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Biomedical subjects

L Ni

Publications and source records attributed to L Ni.

At least 55 records · Page 3Linked to original sources
PubMed1998

Effects of talipexole on contraversive rotation and functional impairment in MPTP-induced chronic hemiparkinsonian monkeys.

The effects of talipexole on functional motor improvement in comparison with contraversive circling were studied in five chronic (5-7 years post MPTP-lesioned) hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotations in a dose of 32 microg/kg for about 1 hr after i.m. injection. Larger doses (56 and 100 microg/kg, i.m.) produced less effect due to sedation. Three different rating scales were used to assess functional improvement, including a clinical parkinsonism rating scale, volitional responses to fruit presentations, and number of significant hand movements. The optimal dose of talipexole was 32 microg/kg, i.m. Functional improvement by talipexole, including clinical parkinsonian rating scales and significant hand movements, as well as contraversive circling in hemiparkinsonian monkeys, confirm that this chronic animal model is useful in preclinical testing of drugs for the treatment of human parkinsonism.

Animals↗
PubMed1998

Trihexyphenidyl interactions with the dopamine D1-selective receptor agonist SKF-82958 and the D2-selective receptor agonist N-0923 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced hemiparkinsonian monkeys.

The effects of the antiparkinsonian agent trihexyphenidyl, a selective M1 muscarinic cholinergic receptor antagonist, were studied in doses of 100, 320 and 1000 micrograms/kg i.m. alone. Trihexyphenidyl was then studied in combination with the selective dopamine receptor D1 agonist SKF-82958 [(+/-)-6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-benzazepine hydrobromide] and the selective D2 agonist N-0923 [(-)2-(N-propyl-N-2-thienylethyl)amino-5-hydroxytetralin HCl] on rotational behavior in five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned hemiparkinsonian monkeys. Given alone, trihexyphenidyl had no effect on ipsiversive and slightly enhanced contraversive circling. Contraversive circling produced by 74.8 and 234 micrograms/kg SKF-82958 i.m. was potentiated by increasing doses of trihexyphenidyl. On the other hand, contraversive circling produced by 10 and 32 micrograms/kg N-0923 i.m. was progressively reduced with increasing doses of trihexyphenidyl. The results obtained indicate differential actions on circling behavior between a selective M1 muscarinic cholinergic receptor antagonist and selective D1 and D2 receptor agonists in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of hemiparkinsonism.

Animals↗
PubMed1998

[Investigation of the genetic instability of tumor cells by transfection of RER+ cell lines with exogenous microsatellite sequence].

OBJECTIVE: Frequent alterations of microsatellite sequence of cancer cells were found recently in a substantial fraction of human cancers including hereditary non-polyposis colon cancer. This paper aimed to investigate the genetic instability of tumor cells by using microsatellite instability(MI) as the marker in vitro. METHODS: Two RER+ cell lines (replication error phenotype), RKO and HCT116 and one RER- cell line, sw480, were used as the hosts for transfection with an episomal plasmid, pCMV-CAR, containing an exogenous (CA)14 repeat which was inserted within the coding sequence of lacZ reporter gene and thus made lacZ misreading. The transfectant clones were selected and established by hygromicin. Expression and production of lacZ reporter gene of restored reading frame were detected with X-gal staining assay. RESULTS: After hygromicin selection, stable pCMV-CAR transfectant clones were established. It was shown that mutation of deletion of insertion within(CA)14 occurred in the transfectant RER+ cells but not in the RER-cells. The mutation restored normal reading frame of lacZ gene, and resulted in expression and production of bio-active beta galactosidase which was detected with X-gal staining. This feature of the transfectant clones was maintained during culture passages. CONCLUSION: The alterations of the exogenous(CA)14 repeat in the transfectant RER+ clones revealed genetic instability and complicated mutation status of cancer cells. It is suggested that the exogenous (CA)14 in transfectant clones could be a useful target sequence for monitoring the effects of environmental agents on MI of human cancer cells.

Cell Line↗
PubMed1998

Effects of pramipexole on contraversive rotation and functional motor impairments in 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine-induced chronic hemiparkinsonian monkeys.

Rotational and functional motor behavioral changes were studied in five MPTP lesioned chronic hemiparkinsonian Macaca nemestrina monkeys after i.m. pramipexole, a predominant D2 subfamily agonist. Pramipexole induced contraversive rotations in a dose-dependent manner with an optimal dose of 56 microg/kg for approximately 2 to 4 hr after injection. Three different rating scales were used to determine drug-induced functional improvement. They included a monkey parkinsonism rating scale, volitional responses to fruit presentations, and number of hand movements that appeared volitional. A dose of 56 microg/kg of pramipexole produced functional improvements on hand disability, and on a parkinsonian rating scale for monkeys in a dose-dependent manner from 32 to 100 microg/kg. These doses produced an increase in significant hand movements in the affected (contralateral) as well as in the normal (ipsilateral) hand to the side of the brain lesion compared with 5% dextrose in water vehicle control. With a dose of 100 microg/kg, the therapeutic effects of pramipexole on hand movements were less than with 56 microg/kg, due to side effects such as scratching.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

The potential roles of the conserved amino acids in human liver mitochondrial aldehyde dehydrogenase.

The sequence alignment of all known aldehyde dehydrogenases showed that only 23 residues were completely conserved (Hempel, J., Nicholas, H., and Lindahl, R. (1993) Protein Sci. 2, 1890-1900). Of these 14 were glycines and prolines. Site-directed mutagenesis showed that Cys302 was the essential nucleophile and that Glu268 was the general base necessary to activate Cys302 for both the dehydrogenase and esterase reaction. Here we report the mutational analysis of other conserved residues possessing reactive side chains Arg84, Lys192, Thr384, Glu399, and Ser471, along with partially conserved Glu398 and Lys489, to determine their involvement in the catalytic process and correlate these finding with the known structure of mitochondrial ALDH (Steinmetz, C. G., Xie, P.-G., Weiner, H., and Hurley, T. D. (1997) Structure 5, 701-711). No residue was found to be absolutely essential, but all the mutations caused a decrease in the specific activity of the enzyme. None of the mutations affected the Km for aldehyde significantly, although k3, the rate constant calculated for aldehyde binding was decreased. The Km and dissociation constant (Kia) for NAD+ increased significantly for K192Q and S471A compared with the native enzyme. Mutations of only Lys192 and Glu399, both NAD+-ribose binding residues, led to a change in the rate-limiting step such that hydride transfer became rate-limiting, not deacylation. Esterase activity of all mutants decreased even though mutations affected different catalytic steps in the dehydrogenase reaction.

Aldehyde Dehydrogenase↗
PubMed1997

Involvement of glutamate 399 and lysine 192 in the mechanism of human liver mitochondrial aldehyde dehydrogenase.

Mutation to the conserved Glu399 or Lys192 caused the rate-limiting step of human liver mitochondrial aldehyde dehydrogenase (ALDH2) to change from deacylation to hydride transfer (Sheikh, S., Ni, L., Hurley, T. D., and Weiner, H. (1997) J. Biol. Chem. 272, 18817-18822). Here we further investigated the role of these two NAD+-ribose-binding residues. The E399Q/K/H/D and K192Q mutants had lower dehydrogenase activity when compared with the native enzyme. No pre-steady state burst of NADH formation was found with the E399Q/K and K192Q enzymes when propionaldehyde was used as the substrate; furthermore, each mutant oxidized chloroacetaldehyde slower than propionaldehyde, and a primary isotope effect was observed for each mutant when [2H]acetaldehyde was used as a substrate. However, no isotope effect was observed for each mutant when alpha-[2H]benzaldehyde was the substrate. A pre-steady state burst of NADH formation was observed for the E399Q/K and K192Q mutants with benzaldehyde, and p-nitrobenzaldehyde was oxidized faster than benzaldehyde. Hence, when aromatic aldehydes were used as substrates, the rate-limiting step remained deacylation for all these mutants. The rate-limiting step remained deacylation for the E399H/D mutants when either aliphatic or aromatic aldehydes were used as substrates. The K192Q mutant displayed a change in substrate specificity, with aromatic aldehydes becoming better substrates than aliphatic aldehydes.

Acetaldehyde↗
PubMed1997

Talipexole or pramipexole combinations with chloro-APB (SKF 82958) in MPTP-induced hemiparkinsonian monkeys.

The effects of two predominant dopamine D2-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL2) and pramipexole (S(-)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL2Y), were studied alone and in combination with the selective dopamine D1-like receptor agonist chloro-APB ((+/-)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 microg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 microg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D2-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 microg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 microg/kg) of pramipexole. Talipexole, in the largest dose studied (100 microg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

Animals↗
PubMed1997

DNA polymorphisms in the chicken growth hormone gene: response to selection for disease resistance and association with egg production.

Analysis of the growth hormone (GH) gene in 12 strains of White Leghorn chickens revealed restriction fragment length polymorphisms (RFLPs) at three MspI sites and at a SacI site. Based on linkage disequilibrium analysis, they gave rise to eight different alleles (i.e. combinations of RFLPs), with five occurring at frequencies above 5% in at least one strain. Pairs of GH-RFLPs were at near maximal linkage disequilibrium, suggesting either a lack of recombination or the presence of selection pressure during evolution of the GH gene. Allele frequencies were determined in 12 non-inbred strains derived from three different genetic bases. These strains had been selected either for an array of egg production traits, resistance to Marek's disease or resistance to avian leukosis. Selection for disease resistance was consistently correlated with an increase in the frequency of one of the alleles. One strain segregated for only two alleles, which differed by three RFLPs. Analysis of variance in this strain indicated that the GH allele co-selected with resistance was associated with a delayed onset of ovulation but a higher persistency of ovulation as age progressed, resulting in an overall increase of egg production by 15% (age at first egg to 497 days). The resistance-associated GH allele was dominant for the onset of ovulation and recessive for the persistency of egg production. There was no significant effect of the GH genotype on juvenile body weight, egg weight or egg specific gravity.

Animals↗
PubMed1997

Usher's syndrome type IC: clinical studies and fine-mapping the disease locus.

Usher's syndrome type I is a heterogeneous group of diseases characterized by severe to profound sensorineural hearing loss, absent vestibular function, and progressive pigmentary retinopathy. Other identifying clinical features have not been documented. In this study, we examined olfactory acuity, plasma levels of polyunsaturated fatty acids and sarcosine, and cilia ultrastructure in a homogeneous cohort of patients with Usher's syndrome type IC. The normal age-dependent decline in olfactory acuity was observed, and normal plasma levels of polyunsaturated fatty acids and sarcosine were found. However, the incidence of compound cilia in biopsies from the inferior turbinate was significantly higher than that reported in control populations. By reconstructing haplotypes in affected persons. D11S902 and D11S1310 were identified as flanking markers over an interval that contains a candidate gene, KCNC1. No mutations in the coding sequence of this gene could be demonstrated in affected persons.

Adolescent↗
PubMed1997

[Experimental treatment of rhubarb on mesangio-proliferative glomerulonephritis in rats].

Accumulation of extracellular matrix is a prominent feature of progressive glomerulonephritis (GN). Previously, we have shown that Emodin, an important component of Rhubarb, inhibits the fibronectin (FN) production of cultured mesangial cells. We now provide evidence of the same effect of Rhubarb in immune complex GN induced in rats by injection of anti-thymocyte serum (ATS). Rhubarb ameliorated mesangial matrix expansion on day 7 after ATS administration. Decreased FN level and IL-1 activity were found in the supernatant of cultured glomeruli from Rhubarb-treated animal at the 7th day. Glomerular tissue FN fluorescence staining was also much weaker than that of the untreated rats. These studies demonstrated that Rhubarb-treated anti-Thy-1 animal model should develop significantly less matrix expansion. Rhubarb also inhibited synthesis and secretion of fibronectin, an important component of mesangial extracellular matrix. Decreased IL-1 activity might be involved in the therapeutic effect of Rhubarb on mesangioproliferative glomerulonephritis.

Animals↗
PubMed1996

Conditioned medium from activated microglia promotes cholinergic differentiation in the basal forebrain in vitro.

In earlier studies we found that treatment with interferon-gamma (IFN-gamma) produced an 8- to 11-fold increase in choline acetyltransferase (ChAT) in cultured cells taken from Embryonic Day 16 (E16) septal nuclei with adjacent basal forebrain (SN/BF). Since younger cultures responded even more profoundly to IFN treatment, we have tested the possibility that the action of IFN (or its intermediate; see below) is to prompt the cholinergic differentiation of neuronal precursors. SN/BF cultures of various ages were labeled with a retrovirus engineered to express beta-galactosidase (Lac-Z), and ChAT-positive descendants of the retrovirally labeled precursors were counted. IFN-gamma treatment of cultures caused as much as an 8.8-fold increase in the proportion of ChAT-positive cells present in Lac-Z-positive clones, suggesting that IFN promoted cholinergic differentiation in precursor populations. By contrast, bFGF increased clone size but did not change the proportion of ChAT-positive cells. NGF affected neither. Only ameboid microglia present in the cultures responded to IFN with characteristic nuclear translocation of the signal transducing molecule p91, suggesting that a microglial-derived molecule may mediate the action of IFN. Consistent with this hypothesis, conditioned media from cultures of enriched, activated microglia also increased ChAT activity in a dose-dependent fashion. Conditioned media from an unstimulated macrophage/monocyte cell line (RAW 264.7) also proved extremely efficacious in raising ChAT activity. In addition, conditioned media from both activated microglia and RAW 264.7 cells increased the proportion of ChAT-positive cells in retrovirally labeled clones to the same extent as IFN itself, suggesting the possibility that they contain the molecule(s) that mediates the action of IFN. Preliminary characterization of this molecule suggests that it is a very stable and large protein. Together these data suggest that a molecule promoting cholinergic differentiation is produced by activated microglia and other macrophage-like cells. The identity of this molecule and its precise role in normal development await its further purification.

Animals↗
PubMed1996

Cellular localization of antiviral polyoxometalates in J774 macrophages.

The cellular localization of the polyoxometalates, K12H2[P2W12O48].24H20 (JM 1591), K10[P2W18-Zn4(H2O)2O68].20H2O (JM 1596), and [Me3NH]8[Si2W18Nb6O77] (JM 2820) were examined in cultured J774 cells by inhibition of cellular uptake of acetylated low-density lipoprotein (LDL) and by electron microscopy. All three polyoxometalates inhibited the cellular uptake of acetylated LDL, suggesting that the polyoxometalates block the association of acetylated LDL with cellular scavenger receptors. Fluorescence microscopy showed increased numbers of vacuoles in the presence of polyoxometalates, suggesting their uptake by cells. Using scanning electron microscopy (SEM), no significant cell surface morphological differences were observed between treated and non-treated J774 cells, suggesting that the compounds are not toxic to J774 cells up to a concentration of 200 micrograms/ml. Transmission electron microscopy (TEM) revealed large amounts of high electron dense granules were observed in the ramifying system of tubular cavities and vacuoles. TEM-energy dispersive spectroscopy (EDS) X-ray microanalysis was unable to differentiate the dense particles, most likely because the amount of tungsten in the cells was below the limit of detection. X-ray microanalysis conducted using the SEM-wavelength dispersive spectroscopy (WDS) detected tungsten, averaging 0.45 +/- 0.16% (mean +/- S.D.), in the J774 cells treated with JM 2820, suggesting that this polyoxometalate was taken up by the macrophages or was bound to their surface. Polyoxometalates interact at the cell surface and appear to be taken up by J774 macrophages. The cellular localization of polyoxometalates may be associated with anti-HIV activity.

Animals↗
PubMed1996

A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6.

Late-onset non-syndromic hearing impairment is the most common type of neurological dysfunction in the elderly. It can be either acquired or inherited, although the relative impact of heredity on this type of loss is not known. To date, nine different genes have been localized, but none has been cloned. Using an extended American family in which a gene for autosomal dominant late-onset non-syndromic hearing impairment is segregating, we have identified a new locus, DFNA10, on chromosome 6.

Chromosome Mapping↗
PubMed1996

[A study of gingivain from extracellular vesicles of Porphyromonas gingivalis W50: purification and cytotoxic characterization].

Gingivain was purified from extracellular vesicles of Porphyromonas gingivalis W50 with high performance liquid chromatography (HPLC) and its cytotoxic characterization on L929 cell line was examined. The result showed that gingivain might belong to systeine proteinases. The molecular weight of gingivain was about 27,800 unit by HPLC in which there might be one or two peptides being 10,900 unit, the enzyme was activated by Ca2+ and thiol-containing agents such as dithiothycitol and inhibited by Na-4-tosyl-L-lysine chioromethyl and EDTA. The maximum activity of the enzyme were found at pH 7.5, purified gingivain was toxic to L929 cell line at the content of 10 micrograms/ml. The study indicates that gingivain carried by vesicles might be more important in bacterial toxic activities.

Bacterial Proteins↗