymph node metastasis and tumor differentiation degree were associated with the overall survival time of patients with GAC (P<0.05). However, only p-STAT3 and VM expression were identified as the independent risk factors of GAC OS when analyzed with multivariate analysis. p-STAT3 and VM play a significant role in indicating the prognosis of patients with GAC. STAT3 activation may play a positive role in VM formation of GAC by the STAT3-p-STAT3-HIF-1α-VM effect axis.
doi:10.3892/ol.2014.2059
PMCID: PMC4063567  PMID: 24959290
gastric adenocarcinoma; signal transducer and activator of transcription-3; phosphor-signal transducer and activator of transcription-3; hypoxia-inducible factor-1α; vasculogenic mimicry; prognosis
5.  Dietary therapy to promote neuroprotection in chronic spinal cord injury 
Journal of neurosurgery. Spine  2012;17(2):134-140.
Object
The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission.
Methods
An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period.
Results
At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane.
Conclusions
Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy.
doi:10.3171/2012.5.SPINE1216
PMCID: PMC3951955  PMID: 22735048
myelopathy; docosahexaenoic acid; curcumin; membrane; spinal cord injury; rat
6.  Increasing Newly Diagnosed Rate and Changing Risk Factors of HCV in Yanbian Prefecture, a High Endemic Area in China 
PLoS ONE  2014;9(1):e86190.
Background
The newly diagnosed rate of HCV infection is increasing in China. However, the risk factors have not been fully identified. Here, a survey was performed in Yanbian Prefecture, a high-endemic area in China.
Methods
We identified newly diagnosed HCV infection in 2007–2011, using the local National Disease Supervision Information Management System from the Chinese Center for Disease Control and Prevention. We determined the risk factors using a case-control survey by questionnaire.
Results
Yanbian Prefecture had a rapid increase in the yearly newly diagnosed rate of HCV infection from 32.6 to 72.1/100.000 from the year 2007 to 2011. People aged 50–64 years had a high HCV infection of 43.4%, but only 0.3% of cases were reported in those aged less than 20 years. Cosmetic treatment, family history, blood transfusion, and dental treatment were independent risk factors for HCV infection. Unexpectedly, cosmetic treatments [odd ratio (OR) = 5.15, 95% confidence interval (CI) = 2.31–11.48, P = 0.00] and family history (OR = 4.68, 95% CI = 2.67–8.75, P = 0.00) showed a higher risk than the conventional risk factors of blood transfusion (OR = 4.49, 95% CI = 1.95–10.37, P = 0.001) and dental treatment (OR = 2.98, 95% CI = 1.42–6.25, P = 0.00). To further analyze the intrafamilial transmission, we found that spouses of HCV patients had an increased risk for acquiring HCV (OR = 5.75, 95% CI: 1.94–17.07), without significant association between either HCV RNA viral load (P = 0.29) or genotype (P = 0.43).
Conclusions
HCV infection was increased in Yanbian Prefecture. Cosmetic treatment was a higher risk factor than medical procedure. HCV infection had a clear family clustering phenomenon, especially between spouses.
doi:10.1371/journal.pone.0086190
PMCID: PMC3903515  PMID: 24475084
7.  Loss of miR-204 Expression Enhances Glioma Migration and Stem Cell-Like Phenotype 
Cancer research  2012;73(2):990-999.
Phenotypic similarities have long been recognized between subpopulations of glioma cells and neural stem cells. Many of these similar properties, including the robust abilities to self-renew, migrate and invade, are hallmarks of glioma cells that render them extremely aggressive. However, the molecular mechanisms underlying this character, particularly in glioma stem-like cells that drive this disease, remain poorly understood. Here we report the results of a differential miRNA expression screen that compared glioma cells and neural stem cells, where we found that miR-204 was markedly down-regulated in both types of cells. Mechanistic investigations revealed that miR-204 simultaneously suppressed self-renewal, stem cell associated phenotype and migration of glioma cells via targeting the stemness-governing transcriptional factor SOX4 and the migration-promoting receptor EphB2. Restoring miR-204 expression in glioma cells suppressed tumorigenesis and invasiveness in vivo and increased overall host survival. Further evaluation revealed that the miR-204 promoter was hypermethylated and that attenuating promoter methylation was sufficient to upregulate miR-204 in glioma cells. Together, our findings reveal miR-204 as a pivotal regulator of the development of stem cell-like phenotypes and cell motility in malignant glioma cells.
doi:10.1158/0008-5472.CAN-12-2895
PMCID: PMC3548958  PMID: 23204229
miR-204; glioma; stem cell like phenotype; cell migration
8.  Hypothalamic stimulation enhances hippocampal BDNF plasticity in proportion to metabolic rate 
Brain stimulation  2012;5(4):642-646.
Background
Energy metabolism is emerging as a driving force for cellular events underlying cognitive processing. The hypothalamus integrates metabolic signals with the function of centers related to cognitive processing such as the hippocampus.
Objective/Hypothesis
Hypothalamic activity can influence molecular systems important for processing synaptic plasticity underlying cognition in the hippocampus. The neurotrophin BDNF may act as a mediator for the effects of energy metabolism on synaptic plasticity and cognitive function.
Methods
The hypothalamus of rats confined to a respiratory chamber was electrically stimulated, and energy expenditure (EE) was assessed via indirect calorimetry. MRNA levels for BDNF and molecules related to synaptic plasticity and control of cellular energy metabolism were assessed in the hippocampus.
Results
Electrical stimulation of the rat hypothalamus elevates mRNA levels of hippocampal BDNF. BDNF mRNA levels increased according to the metabolic rate of the animals, and in proportion to the mRNA of molecules involved in control of cellular energy metabolism such as ubiquitous mitochondrial creatine kinase (uMtCK).
Conclusions
Results show a potential mechanism by which cellular energy metabolism impacts the substrates of cognitive processing, and may provide molecular basis for therapeutic treatments based on stimulation of deep brain structures.
doi:10.1016/j.brs.2011.11.001
PMCID: PMC3383390  PMID: 22441161
Energy metabolism; cognition; diabetes; hippocampus; trophic factors
9.  Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells 
The Journal of Clinical Investigation  2013;123(6):2576-2589.
JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple mutations within JAK2, which abrogate the function of JH2 and sustain JAK2 activation, are widely observed in hematological malignancies, comparable mutations have not been detected in solid tumors. How solid tumor cells override the autoinhibitory effect of the JH2 domain to maintain constitutive activation of JAK2/STAT3 signaling remains puzzling. Herein, we demonstrate that AGK directly interacted with the JH2 domain to relieve inhibition of JAK2 and activate JAK2/STAT3 signaling. Overexpression of AGK sustained constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly correlated with increased STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. These findings uncover a mechanism for constitutive activation of JAK2/STAT3 signaling in solid tumors and may represent a prognostic biomarker and therapeutic target.
doi:10.1172/JCI68143
PMCID: PMC3668815  PMID: 23676499
10.  Dietary Omega-3 Deficiency from Gestation Increases Spinal Cord Vulnerability to Traumatic Brain Injury-Induced Damage 
PLoS ONE  2012;7(12):e52998.
Although traumatic brain injury (TBI) is often associated with gait deficits, the effects of TBI on spinal cord centers are poorly understood. We seek to determine the influence of TBI on the spinal cord and the potential of dietary omega-3 (n-3) fatty acids to counteract these effects. Male rodents exposed to diets containing adequate or deficient levels of n-3 since gestation received a moderate fluid percussion injury when becoming 14 weeks old. TBI reduced levels of molecular systems important for synaptic plasticity (BDNF, TrkB, and CREB) and plasma membrane homeostasis (4-HNE, iPLA2, syntaxin-3) in the lumbar spinal cord. These effects of TBI were more dramatic in the animals exposed to the n-3 deficient diet. Results emphasize the comprehensive action of TBI across the neuroaxis, and the critical role of dietary n-3 as a means to build resistance against the effects of TBI.
doi:10.1371/journal.pone.0052998
PMCID: PMC3532480  PMID: 23300842
11.  The Salutary Effects of DHA Dietary Supplementation on Cognition, Neuroplasticity, and Membrane Homeostasis after Brain Trauma 
Journal of Neurotrauma  2011;28(10):2113-2122.
Abstract
The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.
doi:10.1089/neu.2011.1872
PMCID: PMC3191367  PMID: 21851229
brain-derived neurotrophic factor; plasticity; Sir2; superoxide dismutase; traumatic brain injury
12.  Exercise influences hippocampal plasticity by modulating BDNF processing 
Neuroscience  2011;192:773-780.
Exercise has been shown to impact brain plasticity and function by involving the action of BDNF; however, mechanisms involved are poorly understood. Two types of BDNF coexist in the brain, the precursor (proBDNF) and its mature product (mBDNF), which preferentially bind specific receptors and exert distinct functions. It is crucial to understand how exercise affects crucial steps in the BDNF processing and signaling to evaluate therapeutic applications. We found that 7 days of voluntary exercise increased both pro and mature BDNF in the rat hippocampus. Exercise also increased the activity of tissue-type plasminogen activator (tPA), a serine proteinase shown to facilitate proBDNF cleavage into mBDNF. The blockade of tPA activity reduced the exercise effects on proBDNF and mBDNF. The tPA blocking also inhibited the activation of TrkB receptor, and the TrkB signaling downstream effectors phospho-ERK, phospho-Akt, and phospho-CaMKII. The blocking of tPA also counteracted the effects of exercise on the plasticity markers phospho-synapsin I and GAP-43. These results indicate that the effects of exercise on hippocampal plasticity are dependent on BDNF processing and subsequent TrkB signaling, with important implications for neuronal function.
doi:10.1016/j.neuroscience.2011.06.032
PMCID: PMC3225196  PMID: 21756980
Brain-derived neurotrophic factor; hippocampus; rat; signaling; synaptic plasticity
13.  TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets 
The Journal of Clinical Investigation  2012;122(10):3563-3578.
The strength and duration of NF-κB signaling are tightly controlled by multiple negative feedback mechanisms. However, in cancer cells, these feedback loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses IκBα expression and leads to hyperactivation of NF-κB. Here, we report that miR-182 was overexpressed in a different set of gliomas with relatively lower miR-30e* expression and that miR-182 directly suppressed cylindromatosis (CYLD), an NF-κB negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-κB signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo. Furthermore, we found that TGF-β induced miR-182 expression, leading to prolonged NF-κB activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-β hyperactivation and activated NF-κB in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained NF-κB activation in malignant gliomas and may suggest a new target for clinical intervention in human cancer.
doi:10.1172/JCI62339
PMCID: PMC3589141  PMID: 23006329
14.  Effects of Diet and/or Exercise in Enhancing Spinal Cord Sensorimotor Learning 
PLoS ONE  2012;7(7):e41288.
Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA∶DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury.
doi:10.1371/journal.pone.0041288
PMCID: PMC3401098  PMID: 22911773
15.  The influence of naturalistic experience on plasticity markers in somatosensory cortex and hippocampus: effects of whisker use 
Brain research  2011;1388:39-47.
We have previously demonstrated that exposure of adult rat to a type of enriched environment, known as ‘naturalistic habitat’ (NH), induces extensive functional plasticity in the whiskers’ representations within the primary somatosensory cortex. Here we have investigated the molecular basis for such functional plasticity involved in this model. Based on the role of BDNF on synaptic plasticity and neuronal growth, the focus of this study is on BDNF and its downstream effectors CREB, synapsin I, and GAP-43. In particular, we determined the effects of natural whiskers use during 2, 7 or 28 days exposure to a NH on barrel cortex and hippocampus, as compared to standard cage controls. Naturalistic whiskers use resulted in increased levels of mRNAs and proteins for BDNF and its downstream effectors. Level changes for these markers were already detected after 2 days in the naturalistic habitat and grew larger over longer exposures (7 and 28 days). The cerebral cortex was found to be sensitive to the naturalistic habitat exposure at all time points, and more sensitive than the hippocampus to the trimming of the whiskers. Trimming of the whiskers decreased the level of most of the markers under study suggesting that whiskers exert a tonic influence on plasticity markers that can be further enhanced by naturalistic use. These results implicate BDNF and its downstream effectors in the plasticity induced by the naturalistic habitat. The critical action of experience on molecular substrates of plasticity seems to provide molecular basis for the design of experienced-based rehabilitative strategies to enhance brain function.
doi:10.1016/j.brainres.2011.02.068
PMCID: PMC3225184  PMID: 21385568
Rat; somatosensory cortex; hippocampus; environmental enrichment; cortical plasticity
16.  Brain and Spinal Cord Interaction: Protective Effects of Exercise Prior to Spinal Cord Injury 
PLoS ONE  2012;7(2):e32298.
We have investigated the effects of a spinal cord injury on the brain and spinal cord, and whether exercise provided before the injury could organize a protective reaction across the neuroaxis. Animals were exposed to 21 days of voluntary exercise, followed by a full spinal transection (T7–T9) and sacrificed two days later. Here we show that the effects of spinal cord injury go beyond the spinal cord itself and influence the molecular substrates of synaptic plasticity and learning in the brain. The injury reduced BDNF levels in the hippocampus in conjunction with the activated forms of p-synapsin I, p-CREB and p-CaMK II, while exercise prior to injury prevented these reductions. Similar effects of the injury were observed in the lumbar enlargement region of the spinal cord, where exercise prevented the reductions in BDNF, and p-CREB. Furthermore, the response of the hippocampus to the spinal lesion appeared to be coordinated to that of the spinal cord, as evidenced by corresponding injury-related changes in BDNF levels in the brain and spinal cord. These results provide an indication for the increased vulnerability of brain centers after spinal cord injury. These findings also imply that the level of chronic activity prior to a spinal cord injury could determine the level of sensory-motor and cognitive recovery following the injury. In particular, exercise prior to the injury onset appears to foster protective mechanisms in the brain and spinal cord.
doi:10.1371/journal.pone.0032298
PMCID: PMC3284558  PMID: 22384207
17.  Brain and Spinal Cord Interaction: A Dietary Curcumin Derivative Counteracts Locomotor and Cognitive Deficits After Brain Trauma 
Background
In addition to cognitive dysfunction, locomotor deficits are prevalent in traumatic brain injured (TBI) patients; however, it is unclear how a concussive injury can affect spinal cord centers. Moreover, there are no current efficient treatments that can counteract the broad pathology associated with TBI.
Objective
The authors have investigated potential molecular basis for the disruptive effects of TBI on spinal cord and hippocampus and the neuroprotection of a curcumin derivative to reduce the effects of experimental TBI.
Methods
The authors performed fluid percussion injury (FPI) and then rats were exposed to dietary supplementation of the curcumin derivative (CNB-001; 500 ppm). The curry spice curcumin has protective capacity in animal models of neurodegenerative diseases, and the curcumin derivative has enhanced brain absorption and biological activity.
Results
The results show that FPI in rats, in addition to reducing learning ability, reduced locomotor performance. Behavioral deficits were accompanied by reductions in molecular systems important for synaptic plasticity underlying behavioral plasticity in the brain and spinal cord. The post-TBI dietary supplementation of the curcumin derivative normalized levels of BDNF, and its downstream effectors on synaptic plasticity (CREB, synapsin I) and neuronal signaling (CaMKII), as well as levels of oxidative stress–related molecules (SOD, Sir2).
Conclusions
These studies define a mechanism by which TBI can compromise centers related to cognitive processing and locomotion. The findings also show the influence of the curcumin derivative on synaptic plasticity events in the brain and spinal cord and emphasize the therapeutic potential of this noninvasive dietary intervention for TBI.
doi:10.1177/1545968310397706
PMCID: PMC3258099  PMID: 21343524
traumatic brain injury; hippocampus; learning; BDNF; curcumin derivative
18.  MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop 
Constitutive activation of NF-κB is a frequent event in human cancers, playing important roles in cancer development and progression. In nontransformed cells, NF-κB activation is tightly controlled by IκBs. IκBs bind NF-κB in the cytoplasm, preventing it from translocating to the nucleus to modulate gene expression. Stimuli that activate NF-κB signaling trigger IκB degradation, enabling nuclear translocation of NF-κB. Among the genes regulated by NF-κB are those encoding the IκBs, providing a negative feedback loop that limits NF-κB activity. How transformed cells override this NF-κB/IκB negative feedback loop remains unclear. Here, we report in human glioma cell lines that microRNA-30e* (miR-30e*) directly targets the IκBα 3ι-UTR and suppresses IκBα expression. Overexpression of miR-30e* in human glioma cell lines led to hyperactivation of NF-κB and enhanced expression of NF-κB–regulated genes, which promoted glioma cell invasiveness in in vitro assays and in an orthotopic xenotransplantation model. These effects of miR-30e* were shown to be clinically relevant, as miR-30e* was found to be upregulated in primary human glioma cells and correlated with malignant progression and poor survival. Hence, miR-30e* provides an epigenetic mechanism that disrupts the NF-κB/IκBα loop and may represent a new therapeutic target and prognostic marker.
doi:10.1172/JCI58849
PMCID: PMC3248293  PMID: 22156201
19.  Omega-3 Fatty Acid Deficiency during Brain Maturation Reduces Neuronal and Behavioral Plasticity in Adulthood 
PLoS ONE  2011;6(12):e28451.
Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.
doi:10.1371/journal.pone.0028451
PMCID: PMC3233581  PMID: 22163304
20.  Differential effects of exercise and dietary docosahexaenoic acid (DHA) on molecular systems associated with control of allostasis in the hypothalamus and hippocampus 
Neuroscience  2010;168(1):130-137.
Given the robust influence of diet and exercise on brain plasticity and disease, we conducted studies to determine their effects on molecular systems important for control of brain homeostasis. Studies were centered on a battery of proteins implicated in metabolic homeostasis that have the potential to modulate brain plasticity and cognitive function, in rat hypothalamus and hippocampus. Adult male rats were exposed to a docosahexaenoic acid (DHA) enriched diet (1.25% DHA) with or without voluntary exercise for 14 days. Here we report that the DHA diet and exercise influence protein levels of molecular systems important for the control of energy metabolism (primarily phospho - AMPK, silent information regulator type 1), food intake (primarily leptin and ghrelin receptors), stress (primarily glucocorticoid receptors, and 11beta-hydroxysteroid dehydrogenase 1 (11βHSD1). Exercise or DHA dietary supplementation had differential effects on several of these class proteins, and the concurrent application of both altered the pattern of response elicited by the single applications of diet or exercise. For example, exercise elevated levels of glucocorticoids receptors in the hypothalamus and the DHA diet had opposite effects, while the concurrent application of diet and exercise counteracted the single effects of diet or exercise. In most of the cases, the hypothalamus and the hippocampus had a distinctive pattern of response to the diet or exercise. The results harmonize with the concept that exercise and dietary DHA exert specific actions on the hypothalamus and hippocampus, with implications for the regulations of brain plasticity and cognitive function.
doi:10.1016/j.neuroscience.2010.02.070
PMCID: PMC3225187  PMID: 20303394
Stress; metabolism; synaptic plasticity; homeostasis; mood; depression; anxiety
21.  A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma 
Experimental neurology  2010;226(1):191-199.
We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA2) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.
doi:10.1016/j.expneurol.2010.08.027
PMCID: PMC3225197  PMID: 20816821
rat; membrane damage; curcumin; 4-hydoxynonenal; cognition
22.  Astrocyte elevated gene 1: biological functions and molecular mechanism in cancer and beyond 
Cell & Bioscience  2011;1:36.
Since its discovery, nearly one decade of research on astrocyte elevated gene 1 (AEG-1) has witnessed expanding knowledge of this molecule, ranging from its role in cancer biology to molecular mechanisms underlying the biological functions. As a multifunctional oncoprotein, AEG-1 has been shown to overexpress in multiple types of human cancer, and the elevation of AEG-1 in tumor cells leads to enhanced phenotypes characteristic of malignant aggressiveness, including increased abilities to proliferate robustly, to invade surrounding tissues, to migrate, to induce neovascularization, and to enhance chemoresistance. The multifunctional role of AEG-1 in tumor development and progression has been found to be associated with several signaling cascades, namely, 1) activation of NF-kappa B, partially through direct interaction with p65; 2) PI3K/AKT signaling triggered by AEG-1 indirectly; 3) enhancement of the transcriptional activity of beta-catenin by indirect activation of MAPK and induction of LEF1; 4) regulation of mi/siRNA-mediated gene silencing by interacting with SND1; and 5) promotion of protective autophagy; in addition to possibly unknown mechanisms. Elevated AEG-1 expression is seen in nearly all tumor types, and in most cases AEG-1 positively correlates with tumor progression and poorer patient survival. Taken together, AEG-1 might represent a potential prognostic biomarker and therapeutic target.
doi:10.1186/2045-3701-1-36
PMCID: PMC3221637  PMID: 22060137
23.  DHA dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition 
Neuroscience  2008;155(3):751-759.
Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-BDNF and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhance the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.
doi:10.1016/j.neuroscience.2008.05.061
PMCID: PMC3208643  PMID: 18620024
DHA; exercise; BDNF; omega-3 fatty acids; cognition
24.  Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems 
Brain research  2009;1341C:32-40.
Dietary omega-3 fatty acid (i.e. docosohexaenoic acid (DHA)) and exercise are gaining recognition for supporting brain function under normal and challenging conditions. Here we evaluate the possibility that the interaction of DHA and exercise can involve specific elements of the synaptic plasma membrane. We found that voluntary exercise potentiated the effects of a 12-day DHA dietary supplementation regimen on increasing the levels of syntaxin 3 (STX-3) and the growth-associated protein (GAP-43) in the adult rat hippocampus region. STX-3 is a synaptic membrane-bound protein involved in the effects of DHA on membrane expansion. The DHA diet and exercise also elevated levels of the NMDA receptor subunit NR2B, which is important for synaptic function underlying learning and memory. The actions of exercise and DHA dietary supplementation reflected on enhanced learning performance in the Morris water maze as learning ability was associated with higher levels of STX-3 and NR2B. The overall findings reveal a mechanism by which exercise can interact with the function of DHA dietary enrichment to elevate the capacity of the adult brain for axonal growth, synaptic plasticity, and cognitive function.
doi:10.1016/j.brainres.2009.05.018
PMCID: PMC2884051  PMID: 19446534
Omega-3 fatty acid; Voluntary exercise; Syntaxin; Synaptic membrane; Hippocampus
25.  Voluntary exercise may engage proteasome function to benefit the brain after trauma 
Brain research  2009;1341C:25-31.
Brain trauma is associated with long-term decrements in synaptic plasticity and cognitive function, which likely reside on the acute effects of the injury on protein structure and function. Based on the action of proteasome on protein synthesis and degradation we have examined the effects of brain injury on proteasome level/activity and the potential of exercise to interact with the effects of the injury. Exercise has a healing ability but its action on proteasome function is not understood. Male Sprague-Dawley adult rats (n=19) were performed mild brain fluid percussion injury (FPI) prior to exercise. Animals were assigned to four groups: sedentary (Sed) or exercise (Exc) with sham surgery (Sham) or FPI: Sham/Sed, Sham/Exc, FPI/Sed, FPI/Exc. Animals were sacrificed after 14 days of treatment. FPI elevated levels of carbonyl (160.1±9.6% SEM, p<0.01) and reduced synapsin I levels (58.3±4.3% SEM, p<0.01) in the ipsilateral side of caudal cerebral cortex (FPI/Sed compared to Sham/Sed controls), and it appears that increased levels of carbonyls were associated with increased chymotripsin like activity. These results seem to indicate that proteasome function may be associated with levels of oxidative stress, and that these events may contribute to the action of exercise on synaptic plasticity. Interestingly, exercise attenuated changes in carbonyls, proteasome activity, and synapsin I following FPI, which may indicate an action of exercise on the molecular substrates that control protein turnover following brain trauma. Levels of the regulatory transcription factor of proteasome, Zif 268 were reduced by exercise in Sham and FPI animals and changed in proportion with proteasome activity/content. The overall results indicate that the action of exercise interfaces with that of brain injury on molecular systems involved with protein fate and function, which may be significant for synaptic plasticity.
doi:10.1016/j.brainres.2009.01.035
PMCID: PMC2884074  PMID: 19368831
Fluid percussion injury; Proteasome; Synaptic plasticity; Oxidative stress; Exercise

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