Role of superoxide dismutase in ischemic brain injury: reduction of edema and infarction in transgenic mice following focal cerebral ischemia.
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Animals↗
Biomedical subjects
S F Chen
Publications and source records attributed to S F Chen.
XB596, a promising bis-naphthalimide anti-cancer agent.
We have synthesized a promising class of bis-naphthalimide anti-tumor agents. A representative compound in this series, XB596, exhibits potent in vitro growth inhibitory activity against several human and murine leukemic and solid tumor lines in culture, with IC50 values ranging from 7.2 to 147.5 nM. XB596 was almost as equally growth inhibitory against three doxorubicin-resistant cell lines compared with their parental lines. Using a human tumor colony-forming assay, XB596 demonstrated cytocidal activity against fresh human tumors taken directly from patients, with 23 of 25 evaluable tumors responding to a continuous exposure of 1 microgram/ml of XB596. When L1210 cells were incubated with XB596 for 1 h, the incorporation of uridine and thymidine into RNA and DNA, respectively, was inhibited with IC50 values of 0.14 microM. DNA single-strand breaks, but not double-strand breaks, were detected in XB596-treated L1210 cells. XB596 bound to DNA with guanine-cytosine sequence selectivity as shown by an indirect ethidium bromide displacement assay. XB596 was shown to interact with DNA by a spectrophotometric titration assay, with an estimated binding constant of 4.7 +/- 2.2 +/- 10(6) M-1. XB596 unwound supercoiled DNA as measured by agarose gel electrophoresis. These data are consistent with XB596 being a DNA intercalator. In vivo, XB596 demonstrated good anti-tumor activity against two human solid tumors (DLD-2 colon adenocarcinoma and MX-1 mammary carcinoma) xenografted in nude mice, but has not demonstrated anti-leukemic activity. In summary, XB596 is a pre-clinical anti-cancer agent which interacts with DNA and demonstrates good in vivo anti-tumor activity against human solid tumor xenografts.
Animals↗
The unique immunosuppressive activity of brequinar sodium.
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Animals↗
Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium.
The novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline- carboxylic acid sodium salt) was shown previously to be an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme of the de novo pyrimidine biosynthetic pathway. Brequinar sodium inhibits the activity of this enzyme isolated from mammalian sources only but not those forms isolated from yeast or bacteria, which also use ubiquinone as the cofactor. Brequinar sodium also does not inhibit the activity of a soluble Zymobacterium oroticum dihydroorotate dehydrogenase which uses NAD+ as a cofactor. Brequinar sodium inhibits L1210 dihydroorotate dehydrogenase with mixed inhibition kinetics with respect to either the substrate (dihydroorotate) or the cofactor (ubiquinone Q6) with Ki' values in the 5-8 nM range. Our results suggest that brequinar sodium inhibits dihydroorotate dehydrogenase by binding to the enzyme at a unique site that is distinct from the dihydroorotate or the ubiquinone-binding site. This binding site appears to be unique to the mammalian enzyme, because brequinar sodium does not inhibit the yeast, Escherichia coli, or Z. oroticum forms of the enzyme.
Animals↗
Edema, cation content, and ATPase activity after middle cerebral artery occlusion in rats.
BACKGROUND AND PURPOSE: Reduction of cerebral blood flow results in several acute metabolic disturbances, including a reduction in Na,K-ATPase activity. The relation between this reduction and the onset of edema is unknown, as is the effect of restoration of blood flow. Therefore, we investigated the role of decreased Na,K-ATPase activity in the pathogenesis and time course of ischemic brain edema and reperfusion. METHODS: The middle cerebral arteries of rats were occluded by cannulation with a nylon suture for 30, 60, 120, or 240 minutes. The animals were then decapitated (permanent occlusion) or the suture was withdrawn to allow 24 hours of reperfusion before decapitation (temporary occlusion). Na,K-ATPase activity and Na+, K+ and water contents were measured at various intervals. RESULTS: In the ischemic hemisphere, Na,K-ATPase activity was significantly decreased at 30, 60, 120, and 240 minutes of permanent occlusion (p less than 0.05). There was also a significant decrease in rats subjected to 60 or 120 minutes of temporary occlusion followed by 24 hours of reperfusion. Water content increased after 60, 120, or 240 minutes of permanent occlusion (p less than 0.01); after 24 hours of reperfusion, water content remained elevated (p less than 0.01). The Na+ content increased after both permanent and temporary occlusion, and the K+ content decreased only after permanent occlusion. Increases in water content correlated with decreases in Na,K-ATPase activity after temporary occlusion and with the Na+:K+ ratio after permanent occlusion. CONCLUSION: Reduction in Na,K-ATPase activity resulting in disruption of cellular ionic homeostasis may account for early development of cytotoxic brain edema after permanent occlusion of the middle cerebral artery. Such edema is also present 24 hours after 60 and 120 but not 30 minutes of temporary occlusion.
Animals↗
[Low social economic status family and child maltreatment].
The purpose of the present research was to develop child abuse potential inventories as a screening tool. The sample was 248 families who were all financially supported by Chinese Children's Fund. Kaohsiung Family Helper. One of the inventories selected, that was translated into Chinese by the expert committee, was the Child Abuse Potential Inventory developed by Milner. The internal consistency and test-retest reliabilities obtained by this research were as good as Milner's and basic interpretation of four factors was found to be was consistent with Milner's data. The other inventory developed by the expert committee was the Child Abuse Potential Interview used by social workers to interview caretakers. Having completed the questionnaire social workers rated 15 items, i.e. immaturity, lack of parenting skills, unrealistic expectancy, social isolation, unresolved affective needs, abused experiences, crisis, substance abuse etc. The coefficients of correlation between these two inventories were 0.20-0.37, respectively, which indicated that these inventories assessed abuse potential trait and uniqueness. Therefore, these inventories were considered both highly applicable.
Adolescent↗
Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase.
Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischemia and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemia. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgenic mice bearing the human SOD1 gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were significantly decreased in transgenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemic hemisphere, but levels in surrounding cortex and striatum were significantly higher in transgenic mice than in nontransgenic mice. These results indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the pathogenesis of infarction and edema following focal cerebral ischemia.
Animals↗
Cold-induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn-superoxide dismutase.
It has been proposed that oxygen-derived radicals, superoxide in particular, are involved in the alteration of blood-brain barrier permeability and the pathogenesis of brain edema following trauma, ischemia, and reperfusion injury. Using transgenic mice that overexpress the human gene for copper-zinc-superoxide dismutase, we studied the role of superoxide radicals in the blood-brain permeability changes, edema development, and delayed infarction resulting from cold-trauma brain injury. At 2 hours after a 30-second cold injury, cerebral water and Evans blue contents were reduced, respectively, from 80 +/- 0.2% and 132.7 +/- 12.9 micrograms/gm of dry weight for nontransgenic mice to 78.5 +/- 0.3% and 87.1 +/- 9.9 micrograms/gm of dry weight for transgenic mice. Infarction, as measured by 2,3,5-triphenyltetrazolium chloride staining, was reduced by 52% in transgenic brains. These data indicate that an increased level of superoxide dismutase activity in the brain reduces the development of vasogenic brain edema and infarction. Superoxide radicals play an important role in the pathogenesis of these lesions in cold-traumatized brain.
Animals↗
Chunking during serial learning by a pigeon: III. What are the necessary conditions for establishing a chunk?
What are the minimal conditions for the formation of chunks by a pigeon learning an arbitrary list? Experiment 1 compared the acquisition of two types of chunkable list (each composed of colors and achromatic geometric forms): A----B----C----D'----E' (or A'----B'----C'----D----E) and A----B----C'----D'----E' (or A'----B'----C----D----E). The first type of list was acquired more rapidly than the second. On both lists, however, evidence of chunking did not emerge until the four-item phase of training (e.g., pauses at the end of one category of list item). In Experiment 2, chunking was shown to occur on four-item lists in which colors and forms were segregated (A----B----C'----D' and A'----B'----C----D), but not on lists in which the two types of items were interspersed (A----B'----C'----D and A'----B----C----D'). As in Experiment 1, evidence of chunking (pauses at chunk boundaries) did not appear until the fourth item was added.
Animals↗
Chunking during serial learning by a pigeon: II. Integrity of a chunk on a new list.
Can a group of items that a pigeon chunks on one list function as such on a second list? In Experiment 1, the ordinal position of the chunk was held constant across both lists. Following training on a list of colors and achromatic geometric forms (A----B----C----D'----E'), the integrity of the color chunk [A----B----C] was maintained on a list of five colors (A----B----C----F----G) even though the basis for establishing that chunk was eliminated. The integrity of the chunk [A----B----C] was also maintained on a new list of colors and forms (A----B----C----D*----E*). In Experiment 2, the ordinal position of a chunk established on list1 (A----B----C'----D') was changed on list 2. As shown by positive transfer between lists 1 and 2, the integrity of the chunks [A----B] and [C'----D'] was maintained on lists X'----A----B----Y' and X'----C'----D'----Y', respectively. Conversely, the heterogeneous list X'----B----C'----Y' took longer to learn than the original list.
Animals↗
Serial learning by rhesus monkeys: I. Acquisition and retention of multiple four-item lists.
Two rhesus monkeys were trained to learn eight 4-item lists, each composed of 4 different photographs. Lists were trained in successive phases: A, A----B, A----B----C, and A----B----C----D. After List 4, retention, as measured by the method of savings, was, on average, 66% (range: 44-84%). Indeed, all 4 lists could be recalled reliably during a single session with neither a decrement in accuracy nor an increase in the latency of responding to each item. Response latencies on a subset test employing all possible 2- and 3-item subsets of each 4-item list support the hypothesis that monkeys form linear representations of a list. Latencies to Item 1 of a subset varied directly with the position of that item in the original list. On List 1, latencies to Item 2 varied directly with the number of intervening items between Item 1 and Item 2 in the original list. During the acquisition of Lists 5-8, both Ss mastered the A----B and A----B----C phases of training in the minimum number of trials possible.
Animals↗
Phosphatidylcholine transfer protein from porcine liver.
A phosphatidylcholine transfer protein (PC-TP) of porcine liver was purified to exhibit transfer activity similar to that of bovine liver but with different structural properties. By using hydrophobic Phenyl-agarose column as the last purification step, a 1400-fold purification with 20% yield was attained. Comparative studies on the effects of pH, salt, and temperature on the phosphatidylcholine transfer activity revealed that PC-TP from porcine and bovine livers were similar as far as its activity is concerned. However, the amino acid compositions, the molecular weight, and the elution profiles during protein purification for the two proteins are markedly different. It is suggested that the amino acid composition of PC-TP could be significantly altered without changing its activity and specificity.
Amino Acids↗
Structure-activity relationship of quinoline carboxylic acids. A new class of inhibitors of dihydroorotate dehydrogenase.
The novel anticancer drug candidate brequinar sodium [DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt] inhibits dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine biosynthetic pathway leading to the formation of UMP. Sixty-nine quinoline 4-carboxylic acid analogs were analyzed as inhibitors of L1210 dihydroorotate dehydrogenase. This structure-activity relationship study identified three critical regions of brequinar sodium and its analogs, where specific substitutions are required for the inhibition of the activity of dihydroorotate dehydrogenase. The three principal regions are: (i) the C(2) position where bulky hydrophobic substituents are necessary, (ii) the C(4) position which has a strict requirement for the carboxylic acid and its corresponding salts, and (iii) the benzo portion of the quinoline ring with appropriate substitutions. These results will be useful in the elucidation of the precise nature of the interaction between brequinar sodium and dihydroorotate dehydrogenase.
Animals↗
Polyamine accumulation and vasogenic oedema in the genesis of late delayed radiation injury of the central nervous system (CNS).
Polyamine (PA) accumulation has been associated with blood-brain barrier (BBB) disruption and vasogenic oedema after cold injury. PAs and water content were measured in a rat spinal cord model of late-delayed radiation injury and were found to be elevated at paralysis. The elevated PA levels could be significantly reduced by treatment with difluoromethylornithine (DFMO). In unirradiated rats DFMO reduced putrescine to undetectable levels after 10-12 weeks. These data suggest that blockade of PA synthesis may be useful in treating the vasogenic oedema of radiation injury and may improve CNS radiation tolerance.
Animals↗
Liposome-entrapped superoxide dismutase ameliorates infarct volume in focal cerebral ischaemia.
We studied the role of superoxide radicals in the pathogenesis of focal ischaemic brain injury using liposome-entrapped copper-zinc-superoxide dismutase which can penetrate the blood-brain barrier and cell membranes efficiently. Superoxide dismutase activities were significantly elevated in the blood and in the normal brain tissue 1, 2, 8, and 24 hours after a bolus intravenous administration of liposome-entrapped copper-zinc-superoxide dismutase. Copper-zinc-superoxide dismutase activities were also increased significantly in the ischaemic hemisphere and the contralateral cortex as well. The infarct sizes were reduced by 33%, 24% and 18%, respectively, for the anterior artery area, middle artery area, and posterior artery area by treatment at 24 hours following the injection of liposome-entrapped superoxide dismutase. These data demonstrate that superoxide radicals are important determinants of the size of an infarct following focal cerebral ischaemia, and that liposome-entrapped copper-zinc-superoxide dismutase may have pharmacological value for focal cerebral ischaemic injury.
Animals↗
Attenuation of glutamate-induced neuronal swelling and toxicity in transgenic mice overexpressing human CuZn-superoxide dismutase.
The role of oxygen-derived free radicals, superoxide in particular, in the pathogenesis of neuronal cell death induced by glutamate was studied using primary culture cortical neurons from transgenic mice overexpressing human CuZn-superoxide dismutase. Primary cortical neuron cultures were developed form 15-day-old fetuses of both transgenic mice and their normal littermates. Both human CuZn-superoxide dismutase and host mouse CuZn-superoxide dismutase activities in cultured neurons were identified by native gel electrophoresis followed by nitroblue tetrazolium staining. Cultured neurons grown for 10-12 days in vitro were exposed briefly to 0.5 mM glutamate for 5 minutes, followed by biochemical and morphological examinations at 2 and 4 hours. Our data have demonstrated that glutamate neurotoxicity is significantly reduced in transgenic neurons at 2 and 4 hours following exposure to glutamate, as measured by the intracellular 3-0-methyl glucose space, the efflux of lactate dehydrogenase, and by phase-contrast and bright-field trypan blue staining. These data indicate that transgenic neurons containing two- to threefold the normal amount of CuZn-superoxide dismutase activity are protected against glutamate neurotoxicity in vitro. Our results suggest that oxidative stress play an important role in glutamate-induced neuronal swelling and toxicity.
3-O-Methylglucose↗
Phospholipase A2-induced lung edema and its mechanism in isolated perfused guinea pig lung.
Lung injury induced by phospholipase A2 (PLA2, 0.046 IU/ml perfusate) was studied in a continuous weighing system of isolated perfused guinea pig lungs. The results revealed that lung weight increased progressively during the 30-min perfusion of PLA2. No change of pulmonary arterial pressure was observed in the same period. Albumin permeability-surface area product, lung index, lung water content, exudate from pleura, and angiotensin-converting-enzyme activity increased significantly at the end of 30 min PLA2 perfusion. p-Bromophenacyl bromide, a PLA2 inhibitor, may block the above changes nearly completely. The effects of inhibitors of cyclooxygenase (indomethacin, IM), lipoxygenase (diethylcarbamaxine, DE), and platelet-activating factor (SRI 63-441) on PLA2-induced lung injury were also studied. We found: (1) PLA2 may induce high permeability lung edema. The role of endothelial injury in the permeability change remains to be further investigated. (2) DE ameliorated lung injury significantly within 10 min of PLA2 treatment but showed no effect after 15 min. IM ameliorated lung injury during the whole experimental period. SRI 63-441 had no effect. It is suggested that PLA2 may damage lung by inducing products of cyclooxygenase and lipoxygenase besides its direct effect.
Acetylcholinesterase↗
[Studies on the spirocompounds: synthesis of 10-methyl spiro [4.5]dec-6-en-6-carboxylic acid].
3-Methyl-cyclohexenone 4 spiroannulates with 1, 4-dibromobutane in NaNH2/NH3 or t-BuOK/benzene to afford not only the main monospiro compounds 5a and 5b but also the dispiro compounds 6a and 6b. The title compound 11 was synthesized from 5 through the following steps: Catalytic hydrogenation of the spiro olefinic compounds, addition of trimethylsilycyanide to the carbonyl group, hydrolysis of the siloxyl ether, dehydration of the cyanohydrin and hydrolysis of the cyano group.
Anesthetics↗