Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue contents of NADPH and NADP+ were measured in freeze-clamped samples of normal rat liver and in four transplantable rat hepatomas covering a wide range of growth rates. Lowry cycling procedures were employed for analysis, using alkaline extracts for NADPH and acid extracts for NADP+. The mean NADPH content in 33 normal livers was 515 nmol/g wet weight, and mean NADP+ content was 311 nmol/g wet weight. In the four hepatomas, the amounts of both NADPH and NADP+ were low, and the extent of decrease correlated with tumor growth rate. In the slowly growing hepatoma 9618A, total NADP was slightly decreased (63% control) and more extensive decreases were observed in the medium growth rate tumors 47C and 8999 (38% and 19%, respectively, of control). In the rapidly growing hepatoma 3924A, total NADP was drastically decreased to 3% of the control liver value. Measurement of NADPH and NADP+ recovery from extracts of hepatoma 3924A showed that there were no inhibitors that might have blocked the activity of the assay enzymes. The NADPH/NADP+ ratio was close to the normal liver value in all four hepatomas. A 30-sec period of ischemia did not cause significant change in NADPH, but gave 33% decrease in liver NADP+. A 5-min period of ischemia decreased NADP+ to 50% of the zero-time value in liver, and to 71% in hepatoma 3924A, but was without effect on NADPH.
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PMID:Decreased content of reduced and oxidized nicotinamide-adenine dinucleotide phosphate in rat hepatomas. 715 Oct 32

It has been suggested that the portal vein should be occluded during intermittent hepatic dearterialization in order to induce a more complete ischemia of the tumor. In this experiment the influence of portal branch ligation in combination with repeat dearterializations on a liver tumor was investigated. Twenty-seven rats were randomly allocated to sham treatment (n = 6); portal branch ligation (PBL) (n = 7); 120 min of repeat dearterialization (n = 7); and portal branch ligation (PBL) in combination with 50 min of repeat dearterialization (n = 7) (once a day during 5 days). The results showed that portal branch ligation alone did not alter the tumor growth compared with sham treatment (P > 0.05), nor did portal branch ligation in combination with repeat dearterializations for 50 min (P > 0.05). However, tumor growth delay was achieved following 120 min of repeat dearterializations without occlusion of the portal branch (P < 0.01 versus all the other groups). There was a significant weight loss of the lobe undergoing PBL, whether dearterialization was added or not (P < 0.001). The liver nucleotide/DNA and RNA/DNA ratio significantly decreased as well. Histological examination showed that > 50% of tumor cells became necrotic after repeat dearterializations for 2 hr indicating a significant damage to tumor tissue. In contrast, PBL in combination with repeat dearterializations for 50 min induced extensive liver necrosis without having any influence on tumor growth.
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PMID:Influence of portal branch ligation on the outcome of repeat dearterializations of an experimental liver tumor in the rat. 751 73

Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.
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PMID:Proposed toxic oxidant inhibitors fail to reduce brain edema. 797 65

Eradication of malignant brain tumors by in situ intratumoral, retrovirally mediated transfer of the herpes simplex virus thymidine kinase (HSVtk) gene, which sensitizes the tumor cells to ganciclovir, has recently been demonstrated in animal models. The observation that tumors studied in vitro and in animals can be completely eliminated despite only partial transduction of the tumor suggests a bystander mechanism that affects nontransduced tumor cells. Such a bystander effect is not completely understood and may represent a combination of several factors that lead to tumor eradication. Endothelial cells of the tumor blood vessels were shown to occasionally integrate the retroviral vector and thus become sensitized to ganciclovir. In the presence of vector-producer cells, which continuously release infectious viral particles, diffuse multifocal hemorrhages occurred during ganciclovir administration. When the tumor was composed of cells that had been transduced with the thymidine kinase gene before inoculation, no infectious viral particles were present within the tumor, no transduction of endothelial cells occurred, and no hemorrhages were observed during ganciclovir therapy. These observations suggest that tumor regression may be due, in part, to destruction of in vivo HSVtk-transduced endothelial cells after exposure to ganciclovir, resulting in tumor ischemia as one possible bystander mechanism. The authors investigated this hypothesis using the subcutaneous 9L gliosarcoma tumor model in Fischer rats. The tumors were evaluated with Doppler color-flow and ultrasound imaging during the various phases of the study. Twenty rats received intratumoral injections of HSVtk retroviral vector-producer cells (6 x 10(7) cells/ml) 21 days after bilateral flank tumor inoculation. Ten rats were subsequently treated with intraperitoneal ganciclovir (15 mg/kg/ml twice a day) for 14 days starting on Day 7 after producer cell injection; 10 control rats received intraperitoneal saline injections (1 ml twice a day) instead of ganciclovir. Ultrasound and flow images were obtained before cell injection, before and during ganciclovir or saline administration, and after cessation of treatment. The number, location, and ultrasonographic appearance of tumor vessels and the tumor volumes were recorded. The number of blood vessels in the tumors increased over time in both groups before treatment. Intratumoral cell injection without ganciclovir administration did not influence tumor growth or intratumoral vasculature. However, tumor vasculature decreased after initiation of ganciclovir therapy in the HSVtk-transduced tumors (p < 0.05). Early patchy or diffuse necrotic changes associated with ultrasonographic evidence of scattered intratumoral hemorrhage occurred in tumors treated with ganciclovir.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. 802 10

Breakdown of membrane phospholipids is a causative event leading to irreversible cell injury after ischemia and reperfusion insults, which might be one mechanism leading to liver tumor cell death after repeated arterial ischemia as well. After 2 hr of hepatic dearterialization followed by 30 min of reperfusion tumor phospholipid was measured chromatographically, glutathione (GSH) analyzed by determining nonprotein sulfhydryl and activity of glutathione-S-transferase (GST) determined spectrophotometrically using 1-chloro-2,4-dinitrobenzene (CDNB) as the substrate. A transient, arterial ischemia for 2 hr induced a substantial decrease of phosphatidylserine (PS) and phosphatidylinosital (PI) compared with sham treatment (P < 0.01). Although phosphatidylcholine (PC) and phosphatidylethanolamine (PE) did not significantly decline after a single arterial ischemia for 2 hr, they dropped dramatically following repeated arterial ischemia for 2 hr during 5 days (P < 0.01 and P < 0.05 respectively). GSH was depleted in tumors after both a single (P < 0.01) and repeated arterial ischemia (P < 0.05) and GST was inactivated as well (P < 0.001). By contrast, neither liver phospholipid nor liver GSH or GST was significantly changed. Tumor growth was significantly retarded in rats subjected to repeated arterial ischemia compared with sham treatment (P < 0.01). Repeated arterial ischemia facilitated degradation of tumor membrane phospholipids and induced depletion of GSH and inactivation of GST without affecting the normal liver. Thus, ischemia/reperfusion induced depletion of membrane phospholipids and of GSH might represent two mechanisms by which repeated arterial ischemia led to tumor growth delay.
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PMID:Glutathione and phospholipid depletion of liver tumors after arterial ischemia. 862

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.
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PMID:Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. 875 16

Transient hepatic arterial occlusion causes necrosis in solid hepatic tumors in the rat, but regrowth of tumor cells and capillaries takes place from the tumor periphery. It was therefore considered of interest to combine this treatment with the angiogenesis inhibitor TNP-470 (therapeutic model). Wistar rats with a dimethylhydrazine-induced adenocarcinoma implanted into the liver received one of the following treatments: TNP-470 + transient hepatic ischemia, transient hepatic ischemia alone, TNP-470 alone or sham solution alone. Rats were sacrificed one week after the start of treatment. In addition, we investigated if TNP-470 decreases the risk of tumor take in the liver after intraportal injection of viable tumor cells (adjuvant study). Transient hepatic ischemia combined with TNP-470 gave a smaller increase in tumor volume than transient hepatic ischemia (p < 0.01), TNP-470 (p < 0.001) alone or no treatment (p < 0.001). Transient hepatic ischemia or TNP-470 caused a significant suppression of tumor growth when compared to controls (p < 0.01 in both cases). In the adjuvant study, TNP-470 caused retardation of tumor growth (p < 0.01 as compared to controls) but did not affect tumor number. It is concluded that TNP-470 suppressed tumor growth, both alone and in combination with transient hepatic ischemia, but did not affect take of tumor.
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PMID:Angiogenesis inhibitor TNP-470 augments the effect of repeated arterial ischemia on growth but does not affect take in a rat liver tumor model. 925 54

Hypoxia is a pathophysiological condition that occurs during injury, ischemia, and stroke. It is characterized by a decrease of reactive oxygen intermediates and a change of the intracellular redox level. In tumors hypoxia is regarded as a trigger for enhanced growth and metastasis. Here we report that in HeLa cells, hypoxic conditions induce the transcriptional activation of c-fos transcription via the serum response element. Mutations in the binding site for the ternary complex factor Elk-1 and the serum response factor abolished this induction, indicating that a ternary complex at the serum response element is necessary for the induction of the c-fos gene under hypoxia. The transcription factor Elk-1 was covalently modified by phosphorylation in response to hypoxia. Furthermore this hyperphosphorylation of Elk-1, the activation of mitogen-activated protein kinase (MAPK), and the induction of c-fos transcripts were blocked by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase 1. An in vitro kinase assay with Elk-1 as substrate showed that MAPK is activated under hypoxia. The activation of MAPK corresponds temporally with the phosphorylation and activation of Elk-1. Thus, a decrease of the intracellular reactive oxygen intermediate level by hypoxia induces c-fos via the MAPK pathway. These results suggest that the intracellular redox levels may be directly coupled to tumor growth, invasion, and metastasis via Elk-1-dependent induction of c-Fos controlled genes.
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PMID:Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway. 928 59

Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor. Angiogenesis stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. The level of VEGF is increased in several skin disorders and is stimulated by ischemia. Tissue expansion has been shown to induce angiogenesis and ischemia on the overlying skin. We therefore investigated the hypothesis that VEGF was expressed in expanded tissue. Three samples of skin were obtained from five patients who sustained reconstruction with tissue expansion. One sample was taken on the implantation site of the expander before implantation. Two samples were taken at the time of removal, respectively, one on the nonexpanded skin adjacent to the expanded area and one on the expanded skin on the site of expansion. On these samples we performed immunolocalization of VEGF. Mouse monoclonal antibody was used, recognized with rabbit anti-mouse immunoglobulin alkaline phosphatase-anti-alkaline phosphatase (APAAP) complex conjugated and revealed with naphthol red. Our results showed clearly an increased number of cells that fixated VEGF antibody on the site of expansion. Cell counts revealed that the numbers of cells expressing VEGF were statistically higher in expanded tissue than in nonexpanded tissue. Before expansion skin specimens did not express VEGF. These findings are the first to show the presence of a growth factor in expanded tissue. They open a new field of research on the biological explanation of tissue-expanded angiogenesis.
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PMID:Vascular endothelial growth factor expression in expanded tissue: a possible mechanism of angiogenesis in tissue expansion. 946 72

The characteristics and outcomes of resected adenocarcinoma with cavity formation were studied in 7 cases, which were 14.9% of all 47 resected adenocarcinomas in the past three years. Tumor size was less than 3 cm in diameter in 3 cases, 3 to 5 cm in 2 and more than 5 cm in 2. Cavities were multiple in 4 cases and single in 3. Cavities were divided into 4 types pathologically. 1. Central necrosis type: central ischemia was suspected. This type was observed in 2 cases that died due to cancer. 2. Cancer cell lining type: the inner wall of the cavity was lined by viable cancer cells without necrosis. The cause of this type may be detachment of the central portion of a papillary growth tumor without necrosis. One of three patients died from cancer. The others are alive without recurrence. 3. Bronchial expansion type: the inner wall was composed of cancer cells and bronchus. This may be caused by ectatic change of peripheral bronchi following tumor invasion to more central bronchi. One of this type of case died due to myocardial infarction. 4. Alveolar expansion type: the inner wall was composed of cancer cells and alveoli. Detachment of destroyed alveoli or invasion along the wall of cavities of a honeycomb lung was suspected as a possible cause. One of this type of case is alive. Cavity formation can occur in adenocarcinoma even when the tumor is small. However there were few inflammatory related findings in adenocarcinoma with cavity formation. The outcome of the central necrosis type was especially poor, suggesting rapid tumor growth.
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PMID:Cavitating adenocarcinoma of the lung. 966 Sep 14


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