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Biomedical subjects

M R Quinn

Publications and source records attributed to M R Quinn.

At least 19 recordsLinked to original sources
PubMed1999

Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 production is inhibited by taurine chloramine in rat C6 glioma cells.

Taurine monochloramine (Tau-Cl) is formed through the actions of a halide-dependent myeloperoxidase system associated with polymorphonuclear leukocytes (PMN). Tau-Cl inhibits production of inflammatory mediators by activated macrophages, and PMN. Recently, Tau-Cl was shown to inhibit production of nitric oxide and prostaglandin E2 by activated C6 glioma cells. Since chemokines, secreted by activated glial cells, play a prominent role in eliciting inflammatory responses in the central nervous system, the effects of Tau-Cl on production of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were determined in activated C6 glioma cells. Tau-Cl inhibited production of MCP-1 and MIP-2 in a concentration-dependent manner, and was most potent against MCP-1. Tau-Cl exerted a transient inhibition of the temporal expression of MCP-1 and MIP-2 mRNAs during the first 4 h of activation. Although both chemokine mRNA levels were similar to those of control cells after 8-24 h of activation, production of the chemokine proteins, especially MCP-1, remained markedly low. These results suggest that Tau-Cl inhibits production of MCP-1 and MIP-2 in activated C6 cells primarily through post-transcriptional mechanisms.

Animals↗
PubMed1998

Taurine chloramine inhibits production of nitric oxide and prostaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclooxygenase-2 expression.

Taurine prevents tissue damage in various models of inflammation through a mechanism postulated to involve taurine monochloramine (Tau-Cl). Tau-Cl is formed through the action of a halide-dependent myeloperoxidase system associated with polymorphonuclear leukocytes (PMN), eosinophils, and basophils. Production of nitric oxide (NO), PGE2, and other proinflammatory mediators by activated macrophages is inhibited by Tau-Cl. Since glial cells may be activated to produce NO, PGE2 and other proinflammatory mediators, similar to macrophages, we examined the effects of Tau-Cl on the production of NO and PGE2 by rat C6 glioma cells. C6 cells were seeded to grow over 2-3 days to approximately 90% confluency before exposure to various concentrations of Tau-Cl in HBSS for 2 h (37 degreesC, 5% CO2). The HBSS was replaced, after washing the cells, with DMEM containing 4% fetal calf serum and activators (LPS, 10 microgram/ml; rat rIFN-gamma, 50 U/ml; and human rTNF-alpha, 50 ng/ml). Media content of NO2- and PGE2 was measured 48 h after activation and cell lysates were subjected to SDS-PAGE followed by Western blot analyses to determine the relative expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. Media accumulation of NO2- and PGE2 was inhibited by Tau-Cl in a concentration dependent manner and this was accompanied by decreased amounts of iNOS and COX-2 proteins in cell lysates. Additional experiments determined the effects of Tau-Cl on the kinetics of iNOS and COX-2 mRNA expression. Expression of iNOS mRNA was markedly inhibited in activated C6 cells that were previously exposed to Tau-Cl and this persisted for at least 24 h. In contrast, inhibition of COX-2 mRNA expression was only transiently reduced in Tau-Cl exposed cells during the first 4 h of activation and was relatively unimpaired thereafter (8-24 h). These results suggest that Tau-Cl inhibits the transcriptional expression of the iNOS gene but inhibits expression of COX-2 protein by post-transcriptional mechanisms.

Animals↗
PubMed1997

Preactivation exposure of RAW 264.7 cells to taurine chloramine attenuates subsequent production of nitric oxide and expression of iNOS mRNA.

Recent studies demonstrate that taurine chloramine (Tau-Cl) inhibits production of nitric oxide (NO) and other proinflammatory mediators in cultured macrophages when added to the media at the time of activation. Because Tau-Cl may react with various media constituents and it is difficult to measure Tau-Cl in complex solutions, we designed experiments to more carefully control cell exposure to various chloramines and NaOCl. RAW 264.7 cells were exposed to 1 mM of NaOCl, Tau-Cl, or chloramine preparations of the following amino acids: L-alanine (L-Ala-Cl), beta-alanine (beta-Ala-Cl), serine (Ser-Cl), or glycine (Gly-Cl) in Hanks' balanced salt solution (HBSS) for up to 2 h (37 degrees C, 5% CO2). The HBSS solution was then replaced with complete media containing interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) for an additional 24 h before measuring cell viability. The chemical stability of NaOCl and each chloramine was evaluated after various times of preactivation exposure by measuring retention of each solution's UV absorption spectra and ability to oxidize KI. Cytotoxicity of each solution was evaluated by the maintained ability of RAW 264.7 cells to reduce MTT. Whereas Tau-Cl, beta-Ala-Cl, and Gly-Cl were stable chloramines, only Tau-Cl was not cytotoxic. L-Ala-Cl, Ser-Cl, and the highly reactive oxidant NaOCl were unstable and toxic. In further studies RAW 264.7 cells were exposed to Tau-Cl in HBSS for 2 h and the solution was then replaced with complete media containing IFN-gamma and LPS, taxol, lipoarabinomannan, or interleukin-2. Production of NO was measured 24 h later and was inhibited in activated cells that were previously exposed to Tau-Cl. Inhibition of NO production was dependent on Tau-Cl concentration and was accounted for by reduced expression of inducible nitric oxide synthase mRNA, regardless of activator combinations. These results support the idea that Tau-Cl has the potential to function as an inhibitory modulator of inflammations.

Animals↗
PubMed1996

The production of superoxide anion and nitric oxide by cultured murine leukocytes and the accumulation of TNF-alpha in the conditioned media is inhibited by taurine chloramine.

Taurine chloramine (Tau-Cl) inhibits production of nitric oxide (NO) by activated peritoneal macrophages and attenuates accumulation of tumor necrosis factor-alpha (TNF-alpha) in the culture media, similar to that previously reported for activated RAW 264.7 cells. In addition, the effect of Tau-Cl and taurine on superoxide anion (O2-) production in murine peritoneal exudate polymorphonuclear leukocytes (PMN) was examined. Tau-Cl inhibited O2- production in a manner that was dose-dependent and reversible. Taurine also inhibited O2- production by stimulated PMN, but at higher concentrations and to a lesser extent than Tau-Cl. The effects of taurine on O2- production was attributed to the in vitro formation of Tau-Cl catalyzed by PMN associated halide-dependent myeloperoxidase. In contrast, production of NO by activated peritoneal macrophages and accumulation of TNF-alpha in the media was inhibited by Tau-Cl while taurine was without effect. These data lend support to the notion that Tau-Cl may participate in the inflammatory response by modulating production of inflammatory mediators.

Animals↗
PubMed1996

Taurine chloramine inhibits prostaglandin E2 production in activated RAW 264.7 cells by post-transcriptional effects on inducible cyclooxygenase expression.

Taurine chloramine (Tau-Cl) was recently demonstrated to inhibit production of nitric oxide and tumor necrosis factor-alpha (TNF-alpha) by activated macrophages. Since increased production of prostaglandin E2 (PGE2), a reaction catalyzed by induction of cyclooxygenase-2 (COX-2), is also associated with the inflammatory response, we determined the effects of Tau-Cl on PGE2 production and on expression of COX-2 protein and COX-2 mRNA in activated RAW 264.7 cells, a murine macrophage-like cell line. Tau-Cl inhibited production of PGE2 in a concentration dependent manner with an IC50 of 0.4 mM. The decrease in PGE2 production was largely accounted for by decreased expression of COX-2 protein. Although the kinetics of COX-2 mRNA expression was altered in Tau-Cl treated cells, mRNA expression appeared to be quantitatively unimpaired. These results suggest that Tau-Cl affects the post-transcriptional regulation of COX-2 expression and support the idea that Tau-Cl may function as an inhibitory modulator of the inflammatory response.

Animals↗
PubMed1995

Lead inhibits Ca(2+)-stimulated nitric oxide synthase activity from rat cerebellum.

Pb2+ is reported to cause cognitive dysfunctions in children and to inhibit long-term potentiation (LTP), a model form of synaptic plasticity that involves nitric oxide (NO). Since Pb2+ interacts with Ca(2+)-calmodulin, and brain nitric oxide synthase (NOS) is Ca(2+)-calmodulin regulated, we examined the effects of Pb2+ on NOS activity prepared from rat cerebellum. NOS required NADPH and was inhibited by monomethylarginine. Full NOS activity required 0.6 microM free Ca2+ and was inhibited 50% by 17 nM and 100% by 80 nM free Pb2+. NOS inhibition by Pb2+ was reversible by increasing free Ca2+ concentrations. Evaluation of other divalent cations resulted in the following ranked order of potencies: Cu2+ > Pb2+ >> Zn2+; Fe2+, Ba2+, Mg2+, Mn2+, and Sr2+ were ineffective. These results suggest that Pb2+ inhibition of brain NOS activity may account for some of the effects of Pb2+ on the CNS.

Animals↗
PubMed1995

Taurine chloramine inhibits production of nitric oxide and TNF-alpha in activated RAW 264.7 cells by mechanisms that involve transcriptional and translational events.

We previously reported that taurine chloramine (Tau-Cl) inhibits the production of both nitric oxide and TNF-alpha by activated RAW 264.7 cells. The current studies were conducted to gain insight into the mechanisms through which Tau-Cl exerts these effects. RAW 264.7 cells were activated by LPS (10 micrograms/ml) and rIFN-gamma (50 U/ml) in the absence or presence of either 0.8 mM Tau-Cl or taurine. Production of NO and TNF-alpha by RAW 264.7 cells was monitored: NO was measured spectrophotometrically as nitrite and TNF-alpha was measured by ELISA. Cell lysates were analyzed for the inducible form of nitric oxide synthase (iNOS) by Western blot analyses, and TNF-alpha and iNOS mRNAs were assessed by northern blot analyses. Tau-Cl inhibited transcription of the iNOS gene, or some earlier event in the signal transduction pathway, because iNOS protein and iNOS mRNA were undetected in lysates of cells activated in the continuous presence of Tau-Cl. In contrast, steady-state levels of TNF-alpha mRNA increased in the presence of Tau-Cl to at least the same extent as that in untreated activated cells and persisted for a longer period of time. Metabolic labeling experiments demonstrated that Tau-Cl inhibited translation of TNF-alpha mRNA because the presence of the presecretory 26-kDa form and the secreted 17-kDa form of TNF-alpha were greatly reduced in lysates and culture media, respectively, of cells activated in the presence of Tau-Cl. Inhibition of TNF-alpha synthesis by Tau-Cl is not the result of a generalized effect on protein synthesis because the amount of radiolabeled protein precipitated from metabolically labeled cells by TCA was unaffected by Tau-Cl, and cell viability was unaffected. The results of these studies demonstrate that Tau-Cl decreases production of tissue-damaging inflammatory mediators and thus may act as a physiologic modulator of macrophage function.

Amino Acid Oxidoreductases↗
PubMed1995

Taurine allosterically inhibits binding of [35S]-t-butylbicyclophosphorothionate (TBPS) to rat brain synaptic membranes.

The modulatory effects of taurine on [35S]-t-butylbicyclophosphorothionate (TBPS) binding to rat brain synaptic membranes were evaluated and compared with that of GABA. Taurine allosterically inhibited TBPS binding by interacting with a bicuculline-sensitive site, similar to GABA. Taurine was as effective as GABA but less potent. The potency of taurine inhibition of TBPS binding varied among brain regions with cerebellum > olfactory bulb > cortex, similar to that of GABA. Inhibition of TBPS binding to cortical membranes measured under nonequilibrium conditions yielded a dynamic biphasic inhibition curve that was similarly shaped for GABA and taurine. The effect of taurine on TBPS binding was pharmacologically specific in that beta-alanine and guanadinoethanesulfonate were as effective as taurine, while hypotaurine and alpha-aminoethylhydrogen sulfate were only partially effective at high concentrations, and isethionic acid was without effect. Taurine, similar to GABA, enhanced the effects of pentobarbital on TBPS binding when present at concentrations that were otherwise ineffective on their own. The results of these studies support the notion that taurine interacts with the GABA recognition site of the GABAA receptor complex.

Allosteric Regulation↗
PubMed1994

Taurine protects against oxidant-induced lung injury: possible mechanism(s) of action.

It is thought that oxidant-induced tissue damage is not a direct effect of the oxidant per se, but rather results from the inflammatory response that occurs thereafter. As a result of inflammation following oxidant exposure, there are neutrophils, monocytes, and macrophages with myeloperoxidase-H2O2-halide activity in the lung. Leukocytes and especially neutrophils contain high intracellular concentrations (22-50mM) of taurine (6, 8, 11, 20). Taurine acts as a trap for toxic hypochlorous acid (HOCl) and forms the less reactive metabolite, N-chlorotaurine (5-6). Thus, the biological activity of halide-dependent myeloperoxidase may be regulated by endogenous taurine. Although taurine had no effect in the present study, polymorphonuclear leukocytes have an active myeloperoxidase system capable of producing N-chlorotaurine (9, 19) and would be present at the site of inflammation in oxidant-exposed lungs. Our data suggest that taurine via N-chlorotaurine formation may protect the lung from oxidant injury, at least in part, by inhibiting production of nitrite and TNF-alpha. Moreover, lavage cells isolated from rats pretreated with taurine and exposed to O3 have a significant decrease in the production of nitrite and TNF-alpha, compared with lavage cells from rats exposed to O3 without taurine supplementation (preliminary studies). Both the concentration of taurine and the effects of N-chlorotaurine strengthen the potential impact of this chlorinated amine in vivo. N-Chlorotaurine may protect against oxidant-induced lung injury by inhibiting production of nitrite and the release of TNF-alpha which are both known to be directly linked to tissue injury.

Amino Acid Oxidoreductases↗
PubMed1993

Taurine chloramine inhibits the synthesis of nitric oxide and the release of tumor necrosis factor in activated RAW 264.7 cells.

Taurine is present in high concentrations in most mammalian tissues, including those that prodigiously produce oxidants. Taurine protects against bronchiolar damage induced by NO2, ozone, bleomycin, and amiodarone. Taurine is chlorinated to form taurine chloramine (Tau-Cl) by the halide-dependent myeloperoxidase system and, under physiological conditions, reduces HOCl toxicity. Although NO and its metabolites, NO2- and NO3-, are thought to be major mediators of tissue damage resulting from oxidant exposure, cytokines, including tumor necrosis factor (TNF), are also involved. We examined the effects of Tau-Cl on NO production and TNF release by using RAW 264.7 cells activated with recombinant interferon-gamma (rIFN-gamma; 50 U/ml) and lipopolysaccharide (LPS; 10 micrograms/ml). NO was measured spectrophotometrically as NO2- after reaction with Griess reagent and TNF was measured by ELISA. Tau-Cl (0.5 mM) inhibits NO and TNF released into the medium by 47% and 43%, respectively. Tau-Cl is actively transported into RAW 264.7 cells by an uptake system that is energy, temperature, and Na+ dependent. Competition experiments demonstrate that the uptake system for Tau-Cl is distinct from that for taurine. In addition, the NO synthase activity of cytosolic preparations from activated RAW 264.7 cells is irreversibly inhibited by pretreatment with Tau-Cl. We demonstrate that Tau-Cl inhibits production of NO and TNF by activated macrophages and suggest a mechanism through which taurine supplementation may protect against oxidant-induced tissue damage.

Amino Acid Oxidoreductases↗
PubMed1992

Taurine allosterically modulates flunitrazepam binding to synaptic membranes.

Taurine is hypothesized to exert its inhibitory neuromodulatory effects, in part, by interaction with the GABAA receptor. Although taurine displaces GABA agonist binding to synaptic membranes, its allosteric effects on the benzodiazepine recognition site of the GABAA receptor complex is unsettled. We determined the effects of taurine on [3H]flunitrazepam (Flu) binding to well-washed, frozen-thawed synaptic membranes prepared from rat cortex. Comparative binding studies were conducted at 37 degrees C and on ice (0-4 degrees C). At 37 degrees C taurine increased Flu binding in a concentration dependent way by interaction with a bicuculline sensitive site, similar to GABA. Taurine increased Flu binding by causing a decrease in KD. The maximal effectiveness of taurine on Flu binding could not be increased further by addition of GABA. In contrast, the maximal stimulation of Flu binding by GABA was decreased by addition of taurine to the level attained by taurine alone. These mixed agonist/antagonist effects of taurine are pharmacologically specific and qualify taurine as a partial GABA agonist in this type of allosteric interaction. However, taurine causes opposite effects on Flu binding when measured at 0-4 degrees C: taurine interacts with a bicuculline insensitive site to inhibit Flu binding by increasing the KD. Taurine inhibition of Flu binding is not overcome by increasing concentrations of GABA. Although the mechanism of taurine inhibition of Flu binding at 0-4 degrees C is unclear, it may be an indirect effect of taurine interaction with membrane phospholipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Surgical treatment of posterior tibial tendon dysfunctions.

Ruptures and dysfunctions of the tibialis posterior tendon are often overlooked or misdiagnosed and can cause considerable loss of function to the patient. This article reviews the etiology, clinical as well as radiologic diagnosis, classification, and alternative surgical approaches. Case reports and photography of magnetic resonance imaging examples are included as well as a description of flexor digitorum longus tendon transfer in the treatment of this disorder.

Adult↗
PubMed1988

Influence of stereotaxically injected scrapie on neurotransmitter systems of mouse cerebellum.

The 22L strain of scrapie was injected stereotaxically into the cerebellum of C57BL/6J mice to determine its effect on several cerebellar neurotransmitter systems during the early clinical stages of the disease. In this model vacuolar lesions are restricted to the cerebellum with no evidence of vacuolization in other brain regions. Although vacuolar lesions develop throughout all cell layers of the cerebellum, they are most severe in the granule cell layer. Modest but significant (P less than 0.01) reductions in cerebellar weight, glutamate decarboxylase activity, and in the affinity of the N6-[adenine-2,8-3H]cyclohexyladenosine binding sites, were observed in scrapie affected mice. The densities of the high- and low-affinity adenosine receptors were unaffected. Adenosine receptors in the cerebellum are highly localized to the axon terminals of the glutamatergic, GABA receptive granule cells. GABA, benzodiazepine, glutamate, and muscarinic cholinergic receptors were not significantly altered. In addition, the high-affinity uptake of glutamate, and the activity of choline acetyltransferase were not significantly changed. GABA high-affinity uptake was slightly increased. Even though the granule cell layer of the cerebellum had undergone severe vacuolation, only modest neurotransmitter changes were apparent. Although these results suggest a tenuous relationship between scrapie pathology and the integrity of neurotransmitter systems, it is possible that compensatory neurochemical changes in uncompromised neuronal populations may have masked potentially specific neurotransmitter effects.

Animals↗
PubMed1986

Differentiation of a cell line from olfactory epithelium is induced by dibutyryladenosine 3',5'-cyclic monophosphate and 12-O-tetradecanoylphorbol-13-acetate.

Olfactory receptor neurons undergo continual replacement with new cells differentiating from a population of basal cells located in the olfactory epithelium. We have previously described the isolation of a cell line from murine olfactory epithelium (MOE CL1) which is now shown to be sensitive to two differentiation promoting agents, dibutyryladenosine 3',5'-cyclic monophosphate (db-cAMP) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Cells grown in the presence of db-cAMP or TPA, after a lag phase of 72-96 h, became bipolar, with long neurite-like processes. Cells conditioned for at least one passage in db-cAMP or TPA, or cells exposed to a mixture of db-cAMP and TPA, attained a bipolar morphology within 24 h. Cultures grown with db-cAMP, TPA or db-cAMP + TPA showed significant increases in the percentage of process-bearing cells. An increase in population doubling time and decrease in saturation density were also observed in cultures exposed to db-cAMP. Cells exposed to TPA continued to divide at the same rate as control cells, while those treated with db-cAMP + TPA underwent terminal differentiation. Peripheral-type benzodiazepine binding sites, which within the olfactory epithelium are localized on the receptor neurons, were present in homogenate membranes of undifferentiated cells. Cells differentiated by exposure to db-cAMP + TPA for 7 days showed a 65% increase in the density (Bmax) of peripheral-type benzodiazepine binding sites. Undifferentiated cells in control cultures showed no spontaneous changes in membrane potential or regenerative responses during current injection. Small, bipolar cells in morphologically differentiated cultures, however, were capable of generating several types of spontaneous changes in membrane potential including slow, regular oscillations; irregular, slow and fast depolarizations; and trains of action potentials.

Action Potentials↗
PubMed1986

Chloride-dependent binding sites for L-[3H]glutamate on dendrodendritic synaptosomal membranes of rat olfactory bulb.

Dendrodendritic synapses occur between granule cell dendrites and secondary dendrites of mitral cells within the olfactory bulb and are attainable in a subcellular fraction (DDS). Since the mitral cells are thought to utilize an excitatory amino acid as a neurotransmitter, we determined the pharmacologic specificity of Na+-independent L-[3H]glutamate binding to fresh membranes of DDS in 50 mM Tris-HCl, pH 7.1. Binding of L-glutamate to membranes of DDS was specific, Cl(-)-dependent, and saturable. Scatchard plots were analyzed by nonlinear regression analyses using the computer program LIGAND, and the data was best-fitted to a one-site model with KD of 0.56 +/- 0.04 microM and an apparent Bmax of 48 +/- 5 pmol/mg protein. Hill plots also indicated the presence of one site and no cooperativity (nH = 0.99 +/- 0.03). However, the relative effectiveness of several compounds in inhibiting L-glutamate binding to membranes of DDS clearly demonstrated the presence of more than one site. Electrophysiological studies suggest that 2-amino-4-phosphonobutyrate (APB) is a potent antagonist of evoked responses elicited by stimulation of mitral cell axons and that quisqualate is a potent agonist; both of these compounds were highly effective inhibitors of L-glutamate binding to DDS membranes. APB displaced about 70% of the sites labeled with 200 nM L-glutamate with a KI of 1.6 microM, whereas quisqualate inhibition of L-glutamate binding yielded a line that was curvilinear in the Scatchard plot and was resolved into two sites of relatively high affinity (KI values of 0.02 and 0.65 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobutyrates↗
PubMed1984

Decreased high-affinity binding of [3H]muscimol to cerebral synaptic membranes of scrapie-infected mice.

Scrapie is a transmissible disease that results in progressive degeneration of the central nervous system and death. Although scrapie has been studied histopathologically, relatively little is known concerning neurotransmitter alterations. Specific [3H]muscimol binding to whole brain crude synaptic membranes (CSM) from mice clinically affected with scrapie was significantly (p less than 0.01) reduced, to approximately 73% of that of the controls. Of the brain regions examined, binding to only cerebral CSM was significantly (p less than 0.0001) decreased. Scatchard analyses of saturation curves revealed that the high-affinity (KD = 8 +/- 3 nM) site for muscimol was abolished in cerebral CSM from scrapie-infected mice, while the low-affinity site was unaffected. Binding of [3H]flunitrazepam to cerebral CSM was unaffected by scrapie and was stimulated by GABA to the same extent in both scrapie and control mice. These results suggest that scrapie agent 139A in C57BL/6J mice manifests a portion of its CNS pathology via a high-affinity GABA binding site that is unassociated with the benzodiazepine receptor.

Animals↗