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Yong Shen

Publications and source records attributed to Yong Shen.

At least 19 recordsLinked to original sources
PubMed2007

Theoretical studies on the excited states, DNA photocleavage, and spectral properties of complex [Ru(phen)(2)(6-OH-dppz)](2+).

The structures and related properties of the complex [Ru(phen)2(6-OH-dppz)]2+ (phen = 1,10-phenanthroline; dppz = dipyrido [3,2-a:2',3'-c]phenazine) in the ground state (S0), the first singlet excited state (S1), and the first triplet excited state (T1) have been studied using density functional theory (DFT), time-dependent (TD) DFT, Hartree-Fock (HF), and configuration interaction singles (CIS) methods. Three electronic absorption-spectral bands (1MLCT, 1LL, and 1LL) lying in the range of 250-550 nm in vacuo and in aqueous solution were theoretically calculated, simulated, and assigned with TDDFT method. In particular, the theoretical results show the following: (1) The positive charges of central Ru atom in the excited states (S1 and T1) are greatly increased relative to those in the ground state (S0), and thus the Ru atom in the excited states can be regarded as Ru(III). (2) The positive charges on the main ligand (6-OH-dppz) in the excited states are considerably reduced, and thus the interaction between the main ligand (intercalative ligand) and DNA base pairs is considerably weakened. (3) The geometric structures in excited states are also distorted, resulting in obvious increase in the coordination bond length. It is advantageous to the complex forming a high oxidizing center (i.e., Ru(III) ion). On the basis of these results, a theoretical explanation on photoinduced oxidation reduction mechanism of DNA photocleavage by [Ru(phen)2(6-OH-dppz)](2+) has been presented.

DNA↗
PubMed2006

Distinct destructive signal pathways of neuronal death in Alzheimer's disease.

Abundant neuron loss is a major feature of Alzheimer's disease (AD). Hypotheses for this loss include abnormal amyloid precursor protein processing (i.e. excess Abeta production, protein aggregation or misfolding), oxidative stress, excitotoxicity and inflammation. Neuron loss is a major cause of dementia in AD; however, it seems that there is no definitive pathway that causes cell death in the AD brain. Here, we examine the hypotheses for neuron loss in AD and pose the argument that the means by which neurons degenerate is irrelevant for cognitive decline. The best treatment for cognitive decline is to prevent the toxicity that first sets the neuron on its path to destruction, which is the production of Abeta peptide.

Alzheimer Disease↗
PubMed2006

[The clinical study of cervical arthroplasty in management of cervical spondylosis].

OBJECTIVE: To investigate the clinical effects of cervical disc prosthesis in patients of cervical spondylosis early, compared with the anterior cervical interbody fusion. METHODS: Bryan disc prosthesis replacement applied in 21 case (22 levels) of cervical spondylosis, 27 patients (32 levels) were treated by the anterior interbody fusion. Clinic (JOA grade) and radiological (X-ray of bending, extending; left and right bending position) follow-up of 48 patients was performed preoperatively and postoperatively. Systemic radiographic study about stability and rang of movement (ROM) of replaced levels postoperatively was measured; meantime the ROM of adjacent levels of all cases was observed. CT or MRI scan were applied in 21 patients postoperatively to find out the pressure of the spine and heterotopic ossification in the replaced level. RESULTS: There was no complication. Improvement in all case increased obviously, JOA score increased and stabilized postoperatively in all cases (P < 0.01). Replaced segment achieved stability and restored partial of ROM. There was no prosthesis subsidence or excursion. The adjacent ROM of the case treated by the anterior interbody fusion increased obviously (P < 0.01). No heterotopic ossification was found in the replaced level, but the deteriorated adjacent level of 1 case applied by the anterior interbody fusion occurred. CONCLUSIONS: Bryan cervical disc prosthesis restore stability and partial motion to the level of the intact segment in flexion-extension and lateral bending in postoperational images; The adjacent ROM has not increased obviously. At the same time, it can achieve good short-term clinic effect in replaced level, compared with the anterior interbody fusion.

Adult↗
PubMed2005

Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model.

Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased beta amyloid peptide (Abeta) deposition. These mice also exhibited increased Abeta production, and microglia cultures prepared from the brains of these mice were impaired in Abeta clearance/degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.

Amyloid Precursor Protein Secretases↗
PubMed2005

Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment.

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.

Aged↗
PubMed2005

Reaction mechanism of porphyrin metallation studied by theoretical methods.

We have studied the reaction mechanism for the insertion of Mg2+ and Fe2+ into a porphyrin ring with density functional calculations with large basis set and including solvation, zero-point and thermal effects. We have followed the reaction from the outer-sphere complex, in which the metal is coordinated with six water molecules and the porphyrin is doubly protonated, until the metal ion is inserted into the deprotonated porphyrin ring with only one water ligand remaining. This reaction involves the stepwise displacement of five water molecules and the removal of two protons from the porphyrin ring. In addition, a step seems to be necessary in which a porphyrin pyrrolenine nitrogen atom changes its interaction from a hydrogen bond to a metal-bound solvent molecule to a direct coordination to the metal ion. If the protons are taken up by a neutral imidazole molecule, the deprotonation reactions are exothermic with minimal barriers. However, with a water molecule as an acceptor, they are endothermic. The ligand exchange reactions were approximately thermoneutral (+/-20 kJ mol(-1), with one exception) with barriers of up to 72 kJ mol(-1) for Mg and 51 kJ mol(-1) for Fe. For Mg, the highest barrier was found for the formation of the first bond to the porphyrin ring. For Fe, a higher barrier was found for the formation of the second bond to the porphyrin ring, but this barrier is probably lower in solution. No evidence was found for an initial pre-equilibrium between a planar and a distorted porphyrin ring. Instead, the porphyrin becomes more and more distorted as the number of metal-porphyrin bonds increase (by up to 191 kJ mol(-1)). This strain is released when the porphyrin becomes deprotonated and the metal moves into the ring plane. Implications of these findings for the chelatase enzymes are discussed.

Iron↗
PubMed2005

Estrogen and brain: synthesis, function and diseases.

This review summaries recent evidence from clinical and basic science studies on estrogen central nervous system. For decades, estrogen was thought of only as a "sex hormone" and plays a fundamental role in regulating behavioral and physiological events. In recent years, accumulated evidence shows that estrogen also plays very important roles in the brain. Recent basic science studies show that estrogen treatment decreases the neuronal response to various forms of insult through the regulation of both estrogen synthesis and estrogen receptor expression in the brain. Some clinical evidence also suggests that estrogen deprivation might be implicated as a risk factor in various neurodegenerative diseases. Estrogen may play a neuroprotective role through estrogen dependent alterations in cell survival, enhancement of synaptic transmission and neurogenesis. Some of the mechanisms underlying these effects are independent of the classical nuclear estrogen receptors and involve direct modulation of neurotransmitter receptor function, or anti-oxidant activities of estrogen. It is controversial whether estrogen is indicated in the prevention or treatment of various brain disorders such as Alzheimer's disease. The conflicting findings suggest that several variables, including age, estrogen dose and formulation, the length of treatment, may determine whether the potential benefits of estrogen treatment would outweigh the associated risks.

Alzheimer Disease↗
PubMed2004

Deficiency of the Mre11 DNA repair complex in Alzheimer's disease brains.

The hallmarks of Alzheimer's disease (AD) brains are deposition of Abeta plaques, appearance of neurofibrillary tangles, and extensive loss of neuronal cells. While Abeta plaques and neurofibrillary tangles play a significant role in the pathogenic dysfunction of neurons, factors that accelerate the neurodegenerating process remain to be defined. One set of factors examined in this study is the Mre11 protein complex, composed of Rad50, Mre11 and Nbs1. This protein complex plays an essential role in cellular responses to DNA damage, such as initiating cell cycle checkpoints and repairing damaged DNA. A defect in any component of this protein complex is detrimental to cells. Recently, several groups have observed abnormal cell cycle regulation and/or accumulated DNA damage in AD neurons. These pathological alterations could conceivably be caused or exacerbated by any compromise in the Mre11 complex. In this study, we compared the levels of the Mre11 complex proteins in brain samples from AD and age-matched non-dementia controls. We show for the first time that the Mre11 complex proteins are present in neurons of the adult human cortex and cerebellum. These proteins were found substantially reduced in the neurons of AD cortex. Our finding suggests that the loss of the Mre11 complex may be associated with the pathogenesis of AD.

Acid Anhydride Hydrolases↗
PubMed2004

Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients.

Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer's disease (AD) brains remains inconclusive. Here, we report that we used sandwich enzyme-linked immunoabsorbent assay to quantitate various Abeta species in the frontal cortex of AD brains homogenized in 70% formic acid. We found that most of the Abeta species detected in rapidly autopsied brains (<3 h) with sporadic AD were Abeta(1-x) and Abeta(1-42), as well as Abeta(x-42). To establish a linkage between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. The elevation of BACE enzymatic activity in AD is correlated with brain Abeta(1-x) and Abeta(1-42) production. To examine whether BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and performed allelic association analysis. We found no mutations in the ORF of the BACE gene. Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. These findings demonstrate correlation between Abeta loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Abeta production and enhanced deposition of amyloid plaques in sporadic AD patients.

Alzheimer Disease↗
PubMed2004

Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death.

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-beta protein (Abeta), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor kappaB (NF-kappaB). Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-kappaB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Abeta, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.

Active Transport, Cell Nucleus↗
PubMed2004

The structure of sitting-atop complexes of metalloporphyrins studied by theoretical methods.

The metallation of tetrapyrroles is believed to proceed via a sitting-atop (SAT) complex, in which some of the pyrrole nitrogen atoms are still protonated and the metal ion resides above the ring plane. No crystal structure of such a complex has been presented, but NMR and extended X-ray absorption fine structure (EXAFS) data has been reported for Cu(2+) in acetonitrile. We have used density functional calculations to obtain reasonable models for SAT complexes of porphyrins with Mg(2+), Fe(2+), and Cu(2+). The results show that there are many possible SAT complexes with 1-5 solvent molecules, one or two metal ions, and cis or trans protonation of the porphyrin ring. Many of these have similar energies and their relative stabilities vary with the metal ion. A complex with two cis pyrrolenine nitrogens atoms and 2-4 solvent molecules coordinated to Cu(2+) fits the NMR and EXAFS data best. However, we cannot fully exclude the possibility that what is observed is rather a mixture of a doubly protonated porphyrin and the copper porphyrin. Mg(2+) has a lower affinity for porphyrin and stronger affinity for water, so a complex with five water molecules and only one bond to porphyrin seems to be most stable. For Fe(2+), a cis structure with two first-sphere water molecules and four interactions to the porphyrin seems to be most likely.

Journal Article↗
PubMed2003

The temporal localization of frame-shift ubiquitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer's disease pathology.

Transcriptional misreading of dinucleotide repeats that generates deletions in RNA and produces frame-shift proteins with loss of function has been reported in Alzheimer's disease (AD). Here frame-shift ubiquitin-B and amyloid precursor protein were immunochemically shown to exist in the brain of high pathology control (HPC) patients with AD pathology but without prior dementia. These proteins were absent in low pathology control patients with limited AD pathology and no dementia. Since the HPC patients can be regarded as preclinical AD patients, our results suggest the accumulation of these proteins involved in the initial steps of AD pathogenesis. By contrast, complement proteins were detected in the AD patients, whereas only trace amounts were found in the HPC patients, indicating the involvement of complement proteins in the later stage of AD dementia.

Aged↗
PubMed2003

Yin and Yang: complement activation and regulation in Alzheimer's disease.

The spectrum of inflammatory diseases is nowadays considered to include diverse diseases of the central nervous system (CNS). Current evidence suggests that syndromes such as Alzheimer's disease (AD) have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunotherapeutic approaches. Compelling evidence has been reported that complement activation occurs in the brain with Alzheimer's disease, and that this contributes to the development of a local inflammatory state that is correlated with cognitive dysfunction. The complement system is a critical element of the innate immune system recognizing and killing, or targeting for destruction, otherwise pathogenic organisms. In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Complement activation causes inflammation and cell damage, yet it is an essential component in trying to eliminate cell debris and potentially toxic protein aggregates. It is the balance of these seemingly competing events--the "Yin" and the "Yang"--that influences the ultimate state of neuronal function. Knowledge of the unique molecular interactions that occur in the development of Alzheimer's disease, the functional consequences of those interactions, and the proportional contribution of each element to this disorder, should facilitate the design of effective therapeutic strategies for this disease.

Alzheimer Disease↗
PubMed2002

A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains.

P25, a calpain cleavage product of the cyclin-dependent kinase 5 (Cdk5) activator p35, causes prolonged activation of Cdk5. Although p25 has been shown to accumulate in brains of patients with Alzheimer's disease (AD), it is not known whether p25 accumulation in AD is brain region-specific. We analyzed the amounts of p25 and p35 in human autopsy samples from multiple brain regions including frontal cortex, inferior parietal cortex and hippocampus using immunoblotting assays. Our results show that the p25-p35 indices are higher in AD than in the control groups in all three brain regions. The most significant difference in p25-p35 indices between AD and control groups is in the frontal cortex. No significant difference in calpain activity between AD and control groups is observed, indicating that postmortem calpain activation cannot account for the elevation of p25/p35 ratios in AD brains. Our results support the notion that p25 accumulation deregulates Cdk5 activity in AD brains, and the deregulated Cdk5 activity may contribute to the pathogenesis of AD.

Alzheimer Disease↗
PubMed2002

Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways.

Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, but their roles in the brain remain unclear. Here we present a novel interaction between TNFR subtypes and TNF-alpha in the brain. Our studies on target-depleted TNFR in mice show that TNF-alpha has little effect on hippocampal neurons in which TNFRI, containing an "intracellular death domain," is absent (TNFRI -/-), whereas neurons from TNFRII knock-out mice are vulnerable to TNF-alpha even at low doses. Moreover, little nuclear factor-kappaB (NF-kappaB) translocation is induced by TNF-alpha in neurons of TNFRI -/-, whereas NF-kappaB subunit p65 is still translocated from the cytoplasm into the nucleus in neurons from wild-type and TNFRII -/- mice. Furthermore, p38 mitogen-activated protein (MAP) kinase activity is upregulated in neurons from both wild-type and TNFRI -/-, but no alteration of p38 MAP kinase was found in neurons from TNFRII. Results from overexpression of TNF receptors further support the above findings. NT2 neuronal-like cells transiently transfected with TNFRI are very sensitive to TNF-alpha, whereas TNF-alpha is not toxic and even seems to be trophic to the cells with TNFRII overexpression. Last, our radioligand-binding experiments demonstrate that TNF-alpha binds TNFRI with high affinity (K(d) of 0.6 nm), whereas TNFRII shows lower binding affinity (K(d) of 1.14 nm) to TNF-alpha in NT2 transfected cells. Together, these studies reveal novel neuronal responses of TNF-alpha in mediating consequences of TNF receptor activation differently. Subsequent neuronal death or survival may ultimately depend on a particular subtype of TNF receptor that is predominately expressed in neurons of the brain during neural development or with neurological diseases.

Active Transport, Cell Nucleus↗
PubMed2002

Studies on 4,7-di-substitution effects of one ligand in [Ru(phen)3]2+ with DFT method.

Studies on the complex [Ru(phen)3]2+ (phen = 1,10-phenanthroline) and its derivatives with 4,7-di-substitution on one ligand(phen) were carried out using the DFT method at the B3LYP/LanL2DZ level of theory. The trends in the substituent effects caused by the electron-pushing group (OH) and the electron-withdrawing group (F), on the electronic structures and the related properties, for example, the energies and the components of some frontier molecular orbitals, the spectroscopy properties, and the net charge populations of some main atoms of the complexes, etc., have been investigated. The computational results show that the substituents have some interesting effects on the electronic structures and the related properties of the complexes. First, according to the analysis of components of LUMO of the complexes, the electron-withdrawing group (F) can activate the main ligand (the substituted ligand, i.e., 2R-phen) and passivate the coligands, on the contrary, the electron-pushing group (OH) can activate the coligands and passivate the main ligand in the first electronic excited states of complexes. Second, both the electron-pushing group (OH) and the electron-withdrawing group (F) can cause a red shift in the electronic ground bands. Third, the characteristics of the atomic net charge populations on the main ligand can also be analyzed in detail by means of a schematic map expressed by several series of arrowheads based on the law of polarity alternation and the idea of polarity interference. The most negative charges are populated on N1, the next most net negative charges are populated on C3 among the skeleton atoms for the three complexes, etc. The computational results can be better used to explain some experimental phenomena and trends.

Intercalating Agents↗
PubMed2002

Isolation of living neurons from human elderly brains using the immunomagnetic sorting DNA-linker system.

Isolation and culture of mature neurons from affected brain regions during diseased states provide a well-suited in vitro model system to study age-related neurodegeneration under dynamic conditions at cellular levels. We have developed a novel technique to isolate living neurons from rapidly autopsied human elderly brains, and have succeeded in keeping them alive in vitro. Specifically, the parietal cortex blocks were fractionated by density gradients and further enriched for neurons by an immunomagnetic sorting DNA-linker technique. The postmortem interval averaged 2.6 hours. After isolation and purification of neurons using this technology, the cells were maintained in vitro for 2 weeks. Our evaluation revealed that 80% of the isolated cells were neurons and they exhibited neurotransmitter phenotypes (glutamate and gamma-aminobutyric acid) as well as glutamate receptors. Studies on cell viability and calcium influx suggest that these isolated living cortical neurons still retain their typical neuronal functions. Our present study demonstrates that neurons isolated from human elderly brain autopsies can survive in vitro and maintain their functional properties. Our study has opened an opportunity to apply such neurons to dynamic pharmacological studies of neurological disorders at the single-cell level.

Aged↗