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At least 451 records · Page 25Linked to original sources
PubMed1994

Overexpression of the tyrosine phosphatase PTP1B is associated with human ovarian carcinomas.

OBJECTIVE: Our purpose was to determine whether protein tyrosine phosphatase 1B is overexpressed in ovarian cancers, possibly altering the balance of intracellular tyrosine phosphorylation. STUDY DESIGN: The expression of protein tyrosine phosphatase 1B was assayed in frozen sections from 54 human ovarian carcinomas and seven normal ovaries by immunochemical staining with monoclonal antibody AE4-2J, which is specific for protein tyrosine phosphatase 1B. The expression of protein tyrosine phosphatase 1B-specific messenger ribonucleic acid in tumors was determined by Northern analysis. The results were analyzed statistically by means of Fisher's exact test. RESULTS: Minimal staining was observed in normal ovarian epithelium. In contrast, 43 of 54 (79.6%) tumors displayed increased protein tyrosine phosphatase 1B expression, which is statistically associated with malignancy. Overexpression was associated with the expression of the p185c-erbB-2, p170EGFR, and p165mCSFR growth factor receptor protein tyrosine kinases. Protein tyrosine phosphatase 1B messenger ribonucleic acid expression was inconsistently increased in tumor cells. CONCLUSION: Increased expression of protein tyrosine phosphatase 1B in ovarian cancers that also express protein tyrosine kinases suggests that protein tyrosine phosphatase 1B may play a role in the growth regulation of ovarian cancers.

Female↗
PubMed1994

Coordinate expression of urinary-type plasminogen activator and its receptor accompanies malignant transformation of the ovarian surface epithelium.

OBJECTIVE: Because elevated expression and cell surface association of urinary-type plasminogen activator have been linked to invasive potential in certain tumor types, we examined the expression of urinary-type plasminogen activator and urinary-type plasminogen activator receptor in ovarian epithelial carcinoma tissues and cells as compared with normal ovarian epithelium. STUDY DESIGN: Monoclonal antibodies specific for urinary-type plasminogen activator and urinary-type plasminogen activator receptor were used for immunohistochemical staining of tissues and cells to assess expression of these antigens in frozen sections of normal and tumor tissue. Substrate zymography was used to detect plasminogen activator activity in ovarian carcinoma ascites and in conditioned media of cultured cells, whereas a Western blot assay was used to identify urinary-type plasminogen activator receptor in cultured cells. RESULTS: Normal ovarian epithelium expressed urinary-type plasminogen activator receptor (4/4 positive) but little or no urinary-type plasminogen activator (0/4 positive), whereas epithelial ovarian carcinomas frequently expressed urinary-type plasminogen activator (4/8 positive) in conjunction with urinary-type plasminogen activator receptor (7/9 positive). High levels of urinary-type plasminogen activator were detected in 15 of 19 samples of ascites. DOV 13, OVCA 420, OVCA 429, OVCA 432, and OVCA 433 cell lines secreted urinary-type plasminogen activator in variable quantities, whereas normal ovarian epithelial cells did not secrete any detectable plasminogen activator. Urinary-type plasminogen activator receptor had similar levels of expression in all cancer cell lines and normal ovarian epithelium. CONCLUSION: Overexpression of urinary-type plasminogen activator is associated with malignant transformation of the ovarian epithelium. Increased cell surface proteolysis mediated by urinary-type plasminogen activator bound to cell surface urinary-type plasminogen activator receptor may contribute to metastatic behavior in ovarian carcinoma.

Carcinoma↗
PubMed1994

The p53 tumor suppressor gene frequently is altered in gynecologic cancers.

Mutation of the p53 tumor suppressor gene, often accompanied by overexpression of mutant p53 protein, is the most frequent molecular genetic event described thus far in human cancers. In adenocarcinomas of the ovary and endometrium, p53 overexpression is seen in approximately 10% to 15% of early and 40% to 50% of advanced cancers. Similar to many other types of human cancers, ovarian and endometrial cancers that overexpress p53 protein contain mutations in conserved regions of the p53 gene. These mutations are predominantly transitions, which suggests that they arise spontaneously rather than being caused by carcinogen exposure. Alteration of the p53 gene does not appear to be a feature of endometrial hyperplasias or benign or borderline ovarian tumors. Although mutation and overexpression of p53 rarely occur in cancers of the cervix, vulva, and vagina, it has been shown that human papillomavirus E6 oncoproteins bind to and inactivate p53 protein. Studies of the p53 gene have begun to provide insight into the molecular pathogenesis of gynecologic cancers.

Adenocarcinoma↗
PubMed1996

Preoperative evaluation of macrophage colony-stimulating factor levels in patients with endometrial cancer.

OBJECTIVE: Our purpose was to examine the relationship between preoperative serum levels of macrophage colony-stimulating factor, alone and in combination with CA 125, and the presence of prognostic clinicopathologic factors and subclinical metastases in women with endometrial cancer. STUDY DESIGN: Ninety-two women who underwent primary exploration for endometrial adenocarcinoma had preoperative serum samples evaluated for macrophage colony-stimulating factor and CA 125 levels. Multivariate analysis was used to determine the associations of surgicopathologic findings with macrophage colony-stimulating factor and CA 125 levels. Logistic regression analysis was used to identify factors associated with the risk of extrauterine disease. The association of macrophage colony-stimulating factor and CA 125 levels with stage, grade, and depth of myometrial invasion and histologic characteristics were analyzed with Fisher's two-tailed exact test. RESULTS: Elevated levels of macrophage colony-stimulating factor were not associated with depth of myometrial invasion, histologic grade, or histologic cell type; however, advanced stage (p = 0.02) and the presence of lymph node metastases (p = 0.04) were associated with elevated levels. Sensitivity and specificity of macrophage colony-stimulating factor for predicting extrauterine disease were 42% and 89%, respectively. If either an elevated macrophage colony-stimulating factor or an elevated CA 125 level was used to predict extrauterine disease, the sensitivity was increased to 67% but the specificity was decreased to 78%. Macrophage colony-stimulating factor elevations predicted lymph node metastases with a sensitivity of 50% and a specificity of 86%. A multivariate regression model showed CA 125 to be the most significant predictor of extrauterine disease; macrophage colony-stimulating factor also contributed prognostic information (p = 0.02). The sensitivity and specificity of the multivariate model for predicting extrauterine disease were 75% and 73%, respectively. CONCLUSION: Macrophage colony-stimulating factor and CA 125 are neither sensitive nor specific enough to be used as predictors of the presence or absence of extrauterine disease in patients with endometrial cancer.

Adenocarcinoma↗
PubMed2002

The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids.

Phloretin is a dihydrochalcone flavonoid that displays a potent antioxidant activity in peroxynitrite scavenging and the inhibition of lipid peroxidation. Comparison with structurally related compounds revealed that the antioxidant pharmacophore of phloretin is 2,6-dihydroxyacetophenone. The potent activity of 2,6-dihydroxyacetophenone is due to stabilisation of its radical via tautomerisation. The antioxidant pharmacophore in the dihydrochalcone phloretin, i.e., the 2,6-dihydroxyacetophenone group, is different from the antioxidant pharmacophores previously reported in flavonoids.

Acetophenones↗
PubMed2003

Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation.

When an antioxidant scavenges a reactive species, i.e., when it exerts its antioxidant activity, the antioxidant is converted into potentially harmful oxidation products. In this way, the antioxidant quercetin might yield an ortho-quinone, denoted as QQ, which has four tautomeric forms, i.e., the ortho-quinone and three quinonmethides. We evaluated the interaction of QQ with ascorbate or glutathione (GSH). Ascorbate recycles QQ to the parent compound quercetin, while GSH forms two adducts with QQ, i.e., 6-GSQ and 8-GSQ. When both GSH and ascorbate are present, QQ is converted exclusively into GSQ. In the absence of GSH, protein thiols will be arylated by QQ. This protein arylation is not prevented by ascorbate. Thiol arylation by quinones and quinonmethides can impair several vital enzymes. This implies that the product formed when quercetin displays its antioxidant scavenging effect is toxic in the absence of GSH. Therefore, an adequate GSH level should be maintained when quercetin is supplemented.

Antioxidants↗
PubMed2001

No reduction of alpha-tocopherol quinone by glutathione in rat liver microsomes.

The cell membrane is protected against lipid peroxidation by endogenous antioxidants such as vitamin E (alpha-tocopherol). The oxidised form of alpha-tocopherol (alpha-tocopherol quinone) does not have this antioxidant function. However, the literature indicates that alpha-tocopherol quinone can be reduced to alpha-tocopherol in vivo and thereby will add to the total antioxidant potential (Moore AN, Ingold KU. Free Radic Biol Med 1997;22:931-4). We found that GSH (reduced glutathione) did not mediate the reduction of alpha-tocopherol quinone, either directly in solution or in rat liver microsomes fortified with alpha-tocopherol quinone. This renders GSH a less likely candidate for alpha-tocopherol quinone reduction in vivo. In addition, alpha-tocopherol quinone did not enhance GSH-dependent protection against lipid peroxidation, either in control microsomes, or in vitamin E-extracted microsomes. Indeed, alpha-tocopherol quinone blocked GSH-dependent protection against lipid peroxidation in vitamin E-extracted microsomes. This indicates that alpha-tocopherol quinone can act as a pro-oxidant.

Animals↗
PubMed1998

Influence of iron chelation on the antioxidant activity of flavonoids.

The antioxidant activity of flavonoids is believed to be caused by a combination of iron chelation and free radical scavenging activities. Several authors have attempted to separate the iron chelation and scavenging activity of flavonoids in order to study these processes individually. There are, however, several contradictions in the literature, and the outcome largely depends on the experimental conditions and the type of assay used. In order to investigate the contribution of iron chelation to the antioxidant activity of flavonoids, we determined the antioxidant activity of a group of flavonoids from several subclasses in an iron-independent (azobisamidinopropane, [ABAP]) lipid peroxidation (LPO) process and compared them with data from an iron-dependent (Fe2+/ascorbate) LPO process, which we determined earlier. These LPO data were compared with oxidation potentials, which were earlier found to have a good correlation with the scavenging activity of flavonoids. For most flavonoids, it was found that there was no difference between the LPO assays, indicating that iron chelation is either a constant factor among the flavonoids or is not significant in these types of assays. The IC50 values in the iron-independent LPO assay showed an excellent correlation with the oxidation potentials (Ep/2). Therefore, it can be concluded that for the majority of flavonoids tested, iron chelation does not play a role in the antioxidant activity in microsomal lipid peroxidation.

Amidines↗
PubMed2000

Tyrosine as important contributor to the antioxidant capacity of seminal plasma.

A novel post-addition method, based on the trapping of ABTS-radicals, is applied for studying the total antioxidant capacity of seminal plasma. A remarkable profile is observed, in which seminal plasma quenches radicals in a continuous, relatively slow fashion. Five putative antioxidants present in seminal plasma were studied using the same assay. Some of the compounds such as ascorbic acid, alpha-tocopherol and uric acid exert immediate, fast radical trapping, whereas hypotaurine and tyrosine give rise to the same slow radical trapping curve as seminal plasma. Due to this slow, continuous radical trapping, quantification of the total antioxidant capacity (expressed as trolox equivalent antioxidant capacity, TEAC) strongly depends on the chosen time point after onset of radical trapping. When determined during the slow antioxidant trapping phase, tyrosine has a powerful antioxidant capacity, which in combination with its relatively high plasma concentration makes it an important contributor to the total antioxidant capacity of seminal plasma.

Amidines↗
PubMed2001

Hypochlorous acid is a potent inhibitor of GST P1-1.

Glutathione S-transferase is a phase II detoxification enzyme that can be inactivated by H(2)O(2). During oxidative stress various other reactive oxygen species are generated that are more reactive than the relatively stable H(2)O(2). Hypochlorous acid (HOCl) is a powerful oxidant which is highly reactive towards a range of biological substrates. We studied the influence of HOCl on the activity of GST P1-1. HOCl inhibits purified glutathione S-transferase P1-1 in a concentration dependent manner with an IC(50)-value of 0.6 microM, which is more than 1000 times as low as IC(50) reported for H(2)O(2). HOCl lowered the V(max) value, but did not affect the K(m) for CDNB. Our results show that HOCl is a potent, non-competitive inhibitor of GST P1-1. The relevance of this effect is discussed.

Dose-Response Relationship, Drug↗
PubMed2003

Superoxide dismutase: the balance between prevention and induction of oxidative damage.

Cu,Zn-superoxide dismutase (SOD1) has been shown to be effective in several free radical mediated diseases, although some studies have pointed toward SOD1 toxicity at a high concentrations. In the present study, the balance between prevention and induction of damage by SOD1 has been investigated both in vitro and in vivo. In vitro superoxide was generated using xanthine/xanthine oxidase. In vivo superoxide was generated using the redox cycling compound doxorubicin. Furthermore, we determined the pharmacokinetics of lecithinized SOD1 (PC-SOD) in order to compare the results obtained in vivo with those obtained in vitro. It was found that in vitro high concentrations of SOD1 induce hydroxylation of coumarin 3-carboxylic acid (3-CCA). This could be caused by a peroxidative action of SOD1 or formation of the highly reactive hydroxyl radicals. Any signs of toxicity are absent in vivo because these concentrations are not reached. It can be concluded that SOD1 possesses a large therapeutic window and application of SOD1 or its derivatives for strengthening the body's defenses against oxidative stress in a variety of pathologies seems safe.

Animals↗
PubMed1986

The effects of 4-hydroxy-2,3-trans-nonenal on beta-adrenoceptors of rat lung membranes.

Lung membranes are susceptible to oxygen radicals, formed during inflammation, redox cycling of toxic agents, exposition to ozon etc. Oxygen radicals may modify the beta-adrenergic response. However, at the same time beta-adrenoceptors of the lung are frequently addressed in therapy. We embarked upon this problem by studying the effects of the aldehyde 4-hydroxy-2,3-transnonenal (HNE), one of the major products of lipid peroxidation, on the density of beta-adrenoceptors of rat lung membranes. It is shown, that the physiological important sulfhydryl blocking agent HNE inactivates the beta-adrenoceptors in a time- and concentration dependent (0.5-2.5 mM) way, indicated by a decrease in (-)-[3H]dihydroalprenolol (DHA) binding to lung membranes. Moreover, it is shown that combined treatment of HNE with (-)-isoproterenol (0.5 microM) or 1-alprenolol (0.5-10 nM) does not influence the extent of inactivation of beta-adrenoceptors by HNE. This is in contrast with previous studies, conducted with other, synthetic, sulfhydryl blocking agents, such as N-ethylmaleimide (NEM), suggesting that an other mechanism of inactivation is involved upon HNE treatment.

Aldehydes↗
PubMed1998

Capsaicin treatment induces muscarinic hyperreactivity in guinea pig trachea: a warning.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a widely used tool for the depletion of neuropeptides from sensory C-fibres. Upon capsaicin treatment tachykinins are released, resulting in a variety of responses in the airways. We showed that after capsaicin (0.3 microM; 30 min) treatment of guinea pig tracheal smooth muscle preparations, the maximal contraction of the trachea after methacholine stimulation was strongly increased (capsaicin: 1.147 +/- 0.050 g vs. control: 0.717 +/- 0.047 g). This effect was completely nullified after pretreatment with capsazepine (2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3, 4,5-tetrahydro-1H-2benzazepine; a vanilloid receptor antagonist) and YM38336 (a dual tachykinin NK1 and tachykinin NK2 receptor antagonist). Our results serve as a warning against using capsaicin as a putatively clean pharmacological tool to deplete the neuropeptides from pools on the C-fibres because we showed that capsaicin also strongly influences basal mechanisms in tracheal smooth muscle control.

Animals↗
PubMed2000

Flavonoids can replace alpha-tocopherol as an antioxidant.

Endogenous antioxidants such as the lipid-soluble vitamin E protect the cell membranes from oxidative damage. Glutathione seems to be able to regenerate alpha-tocopherol via a so-called free radical reductase. The transient protection by reduced glutathione (GSH) against lipid peroxidation in control liver microsomes is not observed in microsomes deficient in alpha-tocopherol. Introduction of antioxidant flavonoids, such as 7-monohydroxyethylrutoside, fisetin or naringenin, into the deficient microsomes restored the GSH-dependent protection, suggesting that flavonoids can take over the role of alpha-tocopherol as a chain-breaking antioxidant in liver microsomal membranes.

Animals↗
PubMed2003

Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore.

The presumed protective effect of folic acid on the pathogenesis of cardiovascular, hematological and neurological diseases and cancer has been associated with the antioxidant activity of folic acid. Peroxynitrite (PON) scavenging activity and inhibition of lipid peroxidation (LPO) of the physiological forms of folate and of structurally related compounds were tested. It was found that the fully reduced forms of folate, i.e. tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MTHF), had the most prominent antioxidant activity. It appeared that their protection against LPO is less pronounced than their PON scavenging activity. The antioxidant activity of these forms of folic acid resides in the pterin core, the antioxidant pharmacophore is 4-hydroxy-2,5,6-triaminopyrimidine. It is suggested that an electron donating effect of the 5-amino group is of major importance for the antioxidant activity of 4-hydroxy-2,5,6-triaminopyrimidine. A similar electron donating effect is probably important for the antioxidant activity of THF and 5-MTHF.

Animals↗
PubMed1986

Elevated serum concentrations of CA-125 in patients with advanced endometriosis.

CA-125 is a high-molecular-weight glycoprotein that is expressed on the cell surface of some derivatives of embryonic coelomic epithelium. Based on results of an immunoradiometric assay developed to detect CA-125 in peripheral blood, 82% of patients with ovarian cancer and less than 1% of apparently healthy controls have elevated peripheral blood levels of CA-125. Because endometriotic lesions are likely to be derivatives of embryonic coelomic epithelium, the authors investigated serum CA-125 levels in patients with endometriosis. Preoperative serum CA-125 concentrations were measured in 147 patients undergoing diagnostic laparoscopy or laparotomy. Serum CA-125 concentrations were elevated in patients with stage III or IV endometriosis, compared with controls with negative diagnostic laparoscopies (66.5 +/- 14.5 versus 8.20 +/- 0.59 U/ml, mean +/- standard error of the mean; P less than 0.001). Fifty-four percent of patients with stage III or IV endometriosis and 0% of the controls had CA-125 levels greater than 35 U/ml. Occasional patients with stage II endometriosis (13%), leiomyomata uteri (14%), and chronic pelvic inflammatory disease (5%) also had serum CA-125 concentrations greater than 35 U/ml. Immunocytochemical techniques demonstrated the presence of CA-125 on the cell surface of endometriotic lesions.

Adolescent↗
PubMed2001

Psychological job demands as a risk factor for common cold in a Dutch working population.

OBJECTIVE: We investigated the effect of Psychological Job Demands (PJD) on the occurrence of the clinical symptoms of common cold. METHODS: Subjects, participating in a large prospective cohort study on psychological determinants of fatigue at work, were asked to fill in a questionnaire on the occurrence of common cold during the previous four months. High PJD were considered as a potential risk factor. Other factors such as age, gender, and having young children were considered as potential confounders. RESULTS: In logistic regression analysis, the adjusted odds ratio (OR) for having a recent cold in subjects reporting high PJD vs. those reporting low PJD was 1.20 (95% confidence interval (CI), 1.08-1.33). A higher risk emerged among those with young children (OR, 1.70; 95% CI, 1.47-1.96), those having a history of asthma (OR, 1.69; 95% CI, 1.28-2.22), or being under the age of 40 (OR, 1.28; 95% CI, 1.14-1.43) and among smokers (OR, 1.23; 95% CI, 1.09-1.38). CONCLUSION: The results support an association between PJD and common cold. In spite of the almost inevitable shortcoming of a large cohort study using questionnaires, this study gave us the opportunity to study the relationship between common cold and work-related factors in a nonexperimental setting with participants observed in a natural environment with all the normal everyday hassles.

Adult↗