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ABSTRACT: OBJECTIVES: Previous work showed that taurine protects neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by maintaining intracellular calcium homeostasis, membrane integrity, and mitochondrial function, thereby preventing apoptosis from occurring, in primary neuron cultures. In this study, we investigated whether taurine could protect the auditory system against the neurotoxicity associated with hyperbilirubinemia in an in vivo model. METHODS: Hyperbilirubinemia was established in neonatal guinea pigs by intraperitoneal injection of UCB. Hearing function was observed in electrocochleograms (ECochGs) and auditory brainstem responses (ABRs) recorded before and 1, 8, 24, and 72h after UCB injection. For morphological evaluations, animals were sacrificed at 8h post-injection, and the afferent terminals beneath the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and their fibers were examined. RESULTS: It was found that UCB injection significantly increased latencies and inter-wave intervals, and thresholds of ABR and compound action potentials, and caused marked damage to type I SGNs, their axons, and terminals to cochlear IHCs. When baby guinea pigs were pretreated with taurine for 5 consecutive days and then injected with bilirubin, electrophysiological abnormalities and morphological damage were attenuated significantly in both the peripheral and central auditory system. CONCLUSIONS: From these observations, it was concluded that taurine limited bilirubin-induced neural damage in the auditory system. These findings may contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating hearing loss in neonatal jaundice.
International journal of pediatric otorhinolaryngology 12/2012; · 0.85 Impact Factor
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ABSTRACT: Hormone regulation of ion transport in the kidney tubules is essential for fluid and electrolyte homeostasis in vertebrates. A large body of evidence has suggested that transporters and channels exist in multiprotein regulatory complexes; however, relatively little is known about the composition of these complexes or their assembly. The epithelial sodium channel (ENaC) in particular is tightly regulated by the salt-regulatory hormone aldosterone, which acts at least in part by increasing expression of the serine-threonine kinase SGK1. Here we show that aldosterone induces the formation of a 1.0-1.2-MDa plasma membrane complex, which includes ENaC, SGK1, and the ENaC inhibitor Nedd4-2, a key target of SGK1. We further show that this complex contains the PDZ domain-containing protein connector enhancer of kinase suppressor of Ras isoform 3 (CNK3). CNK3 physically interacts with ENaC, Nedd4-2, and SGK1; enhances the interactions among them; and stimulates ENaC function in a PDZ domain-dependent, aldosterone-induced manner. These results strongly suggest that CNK3 is a molecular scaffold, which coordinates the assembly of a multiprotein ENaC-regulatory complex and hence plays a central role in Na(+) homeostasis.
Journal of Biological Chemistry 07/2012; 287(39):33014-25. · 4.77 Impact Factor
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ABSTRACT: Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin-induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy. © 2012 Wiley Periodicals, Inc.
Journal of Neuroscience Research 07/2012; 90(11):2201-13. · 2.74 Impact Factor
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ABSTRACT: Dextran-capped silver nanoparticles were synthesized by reducing silver nitrate with NaBH4 in the presence of dextran as capping agent. The characters of silver nanoparticles were investigated using UV-Vis spectrophotometer, nano-grainsize analyzer, X-ray diffraction, and transmission electron microscopy. Results showed that the silver nanoparticles capped with dextran were in uniform shape and narrow size distribution. Moreover, compared with polyvinylpyrrolidone (PVP)-capped silver nanoparticles, the dextran-capped ones possessed better stability. Antibacterial tests of these silver nanoparticles were carried out for Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Results suggested that the dextran-capped silver nanoparticles had high antibacterial activity against both Gram-positive and Gram-negative bacteria. In addition, the cytotoxicity in vitro of the dextran-capped silver nanoparticles was investigated using mouse fibrosarcoma cells (L929). The toxicity was evaluated by the changes of cell morphology and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Results indicated that these silver nanoparticles had slight effect on the survival and proliferation of L-929 cells at their minimal inhibitory concentration (MIC). After modified by dextran, the physiochemical properties of the silver nanoparticles had been improved. We anticipated that these dextran-capped silver nanoparticles could be integrated into systems for biological and pharmaceutical applications.
Journal of Nanoscience and Nanotechnology 05/2012; 12(5):3766-74. · 1.56 Impact Factor
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Xin Jin,
Mingze He,
Betsy Ferguson,
Yuhuan Meng,
Limei Ouyang,
Jingjing Ren,
Thomas Mailund,
Fei Sun,
Liangdan Sun,
Juan Shen, [......],
Hua Zhao,
Yanyi Wang,
Xiaodong Fang,
Guojie Zhang, Jian Wang,
Xuejun Zhang,
Mikkel H Schierup,
Hongli Du,
Jun Wang,
Xiaoning Wang
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ABSTRACT: Non-human primates have emerged as an important resource for the study of human disease and evolution. The characterization of genomic variation between and within non-human primate species could advance the development of genetically defined non-human primate disease models. However, non-human primate specific reagents that would expedite such research, such as exon-capture tools, are lacking. We evaluated the efficiency of using a human exome capture design for the selective enrichment of exonic regions of non-human primates. We compared the exon sequence recovery in nine chimpanzees, two crab-eating macaques and eight Japanese macaques. Over 91% of the target regions were captured in the non-human primate samples, although the specificity of the capture decreased as evolutionary divergence from humans increased. Both intra-specific and inter-specific DNA variants were identified; Sanger-based resequencing validated 85.4% of 41 randomly selected SNPs. Among the short indels identified, a majority (54.6%-77.3%) of the variants resulted in a change of 3 base pairs, consistent with expectations for a selection against frame shift mutations. Taken together, these findings indicate that use of a human design exon-capture array can provide efficient enrichment of non-human primate gene regions. Accordingly, use of the human exon-capture methods provides an attractive, cost-effective approach for the comparative analysis of non-human primate genomes, including gene-based DNA variant discovery.
PLoS ONE 01/2012; 7(7):e40637. · 4.09 Impact Factor
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ABSTRACT: CA1 pyramidal neurons degenerate after transient forebrain ischemia, whereas neurons in other regions of the hippocampus remain intact. Here we show that in rat hippocampal CA1 neurons, forebrain ischemia induces the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit at Ser1232 (phospho-Ser1232). Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5). Inhibiting endogenous Cdk5, or perturbing interactions between Cdk5 and NR2A subunits, abolished NR2A phosphorylation at Ser1232 and protected CA1 pyramidal neurons from ischemic insult. Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons.
Nature Neuroscience 11/2003; 6(10):1039-47. · 15.53 Impact Factor
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ABSTRACT: Several thousand new neurons are produced each day in the adult mammalian hippocampus, among which only excitatory granule cells (GCs) have thus far been identified. In the present study, we used mutant Semliki Forest Virus vectors to express enhanced green fluorescent protein in the hippocampus, and observed that approximately 14% of newly generated neurons in the dentate gyrus of adult rats are GABAergic basket cells (BCs). With the use of double whole-cell patch-clamp recordings from BC-GC pairs in hippocampal slices, we demonstrate that newly generated BCs in the dentate gyrus form inhibitory synapses with principal GCs. These data show for the first time that functional inhibitory neurons are recruited in the dentate gyrus of adult rats.
Journal of Neuroscience 03/2003; 23(3):732-6. · 7.11 Impact Factor
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Jian Wang,
ShuHong Liu,
Ursula Haditsch,
WeiHong Tu,
Kimberley Cochrane,
Gholamreza Ahmadian,
Linda Tran,
Jadine Paw,
YuTian Wang,
Isabelle Mansuy,
Michael M Salter,
You Ming Lu
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ABSTRACT: Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABA(A)Rs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABA(A)R-gamma(2) subunits. Prevention of the CaN-GABA(A) receptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABA(A) receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.
Journal of Neuroscience 03/2003; 23(3):826-36. · 7.11 Impact Factor
