Biomedical subjects

L Li

Publications and source records attributed to L Li.

At least 253 records · Page 14Linked to original sources

PubMed2001

Beta-alanine-based dendritic beta-peptides: dendrimers possessing unusually strong binding ability towards protic solvents and their self-assembly into nanoscale aggregates through hydrogen-bond interactions.

A series of poly(beta-alanine) dendrimers 1-4 with Boc-carbamate as the surface functionality, beta-alanine as the dendritic branch, 3,5-diaminobenzoic acid as the branching agent, and 1,2diaminoethane as the interior core has been synthesized by a solution-phase peptide-coupling method. The structural identities and purities of the products have been fully characterized by spectroscopic and chromatographic methods. 1H NMR studies on the dendrimers indicated that the Boc-carbamate surface groups exist as a mixture of syn and anti rotamers in solution, and that the dendrimers adopt an open structure in polar solvents; this allows the free interaction of the interior core functionality with solvent molecules. Due to the cooperative effect of a large number of carbamate and amide groups, the dendrimers exhibit an unusually strong binding ability towards protic solvents and behave as H-bond sponges. As a result, the H/D exchange rates of the N-H protons are significantly enhanced in such dendritic structures, as compared to those of nondendritic carbamates and amides. These dendritic peptide dendrimers also exhibit a strong tendency to form nanoscopic aggregates in nonpolar or polar aprotic solvents through intermolecular H-bond interactions.

Hydrogen Bonding↗

PubMed2001

Cytotoxic mechanism of XK469: resistance of topoisomerase IIbeta knockout cells and inhibition of topoisomerase I.

Topoisomerase IIbeta knockout mouse cells (beta-/-) were found to have only slight resistance to m-AMSA, a dual topoisomerase IIalpha-IIbeta poison, as compared to wild-type cells (beta+/+) during 1 h or 3 day exposures to the drug. In contrast, the beta-/- cells were greater than threefold resistant to XK469, a selective topoisomerase IIbeta poison during three day drug exposures (beta+/+ IC(50) = 175 microM, beta-/- IC(50) = 581 microM). Short term (1 h) exposure to XK469 was not cytotoxic to either beta-/- or beta+/+ cells, suggesting that anticancer therapy with XK469 may be more efficacious if systemic levels can be prolonged. During studies on topoisomerase activity in nuclear extracts of the beta+/+ and beta-/- cells, we found evidence that XK469 is a weak topoisomerase I catalytic inhibitor. The high IC(50) for topoisomerase I inhibition (2 mM) suggests that topoisomerase I is not a significant target for XK469 cytotoxicity.

Animals↗

PubMed2001

Sources of variation in patient response to radiation treatment.

PURPOSE: To investigate sources of variation in radiosensitivity displayed by cancer patients and blood donors using the leukocyte apoptosis assay. METHODS AND MATERIALS: Probes were obtained from 105 healthy blood donors, 48 cancer patients displaying normal sensitivity to radiotherapy, 12 cancer patients displaying hypersensitivity to radiotherapy, 12 Ataxia telangiectasia blood donors, and 4 additional individuals with genetic diseases of potentially modified radiosensitivity; 2 neurofibromatosis (NF) donors, a Nijmegen breakage syndrome (NBS) donor, and an Immunodeficiency, Chromosome fragility, Facial anomaly syndrome (ICF) donor. Heparinized blood was diluted in medium, irradiated, and left to incubate for 48 h. CD4 and CD8 T-lymphocyte DNA was stained with propidium iodide and the cells were analyzed by flow cytometry. RESULTS: Radiation-induced apoptosis depended on age and cell type. Cohorts of hypersensitive cancer patients, NBS and AT donors displayed compromised apoptotic response. An asymmetric apoptotic response of T-lymphocytes was observed in an ICF donor and a cryptic hypersensitivity donor. Two NF donors displayed no abnormal sensitivity to radiotherapy but compromised apoptotic T-cell response to X-rays. CONCLUSION: Our studies reveal 4 physiologic sources of variation in radiation response-2 are genetic: cryptic hypersensitivity and hereditary disease, and 2 are epigenetic: cell type and donor age. They emphasize the important role of proteins involved in the recognition and repair of DNA double-strand breaks in determining the response of individuals to radiotherapy.

Adolescent↗

PubMed2001

High levels of delayed radiation-induced apoptosis observed in lymphoblastoid cell lines from ataxia-telangiectasia patients.

PURPOSE: Cells from ataxia-telangiectasia (A-T) patients are extremely sensitive to radiation but display decreased apoptosis, as measured during the first 3 days following radiation. To explain this apparent contradiction, we examined apoptosis in normal and A-T cells at late time points following radiation, under the assumption that radiation-induced apoptosis is delayed in the A-T cells. METHODS AND MATERIALS: Blood cells and lymphoblastoid cell lines from A-T patients, as well as healthy donors, were irradiated with X-rays. Apoptosis was measured at different time points (up to 7 and 30 days for lymphocytes and lymphoblastoid cells, respectively) using a flow cytometric method based on the reduction of intracellular DNA content (sub-G1 population). RESULTS: Compared to normal cells, CD4 and CD8 A-T lymphocytes displayed constantly reduced levels of radiation-induced apoptosis for up to 7 days after treatment. A-T lymphoblastoid cells, however, displayed a delayed and prolonged apoptosis. CONCLUSION: A-T lymphoblastoid cells show high levels of delayed radiation-induced apoptosis, which may contribute to the high cellular radiosensitivity displayed by the A-T phenotype. ATM (the gene mutated in A-T) plays different roles in the apoptotic response to ionizing radiation in quiescent lymphocytes and proliferative lymphoblastoid cells.

Adolescent↗

PubMed2001

The crystal structure of an aldehyde reductase Y50F mutant-NADP complex and its implications for substrate binding.

In order to understand more fully the structural features of aldo-keto reductases (AKRs) that determine their substrate specificities it would be desirable to obtain crystal structures of an AKR with a substrate at the active site. Unfortunately the reaction mechanism does not allow a binary complex between enzyme and substrate and to date ternary complexes of enzyme, NADP(H) and substrate or product have not been achieved. Previous crystal structures, in conjunction with numerous kinetic and theoretical analyses, have led to the general acceptance of the active site tyrosine as the general acid-base catalytic residue in the enzyme. This view is supported by the generation of an enzymatically inactive site-directed mutant (tyrosine-48 to phenylalanine) in human aldose reductase [AKR1B1]. However, crystallization of this mutant was unsuccessful. We have attempted to generate a trapped cofactor/substrate complex in pig aldehyde reductase [AKR1A2] using a tyrosine 50 to phenylalanine site-directed mutant. We have been successful in the generation of the first high resolution binary AKR-Y50F:NADP(H) crystal structure, but we were unable to generate any ternary complexes. The binary complex was refined to 2.2A and shows a clear lack of density due to the missing hydroxyl group. Other residues in the active site are not significantly perturbed when compared to other available reductase structures. The mutant binds cofactor (both oxidized and reduced) more tightly but shows a complete lack of binding of the aldehyde reductase inhibitor barbitone as determined by fluorescence titrations. Attempts at substrate addition to the active site, either by cocrystallization or by soaking, were all unsuccessful using pyridine-3-aldehyde, 4-carboxybenzaldehyde, succinic semialdehyde, methylglyoxal, and other substrates. The lack of ternary complex formation, combined with the significant differences in the binding of barbitone provides some experimental proof of the proposal that the hydroxyl group on the active site tyrosine is essential for substrate binding in addition to its major role in catalysis. We propose that the initial event in catalysis is the binding of the oxygen moiety of the carbonyl-group of the substrate through hydrogen bonding to the tyrosine hydroxyl group.

Aldehyde Reductase↗

PubMed2001

Effects of high-density lipoprotein(2) on cholesterol transport and acyl-coenzyme A:cholesterol acyltransferase activity in P388D1 macrophages.

High-density lipoproteins are the putative vehicles for cholesterol removal from monocyte-derived macrophages, which are an important cell type in all stages of atherosclerosis. The role of HDL(2), an HDL subclass that accounts for most variation in plasma HDL-cholesterol concentration, in cholesterol metabolism in monocyte-derived macrophages is not known. In this study, the dose-dependent effects of HDL(2) on cellular cholesterol mass, efflux, and esterification, and on cellular cholesteryl ester (CE) hydrolysis using the mouse macrophage P388D1 cell line was investigated. HDL(2) at low concentrations (40 microg protein/ml) decreased CE content without affecting cellular free cholesterol content (FC), CE hydrolysis, or cholesterol biosynthesis. In addition, HDL(2) at low concentrations reduced cellular acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity and increased FC efflux from macrophages. Thus, HDL(2) has two potential roles in reverse cholesterol transport. In one, HDL(2) is an acceptor of macrophage FC. In the other, more novel role, HDL(2) increases the availability of macrophage FC through the inhibition of ACAT. Elucidation of the mechanism by which HDL(2) inhibits ACAT could identify new therapeutic targets that enhance the transfer of cholesterol from macrophages to the liver.

Animals↗

PubMed2001

Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells.

A novel regulator of G-protein signaling (RGS) has been isolated from a highly purified population of mouse long-term hematopoietic stem cells, and designated RGS18. It has 234 amino acids consisting of a central RGS box and short divergent NH(2) and COOH termini. The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. Mouse RGS18 is expressed from a single gene and shows tissue specific distribution. It is most highly expressed in bone marrow followed by fetal liver, spleen, and then lung. In bone marrow, RGS18 level is highest in long-term and short-term hematopoietic stem cells, and is decreased as they differentiate into more committed multiple progenitors. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. Purified RGS18 interacts with the alpha subunit of both G(i) and G(q) subfamilies. The results of in vitro GTPase single-turnover assays using Galpha(i) indicated that RGS18 accelerates the intrinsic GTPase activity of Galpha(i). Transient overexpression of RGS18 attenuated inositol phosphates production via angiotensin receptor and transcriptional activation through cAMP-responsive element via M1 muscarinic receptor. This suggests RGS18 can act on G(q)-mediated signaling pathways in vivo.

Amino Acid Sequence↗

PubMed2001

High and low levels of cottontail rabbit papillomavirus E2 protein generate opposite effects on gene expression.

The papillomavirus E2 protein plays an important role in viral transcriptional regulation and replication. We chose to study the cottontail rabbit papillomavirus (CRPV) E2 protein as a transcriptional regulator because of the availability of an animal model for papilloma formation, which may be relevant for human papillomavirus (HPV) infection and replication. We studied the effect of expression levels of E2 on the long control region, which contains transcriptional promoter and enhancer elements, and synthetic E2-dependent artificial promoters in which the E2 was the dominant factor in the transcriptional activation. These experiments indicated that high levels of E2 were inhibitory and low levels were stimulatory for transactivation. In addition, we showed that the complex formed between CRPV E2 and the cognate binding site was less stable than the complex formed between HPV E2 and the same cognate binding site. Furthermore, we showed that CRPV E2 binding to its transcriptional regulatory sequence was stabilized by other proteins such as E1, which produced increments in transcriptional activation of E2-dependent genes. The data may be used to define conditions in which the rabbit model can be used for the screening of drugs which are inhibitory to the HPV and CRPV replication and gene expression.

Animals↗

PubMed2001

CD55 is over-expressed in the tumour environment.

CD55 is a protein that protects cells from complement-mediated attack. 791Tgp72 is an antigen which has been used successfully as a target for both tumour imaging and cancer vaccines. 791Tgp72 has recently been identified as CD55. Quantitative expression of CD55 in the tumour environment was therefore studied. Tumour cells showed a 4-100-fold increase in CD55 cell surface expression when compared to normal cells. Immunohistochemical staining of colorectal tumours also revealed high expression of CD55 in the stroma. To examine the source of this stromal CD55 the ability of both epithelial cells and endothelial cells to produce extracellular CD55 was measured. Tumour cell lines deposit CD55 into their extracellular matrix (ECM) in direct proportion to their cell surface expression. In contrast the ECM from HUVEC cells contained large amounts of CD55 despite expressing low levels of CD55 on their cell surface. Furthermore expression of CD55 on HUVEC cells was increased by exposure to VEGF. Although it remains unclear why CD55 is upregulated in the tumour environment its high level of expression on tumour cells and associated endothelium may explain why it is a good target for both imaging and immunotherapy.

Antigens, Neoplasm↗

PubMed2001

Hoxa-9 represses transforming growth factor-beta-induced osteopontin gene transcription.

Smad2 and Smad3 are downstream transforming growth factor-beta (TGF-beta) signaling molecules. Upon phosphorylation by its type I receptor, Smad2 or Smad3 forms a complex with Smad4 and translocates to the nucleus where the complex activates target gene transcription. In the present study, we report that Smad3 binds directly to the osteopontin (OPN) promoter and that Smad4 interacts with the Hox protein and displaces it from its cognate DNA binding site in response to TGF-beta stimulation. In gel shift assays, the glutathione S-transferase-Smad3 fusion protein was found to bind to a 50-base pair DNA element (-179 to -229) from the OPN promoter. Also, we found that both Hoxc-8 and Hoxa-9 bound to a Hox binding site adjacent to Smad3 binding sequence. Interestingly, Smad4, the common partner for both bone morphogenic protein and TGF-beta signaling pathways, inhibited the binding of Hox protein to DNA. FLAG-tagged Smad4 coimmunoprecipitated with HA-tagged Hoxa-9 from cotransfected COS-1 cells, demonstrating an interaction between Smad4 and Hoxa-9. Transfection studies showed that Hoxa-9 is a strong transcriptional repressor; it suppresses the transcription of the luciferase reporter gene driven by a 124-base pair OPN promoter fragment containing both Smad3 and Hox binding sites. Taken together, these data demonstrate a unique TGF-beta-induced transcription mechanism. Smad3 and Smad4 exhibit different functions in activation of OPN transcription. Smad3 binds directly to the OPN promoter as a sequence-specific activator, and Smad4 displaces the transcription repressor, Hoxa-9, by formation of Smad4/Hox complex as part of the transcription mechanism in response to TGF-beta stimulation.

Animals↗

PubMed2001

Overproduction of perlecan core protein in cultured cells and transgenic mice.

Heparan sulphate proteoglycan (HSPG) and amyloid P component are the only macromolecules consistently associated with all varieties of amyloid, irrespective of the type of amyloid protein, suggesting that HSPG may play a pathogenetic role in amyloid formation through a common mechanism. In the case of Alzheimer's disease (AD), HSPG, such as perlecan, co-accumulates with amyloid-beta protein (Abeta), a main constituent of amyloid plaques, and paired helical filaments (PHFs). Additionally, in vitro, HSPG accelerates both Abeta fibril and PHF formation and protects Abeta from degradation. Therefore, this study first established lines of P19 mouse embryonic carcinoma cells stably carrying an expression vector encoding the complete perlecan core protein (approximately 400 kD). In the cell lysates, overexpressed perlecan was identified as an approximately 400 kD protein without glycosaminoglycan side-chains, while in the media, secreted perlecan was mostly glycosylated, suggesting that the secretion and glycosylation of perlecan are coupled. Next, transgenic mice were produced using the same expression vector. Marked perlecan overexpression occurred in the cytoplasm of multiple tissues including the brain, heart, kidney, and pancreas, without a discernible increase of perlecan in extracellular matrices. The transgenic mice up to 18 months of age did not develop amyloid or AD-like pathology in the brain or elsewhere, based on histochemical and immunohistochemical analyses. Thus, overproduction of perlecan core protein is insufficient to lead to amyloidosis and AD-like pathology.

Alzheimer Disease↗

PubMed2001

Proteomic analysis of human skin fibroblasts grown on titanium: novel approach to study molecular biocompatibility.

Despite the growing use of titanium as an implant material, there is a lack of consensus on what constitutes the molecular basis of its biocompatibility. In the present study we compared the response of skin fibroblasts to two different growth supporting surfaces: commercially pure titanium (cpTi) and tissue culture polystyrene (TCPS). Proteins from extracts of whole cells and adsorbed serum were separated and identified by 2-dimensional gel electrophoresis. In all, 40 proteins (46 spots) were identified by matrix-assisted laser desorption/ionization and mass spectrometry, database searching, immunoblotting, running a standard, or a combination of these techniques. Many of the proteins collected from the two surfaces were found to derive from the serum used in the culture medium. The surface properties of titanium appeared to promote the formation of a more concentrated carpet of serum proteins. Several proteins from bovine or human serum, such as albumin, alpha2-HS-glycoprotein, alpha-fetoprotein, plasminogen, thrombospondin 1, and serotransferrin, along with a few unidentified serum components, were found to adsorb onto cpTi in comparatively high concentrations. The adsorption of serum proteins did not appear to be selective on either substrate. We found that among the major cellular proteins, fibronectin and a cytoskeletal protein (non-muscle myosin heavy chain type A) were expressed at lower levels by fibroblasts grown on cpTi compared to TCPS. By analyzing the changes in the entire proteome of cells in response to different growth substrates, we may gain a better understanding of the molecular basis of biocompatibility.

Animals↗

PubMed2001

Characterization of the execution pathway of developing motoneurons deprived of trophic support.

Avian spinal motoneurons have been well characterized with regard to developmental programmed cell death (PCD). Approximately 50% of the neurons originally generated undergo cell death as they innervate their target muscles, and target derived trophic support plays an important role in regulating survival of these neurons. To investigate events mediating motoneuron PCD, we have examined the role of Bcl-2 family proteins, cytochrome C, and caspase-9 in this process. We report that while protein levels of Bcl-2, Bcl-xL, and Bax do not change within motoneurons as they become committed to die, a translocation of Bax from the cytosol to organelle membranes and the nucleus occurs coincident with the time when motoneurons become committed to cell death. In addition, cytochrome C is released from mitochondria to the cytosol in dying cells prior to the activation of caspases. Consequently, an enhanced caspase-9-like activity was detected in dying cells, and this activity was upstream and necessary for the appearance of a caspase-3-like activity. These results allow us to further define some of the critical events that mediate the execution phase of motoneuron death following trophic factor deprivation.

Animals↗

PubMed2001

Identification of an inward rectifier potassium channel gene expressed in mouse cortical astrocytes.

These experiments identify an inward rectifier K+ (Kir) channel expressed in mouse cortical and white matter astrocytes at the molecular level. Messenger RNA for one of the known Kir channel genes, Kir4.1, is present at much higher levels in cortical astrocytes in primary culture than the other known Kir family members. In culture, the level of Kir4.1 mRNA is lower in proliferating cells and in cells cultured for 16 h under hypoxic conditions, compared to confluent cells. Partial differentiation of the astrocytes with dibutyryl cAMP or by coculture with neurons has no effect on the Kir4.1 mRNA level. In situ hybridization experiments show that Kir4.1 mRNA is broadly distributed in the adult brain, including the neocortex, the stratum pyrimadale of the hippocampus, and the piriform cortex. Immunostaining confirms that the Kir4.1 protein is expressed by cultured astrocytes and also by cocultured cortical neurons. Astrocytes and neurons display a patchy pattern of immunostaining, raising the possibility that the channels sort themselves in clusters in the plasma membrane. Stellate cells in the neocortex and white matter are immunoreactive for Kir4.1, and double immunofluorescence experiments show colocalization of Kir4.1 and glial acidic fibrillary protein (GFAP) on stellate cells in the white matter. The cloned mouse Kir4.1 cDNA, when expressed heterologously in HEK cells, gives rise to inactivating Kir channels similar to those recorded from cultured astrocytes. These results indicate that the Kir4.1 gene product forms a Kir channel, or is a subunit of the channel, in mouse cortical astrocytes both in culture and in vivo.

Animals↗

PubMed2001

Regional-dependent intestinal absorption and meal composition effects on systemic availability of LY303366, a lipopeptide antifungal agent, in dogs.

Low oral bioavailability and a negative meal effect on drug plasma levels motivated studies on formulation and meal composition effects on the absorption of LY303366, a poorly water-soluble, semisynthetic, cyclic peptide antifungal drug. Solid drug particle size and meal composition studies were evaluated in beagle dogs. Canine regional absorption studies were also carried out utilizing surgically implanted intestinal access ports, and Caco-2 studies were performed to evaluate drug candidate intestinal permeability. Particle size and Caco-2 data indicate that drug permeability limitations to absorption are more important than dissolution rate limits. Caco-2 cell-associated LY303366 approached 10% of incubation concentration that is in the range of the oral bioavailability of the drug. Canine regional absorption studies showed that the extent of LY303366 absorption following duodenal administration was similar to that following oral administration. Significantly lower drug plasma levels were obtained following administration through a colonic access port, a result consistent with poor membrane permeation. Administration of drug with meals of mixed composition, as well as simple fat and protein meals, resulted in significant reductions in AUC(0-48h) compared with results from fasted dogs. In contrast, carbohydrate meals did not reduce drug plasma levels compared to controls. Intravenous pretreatment with devazepide, a cholecystokinin (CCK) antagonist that blocks canine biliary secretion, did not reverse the negative effect of the fat meal on LY303366. Taken together, the results from the present study suggest that membrane-permeability-limited absorption is the cause of the observed regionally dependent absorption of LY303366 in the dog and that the observed negative meal effects depend on composition but are independent of biliary secretion.

Anidulafungin↗

PubMed2001

Investigation of the applicability of a sequential digestion protocol using trypsin and leucine aminopeptidase M for protein identification by matrix-assisted laser desorption/ionization--time of flight mass spectrometry.

An investigation of the applicability of a sequential digestion procedure involving endo- and exoprotease digestion of proteins is reported. The procedure involves the digestion of a protein sample with trypsin, yielding peptide fragments characteristic of the protein. The resulting mixture of peptide fragments is then subjected to N-terminal sequencing with leucine aminopeptidase M (LAP), with matrix-assisted laser desorption ionization-time of flight mass spectrometric analysis of the various digestion products. Several proteins in solution, as well as gel extracted proteins were subjected to this sequential enzyme digestion procedure. The results of these experiments reveal that LAP will preferentially cleave specific peptides of the trypsin digested sample with high efficiency, while leaving other peptides undigested. Also, the length of the amino acid sequence tags that can be generated with this method is limited; the longest sequence tag generated from a single tryptic peptide was four amino acids, even though the digestion was allowed to proceed for long times. In the experiments, N-terminal digestion products were detected as early as two minutes, or as late as 90 minutes, following the addition of LAP to the sample. The method was shown to be effective for subpicomole starting quantities of protein, although with some loss in digestion efficiency at lower concentrations of starting material. This method is useful in providing additional sequence information to increase the level of confidence in protein identification, as illustrated in the identification of bacterial proteins fractionated by high-performance liquid chromatography. In some instances, this method can provide additional sequence information where post source decay and nanospray mass spectrometry failed to generate fragment ion spectra. This is illustrated in an example where the procedure was applied to a membrane protein, CD9, that had been isolated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Although the sequential digestion procedure requires more human intervention, it is a straightforward method and can be readily implemented.

Cell Line↗

PubMed2001

Zebrafish mutants: behavioral genetic studies of visual system defects.

Zebrafish are a promising model for behavioral and genetic studies of vertebrate visual system development and retinal degeneration. In the past few years, numerous studies on zebrafish vision have been published. While most of the studies focus on the molecular and cellular characterization of mutations that disrupt zebrafish visual system structure in early development, others examine the mechanisms that underlie inherited visual system disorders in adults. Behavioral assays, along with morphologic and electrophysiological methods, are powerful tools for functional analyses of zebrafish visual development and performance.

Animals↗

PubMed2001

Role of astrocytes in trimethyltin neurotoxicity.

Although the neurotoxicity of trimethyltin (TMT) is well known, mechanisms are still not clear. Glia have been proposed to mediate the toxic action of TMT on nerve cells. Accordingly, the effects of TMT were tested in primary neuronal cultures from rat cerebellum and compared to effects in astrocytes and mixed cultures. Neuronal damage observed following TMT exposure was less in the presence of astrocytes and astrocytes alone were resistant to TMT. Thus, astrocytes have a protective effect against TMT-induced neurotoxicity. TMT caused an oxidative stress in granule cell cultures involving a variety of oxidative species (O2)*-, H2O2, NO), but astrocytes were less sensitive to TMT-induced oxidative species generation. Antioxidants, glutathione and 7-nitroindazole attenuated neuronal cell death induced by TMT. It appears that oxidative stress mediates a large part of the destructive action of TMT in neuronal cultures. The presence of astrocytes appears to modulate TMT-induced oxidative stress so that TMT causes only a small increase in lipid peroxidation in mouse brain after systemic administration. Thus, TMT induces a pronounced oxidative stress in cultured neurons, but when astrocytes are present, oxidative species play a lesser role in the neurotoxic action of TMT.

Animals↗