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W Ni

Publications and source records attributed to W Ni.

At least 19 recordsLinked to original sources
PubMed2001

Antiinflammatory and antiarteriosclerotic actions of HMG-CoA reductase inhibitors in a rat model of chronic inhibition of nitric oxide synthesis.

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be due to their cholesterol-lowering independent effects on the blood vessels. Chronic inhibition of endothelial nitric oxide (NO) synthesis by oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation as well as subsequent arteriosclerosis. The aim of the study is to test whether treatment with statins attenuates such arteriosclerotic changes through their cholesterol-lowering independent effects. We investigated the effect of statins (pravastatin and cerivastatin) on the arteriosclerotic changes in the rat model. We found that treatment with statins did not affect serum lipid levels but markedly inhibited the L-NAME-induced vascular inflammation and arteriosclerosis. Treatment with statins augmented endothelial NO synthase activity in L-NAME-treated rats. We also found the L-NAME induced increase in Rho membrane translocation in hearts and its prevention by statins. Such vasculoprotective effects of statins were suppressed by the higher dose of L-NAME. In summary, in this study, we found that statins such as pravastatin and cerivastatin inhibited vascular inflammation and arteriosclerosis through their lipid-lowering independent actions in this model. Such antiarteriosclerotic effects may involve the increase in endothelial NO synthase activity and the inhibition of Rho activity.

Animals↗
PubMed2001

New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice.

BACKGROUND: Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy. METHODS AND RESULTS: We devised a new strategy for anti-MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E-knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content. CONCLUSIONS: We conclude that this anti-MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.

Animals↗
PubMed2001

HIV-1 Tat neurotoxicity is prevented by matrix metalloproteinase inhibitors.

The release of potentially neurotoxic molecules by HIV-infected brain macrophages is accompanied by neuronal injury and death that results in the development of HIV-associated dementia (HAD). Among the potential neurotoxins implicated in the development of HAD is the HIV-1 transactivating protein, Tat. To investigate the mechanism by which Tat causes neurotoxicity, brain-derived Tat sequences from nondemented (Tat-ND) and demented (Tat-HAD) AIDS patients, which differed primarily in the augmenting region of Tat, were expressed in U937 monoblastoid cells and primary human macrophages. Cells expressing Tat-HAD protein exhibited elevated matrix metalloproteinase (MMP)-2 and -7 release and activation, but cells expressing Tat-ND did not exhibit enhanced MMP expression. Conditioned media from Tat-HAD-transfected cells caused significantly greater neuronal death (15.4 +/- 4.3%) than did Tat-ND (4.4 +/- 2.1%) or nontransfected (2.1 +/- 0.8%) cell-derived conditioned media. The neurotoxicity induced by Tat-HAD was inhibited by anti-MMP-2 or -7 antibodies (p < 0.005) but not by antibodies against MMP-9 or Tat. Similarly, scid/nod mice receiving striatal implants of Tat-HAD-transfected cells exhibited greater neurobehavioral abnormalities and neuronal loss (p < 0.005) than did animals receiving Tat-ND or nontransfected cells, which were reduced by treatment with the MMP inhibitor prinomastat (p < 0.005). These findings indicate that Tat causes neuronal death through an indirect mechanism that is Tat sequence dependent and involves the induction of MMPs.

AIDS Dementia Complex↗
PubMed2001

Grammatism.

Findings from the literature on language development, dyslexia, and adult sentence processing provide a vehicle for comparing two models of the symptom complex associated with agrammatism. One model contends that agrammatism represents a deficit in linguistic structures. The other model maintains that the linguistic behavior associated with agrammatism is the result of a limitation in language processing. To adjudicate between the models, the present paper examines one linguistic construction, the restrictive relative clause. The results of experimental investigations across several subject populations reveal parallel patterns of linguistic behavior on this construction. The findings favor the processing limitation account of the linguistic difficulties experienced by agrammatic aphasics in comprehending sentences with a restrictive relative clause.

Aphasia, Broca↗
PubMed2001

Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-alpha-specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-alpha expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. METHODS: Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-alpha mRNA and protein levels were measured by reverse transcriptase-polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase-mediated uridine 5'triphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. RESULTS: ICH induction (n=6) elevated TNF-alpha mRNA and protein levels (P:<0.01) at 24 hours after the onset of injury compared with sham controls (n=6). Immunohistochemical labeling indicated that ICH was accompanied by elevated expression of TNF-alpha in neutrophils, macrophages, and microglia. Administration of ORF4-PE (2.0 nmol) directly into striatal parenchyma, 15 minutes before (n=4) or 3 hours after (n=6) ICH, decreased levels of TNF-alpha mRNA (P:<0.001) and protein (P:<0. 01) in the brain tissue surrounding the hematoma compared with animals treated with saline alone (n=6). Mean+/-SEM striatal cell death (cells per high-powered field) was also reduced in animals receiving ORF4-PE (34.1+/-5.0) compared with the saline-treated ICH group (80.3+/-7.50) (P:<0.001). ORF4-PE treatment improved neurobehavioral deficits observed at 24 hours (P:<0.001) after induction of ICH (n=6) compared with the untreated ICH group (n=6). This improvement was maintained at 28 days after hemorrhage induction (P:<0.001). CONCLUSIONS: These results indicate a pathogenic role for TNF-alpha during ICH and demonstrate that reducing TNF-alpha expression using antisense oligodeoxynucleotides is neuroprotective.

Animals↗
PubMed2000

Role of monocyte chemoattractant protein-1 in cardiovascular remodeling induced by chronic blockade of nitric oxide synthesis.

BACKGROUND: Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of N:(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 [MCP-1] expression) as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, the role of MCP-1 in this process is not known. METHODS AND RESULTS: We investigated the effect of a specific monoclonal anti-MCP-1 neutralizing antibody in rats treated with L-NAME to determine the role of monocytes in the regulation of cardiovascular remodeling. We found increased expression of MCP-1 mRNA in vascular endothelial cells and monocytes in inflammatory lesions. Cotreatment with an anti-MCP-1 antibody, but not with control IgG, prevented the L-NAME-induced early inflammation and reduced late coronary vascular medial thickening. In contrast, the anti-MCP-1 antibody did not decrease the development of perivascular fibrosis, the expression of transforming growth factor (TGF)-beta(1) mRNA, or systolic pressure overload induced by L-NAME administration. CONCLUSIONS: These results suggest that MCP-1 is necessary for the development of medial thickening as well as monocyte recruitment. In contrast, the pathogenesis of fibrosis may involve other factors, such as TGF-beta(1).

Animals↗
PubMed2000

AIDS- and non-AIDS-related PML association with distinct p53 polymorphism.

A population-based analysis of progressive multifocal leukoencephalopathy (PML) showed PML frequencies of 5.1% among patients with AIDS and 0.07% among patients with hematologic malignancies, but similar clinical features of PML in both groups. Sequencing of the p53 gene, exon 4, showed heterozygosity (Arg-Pro) at codon 72 in five of six PML patients. These findings indicate that frequencies of non-AIDS- and AIDS-related PML differ markedly but p53 polymorphisms may influence the occurrence of PML in both groups.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis.

Monocyte chemoattractant protein-1 (MCP-1) may play an essential part in the formation of arteriosclerosis by recruiting monocytes into the arterial wall. Thus, we devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (missing the amino-terminal amino acids 2 to 8) of the human MCP-1 gene into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene blocked monocyte recruitment induced by a subcutaneous injection of recombinant MCP-1. In a rat model in which the chronic inhibition of endothelial nitric oxide synthesis induces early vascular inflammation as well as subsequent coronary vascular remodeling, this strategy suppressed monocyte recruitment into the coronary vessels and the development of vascular medial thickening, but did not reduce perivascular fibrosis. Thus, MCP-1 is necessary for the development of medial thickening but not for fibrosis in this model. This new strategy may be a useful and feasible gene therapy against arteriosclerosis.

Animals↗
PubMed2000

Lentivirus infection in the brain induces matrix metalloproteinase expression: role of envelope diversity.

Infection of the brain by lentiviruses, including human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus envelope gene has been implicated in the regulation of cell tropism and the host response to infection. Here, we examine the hypothesis that envelope sequence diversity modulates the expression of host molecules implicated in lentivirus-induced brain disease, including matrix metalloproteinases (MMP) and related transcription factors. Infection of primary macrophages by chimeric HIV clones containing brain-derived envelope fragments from patients with HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) showed that MMP-2 and -9 levels in conditioned media were significantly higher for the HAD clones. Similarly, STAT-1 and JAK-1 levels were higher in macrophages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V(1)CSF), the less neurovirulent strain (Petaluma), and a chimera containing the V(1)CSF envelope in a Petaluma background (FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in conditioned media from V(1)CSF- and FIV-Ch-infected macrophages, which was associated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhibitor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expression, in FIV-infected macrophages. Analysis of MMP mRNA and protein levels in brain samples from HIV-infected persons or FIV-infected cats showed that MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression was accompanied by significant increases in STAT-1 and JAK-1 mRNA and protein levels in the same brain samples. The present findings indicate that two lentiviruses, HIV and FIV, have common mechanisms of MMP-2 and -9 induction, which is modulated in part by envelope sequence diversity and the STAT-1/JAK-1 signaling pathway.

AIDS Dementia Complex↗
PubMed2000

An event-related neuroimaging study distinguishing form and content in sentence processing.

Two coordinated experiments using functional Magnetic Resonance Imaging (fMRI) investigated whether the brain represents language form (grammatical structure) separately from its meaning content (semantics). While in the scanner, 14 young, unimpaired adults listened to simple sentences that were either nonanomalous or contained a grammatical error (for example, *Trees can grew.), or a semantic anomaly (for example, *Trees can eat.). A same&frasl;different tone pitch judgment task provided a baseline that isolated brain activity associated with linguistic processing from background activity generated by attention to the task and analysis of the auditory input. Sites selectively activated by sentence processing were found in both hemispheres in inferior frontal, middle, and superior frontal, superior temporal, and temporo-parietal regions. Effects of syntactic and semantic anomalies were differentiated by some nonoverlapping areas of activation: Syntactic anomaly triggered significantly increased activity in and around Broca's area, whereas semantic anomaly activated several other sites anteriorly and posteriorly, among them Wernicke's area. These dissociations occurred when listeners were not required to attend to the anomaly. The results confirm that linguistic operations in sentence processing can be isolated from nonlinguistic operations and support the hypothesis of a specialization for syntactic processing.

Adult↗
PubMed2000

Pravastatin attenuates cardiovascular inflammatory and proliferative changes in a rat model of chronic inhibition of nitric oxide synthesis by its cholesterol-lowering independent actions.

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitors such as pravastatin may be through their cholesterol-lowering independent effects on the blood vessels. We have recently reported that chronic inhibition of nitric oxide (NO) synthesis with N(omega)nitro-L-arginine methyl ester (L-NAME) increases systolic blood pressure and induces coronary vascular inflammatory changes in rats. We designed this study to investigate whether treatment with pravastatin attenuates such proarteriosclerotic changes through their cholesterol-lowering independent effects. Several groups of Wistar-Kyoto rats were studied: the control group, L group received L-NAME in their drinking water (100 mg/kg per day) and L+Px group received L-NAME plus pravastatin (50, 100 or 250 mg/kg per day). We observed marked increases in monocyte infiltration into the coronary arteries, proliferative cell nuclear antigen-positive cells, and monocyte chemoattractant protein-1 (MCP-1) expression in the heart on day 3 after L-NAME administration began. Treatment with pravastatin did not affect serum cholesterol levels or systolic blood pressure but did reduce the L-NAME induced inflammatory and proliferative changes. Pravastatin also attenuated the MCP-1 gene expression induced by L-NAME. In summary, pravastatin inhibited the inflammatory and proliferative changes in the coronary vessels through their cholesterol-independent effects in this model, which may provide an insight into the mechanisms of anti-inflammatory or anti-arteriosclerotic actions of pravastatin.

Animals↗
PubMed1999

Paroxysmal dyskinesias in patients with HIV infection.

OBJECTIVE: To determine the clinical features of paroxysmal dyskinesias among HIV type 1 (HIV-1)-seropositive patients. BACKGROUND: Movement disorders have been associated with HIV infection, although the full spectrum of these disorders remains uncertain. METHODS: Six adult HIV-1-seropositive patients presenting with paroxysmal dyskinesias were identified. Each patient underwent metabolic, CSF, EEG, and neuroimaging studies. RESULTS: Mean age at onset was 34.5 years and five of six patients were AIDS defined. Dyskinesias were focal, multifocal, or hemidystonic in four patients and generalized in another two patients. Two of the six patients had paroxysmal kinesigenic dyskinesias and the remaining four patients had paroxysmal nonkinesigenic dyskinesias. Choreoathetosis (n = 3), myoclonus (n = 2), postural tremor (n = 5), and dysarthria (n = 3) were observed. Benzodiazepines appeared beneficial in three of six patients. Two patients with HIV-associated dementia and paroxysmal nonkinesigenic dyskinesia had a progressive course to death. Autopsy of a patient with paroxysmal nonkinesigenic dyskinesias revealed intense astrogliosis and loss of calbindin-positive neurons in the subcortical gray matter. CONCLUSIONS: Paroxysmal dyskinesias may present as a primary HIV-1-induced neurologic syndrome. The occurrence of paroxysmal dyskinesias is associated with neuronal injury and loss in the subcortical gray matter but the mechanism remains unknown.

AIDS Dementia Complex↗
PubMed1999

Ethanol-extracted soy protein isolate results in elevation of serum cholesterol in exogenously hypercholesterolemic rats.

Soy protein preparations were reported to have hypocholesterolemic actions in experimental animals and humans, while the active components and the mechanism by which this occurs are not clarified yet. The objective of this study is to address these issues by using exogenously hypercholesterolemic rats which are susceptible to dietary cholesterol. Two groups of five rats (male, 12-wk-old) were fed on AIN 93G-based diet with soy protein isolate (SPI) or ethanol-extracted SPI (EE-SPI) for 2 wk. EE-SPI was prepared by ethanol extraction to remove isoflavones and other components. Concentrations of serum and liver total cholesterol were lower in rats fed SPI than in those fed EE-SPI. The abundances of mRNA for 7alpha-hydroxylase and low density lipoprotein receptor in the liver were lower in EE-SPI group than those in SPI group. These results suggest that the ethanol extract from SPI has a factor(s) to alleviate hypercholesterolemia by increasing the removal of cholesterol from serum through the receptor pathway and then from liver through enhancement of bile acid synthesis.

Animals↗
PubMed1999

Antisense oligodeoxynucleotides targeting internal exon sequences efficiently regulate TNF-alpha expression.

ABSTRACT Exon sequences upstream of splice sites play a critical role in mRNA processing, which is dependent on spliceosome interactions with these sites. Using antisense oligodeoxynucleotides (ODN), we targeted these and other sequences of the proinflammatory tumor necrosis factor-alpha (TNF-alpha) gene because it is multiply spliced and has been difficult to regulate with ODN in the past. ODN targeting exon sequences upstream of the donor splice sites of internal exons 2 (ORF4) and 3 (ORF6) significantly reduced TNF-alpha levels in stimulated U937 cells by 62%+/-7% and 51%+/-9%, respectively, in a dose-dependent manner but did not affect interleukin-6 (IL-6) levels. In contrast, ODN targeting the exon sequences downstream of the acceptor splice sites of exons 1, 2, and 3 failed to reduce TNF-alpha levels significantly under the same conditions. End-phosphorothioated ORF4 (ORF4-PE) significantly reduced TNF-alpha mRNA levels by greater than 80% (p < 0.001) and protein levels by 60% (p < 0.001) in U937 cells. ORF4-PE reduced newly synthesized TNF-alpha protein levels by >80% in lipopolysaccharide (LPS)-stimulated human macrophages, by greater than 60% in phorbol myristate acetate/phyto-hemagglutinin (PMA/PHA)-stimulated human peripheral blood mononuclear cells (PBMC), and by approximately 50% in LPS-stimulated murine monocytes. These results suggest that exon sequences flanking donor splice sites are highly susceptible target domains for antisense inhibition of TNF-alpha gene expression.

Animals↗
PubMed1999

Concentration of serum lipids and aortic lesion size in female and male apo E-deficient mice fed docosahexaenoic acid.

Apolipoprotein (apo) E-deficient mice were fed an atherogenic diet with either 1% ethyl ester docosahexaenoic acid (DHA) or safflower oil (SO) as a source of linoleic acid for 8 week. Both genders fed DHA had higher proportions of eicosapentaenoic acid and DHA, and lower proportions of linoleic and arachidonic acids in the liver and serum phospholipids than those fed SO. Males fed DHA had greater liver weight and tended to have higher concentrations of serum lipids and liver cholesterol than those fed SO, and there were opposite trends in females. Dietary fats and gender led to no significant effect on lesion sizes in aortic arch and thoracic plus abdominal aorta. These results indicate that the interactive action of sex-related factor(s) with dietary polyunsaturated fatty acids is involved in metabolic changes of serum lipids in apoE-deficient mice, and addition of DHA, compared with addition of SO, is not effective to abolish the atherosclerosis in this animal model.

Animals↗
PubMed1998

The regulating effects of protein kinase C on the tone of guinea-pig trachea and human lobus bronchi.

The regulating effects of protein kinase C (PKC) on the tone of guinea-pig trachea and human lobus bronchi were investigated by measuring the tone of isolated tracheal and bronchial strips. The effects of PKC on the tone of guinea-pig tracheal and human lobus bronchi were observed and compared. The results showed that: (1) PKC activator PMA induced concentration-dependent relaxation in guinea-pig isolated trachea strips. This relaxation was completely ablated by the pretreatment with 5 x 10(-6) mol/L Ro31-8220 which is a PKC-specific inhibitor, but was not affected by the removal of epithelium (EP), or by the pretreatment with propranolol (beta-receptor blocker) or atropin (M-receptor blocker); (2) PMA led to concentration-dependent contraction in human lobus bronchi. This contractile response was completely depressed by the pretreatment with 5 x 10(-6) mol/L Ro31-8220 and was partly inhibited by 1 x 10(-5) mol/L isoptin (Ca(2+)-antagonist), but was not significantly affected by propranolol or atropin. It is concluded that PKC is involved in the regulation of airway smooth muscle tone. The regulating effects may vary in different animals.

Animals↗
PubMed1998

Anomaly detection: eye movement patterns.

The symptom of a garden path in sentence processing is an important anomaly in the input string. This anomaly signals to the parser that an error has occurred, and provides cues for how to repair it. Anomaly detection is thus an important aspect of sentence processing. In the present study, we investigated how the parser responds to unambiguous sentences that contain syntactic anomalies and pragmatic anomalies, examining records of eye movement during reading. While sensitivity to the two kinds of anomaly was very rapid and essentially simultaneous, qualitative differences existed in the patterns of first-pass reading times and eye regressions. The results are compatible with the proposal that syntactic information and pragmatic information are used differently in garden-path recovery.

Humans↗