Biomedical subjects

Jian Feng

Publications and source records attributed to Jian Feng.

At least 19 recordsLinked to original sources

PubMed2026

Reduced expression of Brain Expressed X-linked genes in Alzheimer's disease.

BackgroundAltered expression of Brain Expressed X-linked (BEX) genes has been implicated in Alzheimer's disease (AD) with inconsistencies and a lack of experimental confirmation.ObjectiveThis study aims to characterize BEX expression patterns, examine the association of their expression with AD pathology, and investigate cellular changes induced by altered BEX expression.MethodsWe integrated bulk and single-cell transcriptomics datasets to characterize cortical BEX expression changes in 5xFAD mice and AD patients, which were validated by RT-qPCR in postmortem AD cortical tissue. We manipulated the expression of BEX genes in SH-SY5Y cells and examined changes in oxidative stress.ResultsCortical expression of BEX genes was reduced in AD. With the dysregulation being more pronounced at a later stage of the disease, the reduction was closely related to the impairment of synaptic transmission and oxidative phosphorylation in excitatory neurons. Consistent with these, BEX3 knockdown increased oxidative stress.ConclusionsOur findings suggest that reduced BEX expression in neurons appears to be a contributing factor to AD pathogenesis and BEX depletion may increase oxidative stress.

Alzheimer Disease↗

PubMed2006

Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin.

The noradrenergic system in the prefrontal cortex (PFC) is involved in many physiological and psychological processes, including working memory and mood control. To understand the functions of the noradrenergic system, we examined the regulation of NMDA receptors (NMDARs), key players in cognition and emotion, by alpha1- and alpha2-adrenergic receptors (alpha1-ARs, alpha2-ARs) in PFC pyramidal neurons. Applying norepinephrine or a norepinephrine transporter inhibitor reduced the amplitude but not paired-pulse ratio of NMDAR-mediated excitatory postsynaptic currents (EPSC) in PFC slices. Specific alpha1-AR or alpha2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The alpha1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca(2+) pathway, whereas the alpha2-AR effect depended on protein kinase A and the microtubule-based transport of NMDARs that is regulated by ERK signaling. Furthermore, two members of the RGS family, RGS2 and RGS4, were found to down-regulate the effect of alpha1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting alpha2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on alpha1-AR signaling were lost in mutant mice lacking spinophilin, which binds several RGS members and G protein-coupled receptors, whereas the effect of RGS4 on alpha2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of alpha1-ARs or alpha2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of alpha1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of alpha2-ARs is modified by RGS4 independent of spinophilin.

Animals↗

PubMed2006

Delivery of 125I-cobrotoxin after intranasal administration to the brain: a microdialysis study in freely moving rats.

In order to determine the contribution of intranasal (i.n.) administration to the uptake of large molecular weight (MW) substances into central nervous system (CNS), concentration in brain of the centrally acting polypeptide cobrotoxin (NT-I) versus time profiles were studied using dual-probe microdialysis in awake free-moving rats. NT-I, radiolabeled with sodium (125)I-Iodide ((125)I-NT-I), was administered at the dose of 105 microg/kg intravenously and intranasally in the same set of rat (n=15). The (125)I-NT-Inasal preparations were formulated with borneol/menthol eutectic mixture (+BMEM) as an absorption enhancer and without (-BMEM). After application, the dialysates sampled simultaneously from olfactory bulb and cerebellar nuclei were measured in a gamma-counter for radioactivity. The real concentrations of NT-I were recalculated by in vivo recoveries of microdialysis probes. The results showed that the area under the curve (AUC) value in cerebellar nuclei (2283.51+/-34.54 min ng/ml) following i.n. administration (+BMEM) was significantly larger than those (AUC(olfactory)=1141.92+/-26.42 min ng/ml; AUC(cerebellar)=1364.62+/-19.35 min ng/ml) after intravenous (i.v.) bolus, respectively. A prolonged time values to peak concentrations after i.n. application (+BMEM) were observed compared with those following i.v. administration. Also, following i.n. application (+BMEM) the measured time value to peak concentration in cerebellar nuclei (85 min) was statistically longer than that in olfactory bulb (75 min), which could be plausibly an indication for NT-I delivery into brain via nose-brain pathway in the presence of absorption enhancer. i.n. administration (-BMEM) had little or no ability of NT-I delivering into brain. In conclusion, i.n. administration (+BMEM) significantly enhanced brain transport of NT-I with uneven distribution in discrete regions of brain compared with i.v. administration. Additionally, multi-probe microdialysis technique should be considerably valuable in brain delivery studies.

Administration, Intranasal↗

PubMed2006

Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons.

Parkinson disease is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra. Long term epidemiological studies have implicated exposure to agricultural pesticides as a significant risk factor. Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral DA neurons and Parkinson disease-like symptoms in rats. Our previous study has shown that the microtubule depolymerizing activity of rotenone plays a critical role in its selective toxicity on DA neurons. Rotenone toxicity is mimicked by the microtubule-depolymerizing drug colchicine and attenuated by the microtubule-stabilizing agent taxol. Here we show that nerve growth factor (NGF) significantly reduced rotenone toxicity on TH(+) neurons in midbrain neuronal cultures. The protective effect of NGF was completely abolished by inhibiting the microtubule-associated protein kinase kinase (MEK) and partially reversed by blocking phosphatidylinositol 3-kinase. In addition, NGF decreased colchicine toxicity on TH(+) neurons in a manner dependent on MEK but not phosphatidylinositol 3-kinase. The protective effect of NGF against rotenone toxicity was occluded by the microtubule-stabilizing drug taxol. In a MEK-dependent manner, NGF significantly attenuated rotenone- or colchicine-induced microtubule depolymerization and ensuing accumulation of vesicles in the soma and elevation in protein carbonyls. Moreover, other neurotrophic factors such as brain-derived neurotrophic factor and glia cell line-derived neurotrophic factor also reduced rotenone- or colchicine-induced microtubule depolymerization and death of TH(+) through a MEK-dependent mechanism. Thus, our results suggest that neurotrophic factors activate the microtubule-associated protein kinase pathway to stabilize microtubules, and this action significantly attenuates rotenone toxicity on dopaminergic neurons.

Animals↗

PubMed2006

Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism.

Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral dopaminergic (DA) neurons and Parkinson's disease-like symptoms in animal models. Our previous study has shown that the microtubule-depolymerizing activity of rotenone plays a critical role in its selective toxicity on tyrosine hydroxylase-positive (TH+) neurons in rat embryonic midbrain neuronal cultures. Here, we show that application of group III metabotropic glutamate receptor (mGluRIII) agonists (e.g., L-AP-4) significantly reduced rotenone toxicity on midbrain TH+ neurons in culture. The protective effect of L-AP-4 was abolished by pharmacological inhibition of the microtubule-associated protein (MAP) kinase kinase (MEK) or overexpression of dominant-negative MEK1, suggesting its dependence on the MAP kinase cascade. We found that L-AP-4 induced a rapid and transient activation of the MAP kinase extracellular signal-regulated kinase (ERK) through a pathway mediated by dynamin, beta-arrestin 2, and Src. ERK activated in this manner targeted cytosolic rather than nuclear substrates. Consistent with this, L-AP-4 significantly attenuated rotenone- or colchicine-induced microtubule depolymerization in an MEK-dependent manner. Moreover, L-AP-4 decreased colchicine toxicity on TH+ neurons in an MEK-dependent manner as well. The protective effect of L-AP-4 against rotenone toxicity was occluded by the microtubule-stabilizing agent Taxol. Together, these results suggest that activation of group III metabotropic glutamate receptors attenuates the selective toxicity of rotenone on DA neurons by activating the MAP kinase pathway to stabilize microtubules. These findings may offer a novel neuroprotective approach against rotenone-induced parkinsonism.

Animals↗

PubMed2006

Phase behavior of polyampholytes from charged hard-sphere chain model.

A molecular thermodynamic theory is developed for polyampholytes from the coarse-grained charged hard-sphere chain model. The phase behavior of polyampholytes with variations in sequence and chain length is satisfactorily predicted by the theory, consistent with simulation results and experimental observations. At a fixed chain length, the phase envelope expands as the sequence of charge distribution becomes less random. With increasing chain length, the phase envelope expands for diblock and random polyampholytes, but shrinks for zwitterionic polyampholytes. The predicted critical temperature, density, and pressure exhibit scaling relations with chain length for all the three (diblock, random, and zwitterionic) polyampholytes.

Journal Article↗

PubMed2006

Observation of solid-state 103Rh NMR by cross-polarization.

Using 103Rh[1H] cross-polarization (CP) methods, we have obtained solid-state 103Rh NMR spectra for diamagnetic Rh(III) compounds. The isotropic chemical shift and chemical shift anisotropy (CSA) are reported for a crystalline form of the dihydroxy-bridged Rh(III) dimer and for a salt of the oxo-centered acetate-bridged Rh(III) trimer, from analysis of conventional CP/MAS spectra. Comparison of the CP kinetics of the dimer with new crystal structure data suggests a strategy for predicting 103Rh CP/MAS properties in solids.

Journal Article↗

PubMed2006

Parkin suppresses the expression of monoamine oxidases.

Mutations of parkin are linked to early onset Parkinson disease. Here we show that stable transfection of parkin in the human dopaminergic neuroblastoma cell line SH-SY5Y markedly reduced the activities of both monoamine oxidase (MAO) A and B. The amount of 3,4-dihydroxyphenylacetic acid, which is produced during dopamine oxidation by MAO, was greatly reduced by parkin overexpression. Radioligand binding assays showed that MAO binding sites were decreased accordingly. Consistent with these, MAO-B protein level was much lower, whereas the amount of MAO-A protein was not determined due to the lack of a suitable antibody. Co-transfection of either MAO with parkin in HEK293 cells did not significantly alter ubiquitination and degradation of each MAO. When we measured MAO expression by real-time quantitative reverse transcription-PCR, marked reductions were seen in SH-SY5Y cells stably expressing parkin compared with the parental cells or a control line stably transfected with luciferase. In addition, parkin mutants defective in E3 ligase activity exhibited different effects on MAO expression. We found that parkin also significantly decreased mRNA levels of both MAOs in the mouse fibroblast cell line NIH3T3. Furthermore, MAO expression was significantly increased in human B lymphocyte cell lines derived from Parkinson disease patients with homozygous but not heterozygous deletion of exon 4 of parkin. Together these results suggest that parkin suppresses MAO expression. This function may limit the production of reactive oxygen species generated by MAO in dopamine oxidation and would, thus, be beneficial to the survival of dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Microtubule: a common target for parkin and Parkinson's disease toxins.

Parkinson's disease (PD) is characterized by the selective loss of nigral dopaminergic (DA) neurons, which have long axons enriched with microtubules. Depolymerization of microtubules by PD toxins such as rotenone disrupts vesicular transport. The ensuing accumulation of vesicles in the cell body leads to increased cytosolic concentration of dopamine due to leakage of the vesicles. Elevated oxidative stress induced by dopamine oxidation may thus trigger the selective demise of DA neurons. Many strategies have been developed to protect DA neurons by stabilizing microtubules either directly or through intracellular signaling cascades. On the other hand, parkin, one of the most frequently mutated genes in PD, encodes for a protein-ubiquitin E3 ligase that strongly binds to microtubules. Parkin stabilizes microtubules through three domains that provide strong and independent interactions with tubulin and microtubules. These interactions anchor parkin on microtubules and may facilitate its E3 ligase activity on misfolded proteins transported along microtubules. Thus, parkin and rotenone, two prominent genetic and environmental factors linked to PD, act in an opposing manner on the same molecular target in the cell, microtubules, whose destruction underlies the selective vulnerability of dopaminergic neurons.

Animals↗

PubMed2005

Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure.

Dopaminergic dysfunction in the prefrontal cortex (PFC) has been implicated in the pathophysiology of schizophrenia. On the other hand, administration of the NMDAR antagonist phencyclidine (PCP) impairs PFC functions and induces a broad range of schizophrenic-like symptoms, thus has been widely used as an animal model for schizophrenia. This study sought to determine the mechanism by which PCP may alter the dopaminergic functions in PFC. In control rats, activation of dopamine D4 receptors produced a significant suppression of NMDA receptor transmission in PFC pyramidal neurons, which was dependent on the inhibition of active CaMKII. However, in PCP-treated rats, the D4 modulation of NMDA receptors was significantly impaired, with the concomitant loss of D4 regulation of CaMKII activity. In contrast, the D4 modulation of voltage-dependent Ca2+ channels was intact following PCP administration. Furthermore, treatment with the antipsychotic drug clozapine restored the D4 regulation of NMDA receptors in PCP-treated rats. These findings suggest that the selective disruption of the interaction between D4 and NMDA receptors in the PCP model, which is attributable to the impaired D4-mediated downstream signaling, may contribute to the aberrant PFC neuronal activity in schizophrenia.

Animals↗

PubMed2005

Selective vulnerability of dopaminergic neurons to microtubule depolymerization.

Parkinson disease (PD) is characterized by the specific degeneration of dopaminergic (DA) neurons in substantia nigra and has been linked to a variety of environmental and genetic factors. Rotenone, an environmental PD toxin, exhibited much greater toxicity to DA neurons in midbrain neuronal cultures than to non-DA neurons. The effect was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine or nocodazole. Microtubule depolymerization disrupted vesicular transport along microtubules and caused the accumulation of dopamine vesicles in the soma. This led to increased oxidative stress due to oxidation of cytosolic dopamine leaked from vesicles. Inhibition of dopamine metabolism significantly reduced rotenone toxicity. Thus, our results suggest that microtubule depolymerization induced by PD toxins such as rotenone plays a key role in the selective death of dopaminergic neurons.

Cell Death↗

PubMed2005

Preparation of Cu-Ni alloy nanocrystallites in water-in-oil microemulsions.

The well-mixed copper-nickel nanoparticles were prepared when the molar ratio of Cu2+ to Ni2+ was 1:1 by simultaneous reduction of CuSO4 and NiCl2 with hydrazine in the microemulsion of SDS/n-butanol/n-heptane/water at 70 degrees C, and was characterized by TEM, ED, TGA, EDS, and XRD. ED analysis and XRD patterns suggest the formation of the homogeneous alloy structure in the bimetallic nanoparticles. Average size of the sample calculated from the full width at medium height of peak 111 in the XRD patterns using Scherrer formula is 5.53 nm. TEM photographs show a narrow distribution of Cu-Ni nanoparticles that essentially are monodispersed and the mean diameter is 12 nm. The results indicate that the composition and size of alloy nanoparticles depend on the mole ratio of H2O to SDS, the method of addition of Cu2+ and Ni2+, and the mole ratio of Cu2+ and Ni2+ in the initial precursor solution.

Journal Article↗

PubMed2005

Microtubule regulation of N-methyl-D-aspartate receptor channels in neurons.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs), which play a key role in synaptic plasticity, are dynamically regulated by many signaling molecules and scaffolding proteins. Although actin cytoskeleton has been implicated in regulating NMDAR stability in synaptic membrane, the role of microtubules in regulating NMDAR trafficking and function is largely unclear. Here we show that microtubule-depolymerizing agents inhibited NMDA receptor-mediated ionic and synaptic currents in cortical pyramidal neurons. This effect was Ca(2+)-independent, required GTP, and was more prominent in the presence of high NMDA concentrations. The NR2B subunit-containing NMDA receptor was the primary target of microtubules. The effect of microtubule depolymerizers on NMDAR currents was blocked by cellular knockdown of the kinesin motor protein KIF17, which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Neuromodulators that can stabilize microtubules, such as brain-derived neurotrophic factor, significantly attenuated the microtubule depolymerizer-induced reduction of NMDAR currents. Moreover, immunocytochemical studies show that microtubule depolymerizers decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Taken together, these results suggest that interfering with microtubule assembly suppresses NMDAR function through a mechanism dependent on kinesin-based dendritic transport of NMDA receptors.

Animals↗

PubMed2005

Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism.

The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT(1A) receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT(1A) receptors. This effect of 5-HT(1A) receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT(1A) modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT(1A) activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT(1A) activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT(1A)-NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.

Animals↗

PubMed2005

Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system.

To explore the role of DNA methylation in the brain, we examined the expression pattern of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the mouse central nervous system (CNS). By comparing the levels of Dnmt3a and Dnmt3b mRNAs and proteins in the CNS, we showed that Dnmt3b is detected within a narrow window during early neurogenesis, whereas Dnmt3a is present in both embryonic and postnatal CNS tissues. To determine the precise pattern of Dnmt3a and Dnmt3b gene expression, we carried out X-gal histochemistry in transgenic mice in which the lacZ marker gene is knocked into the endogenous Dnmt3a or Dnmt3b gene locus (Okano et al. [1999] Cell 99:247-257). In Dnmt3b-lacZ transgenic mice, X-gal-positive cells are dispersed across the ventricular zone of the CNS between embryonic days (E) 10.5 and 13.5 but become virtually undetectable in the CNS after E15.5. In Dnmt3a-lacZ mice, X-gal signal is initially observed primarily in neural precursor cells within the ventricular and subventricular zones between E10.5 and E17.5. However, from the newborn stage to adulthood, Dnmt3a X-gal signal was detected predominantly in postmitotic CNS neurons across all the regions examined, including olfactory bulb, cortex, hippocampus, striatum, and cerebellum. Furthermore, Dnmt3a signals in CNS neurons increase during the first 3 weeks of postnatal development and then decline to a relatively low level in adulthood, suggesting that Dnmt3a may be of critical importance for CNS maturation. Immunocytochemistry experiments confirmed that Dnmt3a protein is strongly expressed in neural precursor cells, postmitotic CNS neurons, and oligodendrocytes. In contrast, glial fibrillary acidic protein-positive astrocytes exhibit relatively weak or no Dnmt3a immunoreactivity in vitro and in vivo. Our data suggest that whereas Dnmt3b may be important for the early phase of neurogenesis, Dnmt3a likely plays a dual role in regulating neurogenesis prenatally and CNS maturation and function postnatally.

Animals↗

PubMed2005

Parkin stabilizes microtubules through strong binding mediated by three independent domains.

Mutations of parkin, a protein-ubiquitin isopeptide ligase (E3), appear to be the most frequent cause of familial Parkinson's disease (PD). Our previous studies have demonstrated that parkin binds strongly to alpha/beta tubulin heterodimers and microtubules. Here we show that the strong binding between parkin and tubulin, as well as that between parkin and microtubules, was mediated by three independent domains: linker, RING1, and RING2. These redundant strong interactions made it virtually impossible to separate parkin from microtubules by high concentrations of salt (3.8 m) or urea (0.5 m). Parkin co-purified with tubulin and was found in highly purified tubulin preparation. Expression of either full-length parkin or any of its three microtubule-binding domains significantly attenuated colchicine-induced microtubule depolymerization. The abilities of parkin to bind to and stabilize microtubules were not affected by PD-linked mutations that abrogate its E3 ligase activity. Thus, the tubulin/microtubule-binding activity of parkin and its E3 ligase activity are independent. The strong binding between parkin and tubulin/microtubules through three redundant interaction domains may not only stabilize microtubules but also guarantee the anchorage of this E3 ligase on microtubules. Because many misfolded proteins are transported on microtubules, the localization of parkin on microtubules may provide an important environment for its E3 ligase activity toward misfolded substrates.

Antineoplastic Agents, Phytogenic↗

PubMed2005

[Preparation and infrared spectral analysis of nanoporous silica thin film].

Crack-free homogeneous nanoporous silica films on silicon wafer have been synthesized via supercritical drying of wet gel films obtained by spin-coating the polymeric silica sol, which was prepared using sol-gel method with tetraethoxysilane (TEOS) as precursor. The film is amorphous and nanoporous, and three-dimensional network, cross-linked by the primary particles whose sizes distribute between 10-20 nm showed respectively by XRD and SEM micrograph. The structure of the nanoporous SiO2 thin film was studied by FTIR spectra. The SiO2 thin film was composed of Si-O-Si and Si-OR, and was hydrophobic. The film contained Si-OH and became hydrophilic after being heat-treated at 250 degrees C or above in air. The heat-treated SiO2 thin film becomes hydrophobic by reacting with trimethylchlorosilane(TMCS). The TMCS-modified SiO2 thin film remains hydrophobic and can keep its nanoporous structure at a temperature lower than 450 degrees C in nitrogen.

Hot Temperature↗

PubMed2005

[Ecological distribution patterns of soil microbes under artificial Eucalyptus grandis stand].

In order to find out the ecological distribution patterns of soil microbes under artificial Eucalyptus grandis stand, the amount and distribution of soil bacteria, fungi and actinomycetes in Hongya County of Sichuan Province were investigated in 2004. The results showed that soil microbial population under Eucalyptus grandis stand varied with seasons, being the maximum in autumn, fewer in spring, and the minimum in summer. The numbers were decreased in order of bacteria > actinomycetes > fungi, which were mainly concentrated in 0-20 cm soil layer, and rapidly decreased with increasing soil depth. In 0-60 cm soil layer, the numbers of aerobic bacteria were 0. 31 x 10(6) - 14.39 x 10(6), actinomycetes were 0.06 x 10(6) - 0.79 x 10(6), fungi were 0.06 x 10(6) - 0.79 x 10(6), and anaerobes were 0.05 x 10(6) - 3.22 x 10(6) CFU x g(-1). Comparing with artificial C. glauca stand and farming land, Eucalyptus grandis stand had a larger number of soil microbes, suggesting that Eucalyptus grandis was benefit for soil microbial activity. The Simpson and Shannon-Wiener index of the physiological groups of bacteria was 0.773 and 1.896, respectively.

Actinobacteria↗