Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models

Trans-3,4',5-trihydroxystilbene (resveratrol), a phytoalexin present in grapes and grape products such as wine, has been identified as a chemopreventive agent. Recent studies performed with MCF-7 human breast cancer cells have demonstrated superestrogenic effects with resveratrol. In contrast, studies performed using estrogen receptor-transfected cell lines have shown that resveratrol acts as a mixed agonist/antagonist. The major objective of this study was to characterize the estrogen-modulatory effects of resveratrol in a variety of in vitro and in vivo mammary models. Thus, the effect of resveratrol alone and in combination with 17beta-estradiol (E2) was assessed with MCF-7, T47D, LY2, and S30 mammary cancer cell lines. With cells transfected with reporter gene systems, the activation of estrogen response element-luciferase was studied, and using Western blot analysis, the expression of E2-responsive progesterone receptor (PR) and presnelin 2 protein was monitored. Furthermore, the effect of resveratrol on formation of preneoplastic lesions (induced by 7,12-dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of BALB/c mice placed in organ culture. Finally, the effect of p.o. administered resveratrol on N-methyl-N-nitrosourea-induced mammary tumors was studied in female Sprague Dawley rats. As a result, in transient transfection studies with MCF-7 cells, resveratrol showed a weak estrogenic response, but when resveratrol was combined with E2 (1 nM), a clear dose-dependent antagonism was observed. Similar mixed estrogenic/antiestrogenic effects were noted with S30 cells, whereas resveratrol functioned as a pure estrogen antagonist with T47D and LY2 cells. Furthermore, in MCF-7 cells, resveratrol induced PR protein expression, but when resveratrol was combined with E2, expression of PR was suppressed. With T47D cells, resveratrol significantly down-regulated steady-state and E2-induced protein levels of PR. With LY2 and S30 cells, resveratrol down-regulated presnelin 2 protein expression. Using the mouse mammary organ culture model, resveratrol induced PR when administered alone, but expression was suppressed in the presence of E2 (1 nM). Furthermore, resveratrol inhibited the formation of estrogen-dependent preneoplastic ductal lesions induced by 7,12-dimethylbenz(a)anthracene in these mammary glands (IC50 = 3.2 microM) and reduced N-methyl-N-nitrosourea-induced mammary tumorigenesis when administered to female Sprague Dawley rats by gavage. Therefore, in the absence of E2, resveratrol exerts mixed estrogen agonist/antagonist activities in some mammary cancer cell lines, but in the presence of E2, resveratrol functions as an antiestrogen. In rodent models, carcinogen-induced preneoplastic lesions and mammary tumors are inhibited. These data suggest that resveratrol may have beneficial effects if used as a chemopreventive agent for breast cancer.     

Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl)retinamide-treated mammary tumors.

The detection of telomerase activity has been proposed as a biomarker of breast cancer development and progression. In this study, we used cell proliferation and telomerase in MNU (N-methyl-N-nitrosourea)-induced mammary carcinomas as targets for assessing the response of tumor cells to 4-(hydroxyphenyl)retinamide (4-HPR), a known inhibitor of mammary carcinogenesis in animal models and premenopausal women. In mammary tumors of rats treated for 1, 2, 4 or 6 weeks with 4-HPR, we observed that telomerase activity decreased progressively with the extension of 4-HPR administration. A marked reduction in telomerase activity was already observed by 2 weeks after treatment and the lowest level was found at 6 weeks after initiation of 4-HPR treatment. The changes in telomerase activity were preceded and accompanied by a significant decrease in the percentage of proliferating cells as evaluated by 5-bromodeoxyuridine (BrdU)-labeling. However, when the values of telomerase activity in the individual tumors were compared with the percentage of proliferating cells, no significant correlation was found. These data suggest that the decreased telomerase activity in the animals treated with 4-HPR is not a simple consequence of the changes in cell proliferation, but a more complex phenomenon involving different cellular mechanisms and pathways. The time-dependent and consistent decrease of telomerase activity in the tumors treated with 4-HPR suggests that, in addition to the percentage of proliferating cells, telomerase activity could also be used as an endpoint in breast cancer chemotherapy studies.     

Giant Asian honeybee or Bambara stings causing myocardial infarction,bowel gangrene and fatal anaphylaxis in Sri Lanka: a case series

The sting of Giant Asian honeybee (Apis dorsata) or Bambara in Sinhala and Karunge Kulavi in Tamil is a common environmental hazard in Sri Lanka known to cause immediate allergic reactions, which could be fatal in sensitized individuals. We reported myocardial infarction, bowel gangrene and fatal anaphylaxis in a prospectively proven case series and the association of these uncommon complications with delayed removal of stingers from the patients' skin.     

Regulation of Human Natural Killing

In this study we demonstrated that natural killer (NK) cell lysis by human peripheral blood nonadherent (NA) cells against K562 target cells was rapidly inhibited by four agents that inhibit the lipoxygenase pathway of arachidonic acid metabolism, nordihydroguaiaretic acid (NDGA), U-60257, alpha-phenanthroline, and esculetin. However, human NK cells activated by interferons (IFN) or poly I:C were partially resistant to suppression by NDGA and U-60257. Pretreatment of the NA cells with the four lipoxygenase inhibitors at 37 degrees C for 18 h led to suppression of NK activity. The inhibition of NK activity by NDGA was not reversed by aspirin at a concentration that inhibits PGE2 synthesis. Thus, suppression of NK activity by NDGA was not mediated by the effects on PGE2 synthesis. However, the inhibition of endogenous NK activity by NDGA, U-60257, alpha-phenanthroline, or esculetin was partially reversed by IFN or poly I:C. These results suggest that products of lipoxygenation are required for maintenance of human NK activity.     

DNA in koilocytotic dysplasia of the cervix uteri, cytophotometric studies

In koilocytotic dysplasia of the uterine cervix the DNA content in squamous cells was quantitated by cytophotometry in histological preparations stained according to Feulgen. Three patterns of DNA distribution in the squamous cells were found. In type one (21.4%) the cells had DNA content in the diploid and paradiploid zone of the histogram. In type two (35.7%) cells with triploid and tetraploid DNA values were found, but with a conspicuous modal class of cells. In type three no modal class cells were found (42.9%). The quantitative DNA changes in squamous cells show that some of the HPV induced alterations may be regarded as precancerous.     

Atheroablation with the Kensey catheter: a pathologic study

The mode of action of the Kensey catheter, a new atheroablation device, was investigated. Fresh above-the-knee amputated legs were used for recanalization of the superficial femoral artery. The variables used were identical to those of clinical trials, including a rotational speed of 50,000 rpm and an injection rate of 40 mL/min. The debris produced by the catheter was studied cytologically, and the arterial segments were examined histologically. The particle size in the debris ranged from 1 to 2,000 microns. The softer plaques produced a fine fibrin dust background with long strips of intima ranging from 10 to 2,000 microns. Complicated calcified plaques produced larger background material (10-120 microns) but smaller strips of intima (50-800 microns). Dissections and perforations occurred. Some of the debris produced by the atheroablation process was used to embolize a canine heart and kidney. Small focal infarctions were found in the heart, and large and multiple infarcts were seen in the kidney. In clinical studies the debris appears to be tolerated in the lower extremities. Its safety in the kidney and heart are questioned.     

Trends in COPD mortality and hospitalizations in countries and regions of Asia-Pacific

Background and objective: The growing burden of COPD in the Asia‐Pacific region supports the need for more intensive research and analysis of the epidemiology of COPD to raise awareness of the disease and its causes, to ensure the development of effective national health policies and to facilitate equitable deployment of finite health‐care resources in the prevention and management of COPD. This study estimated and compared COPD mortality and hospital morbidity rates and trends in these rates over time across countries and regions of Asia‐Pacific. Methods: Data consistent with standard definitions of COPD (ICD‐9/ICD‐10) for the period 1991–2004 were obtained from national health statistics agencies. For countries/regions with complete national mortality and hospitalization data (Australia, Pacific Canada (British Columbia, Hong Kong, South Korea and Taiwan), annual age‐standardized mortality and hospitalization rates were calculated for men and women aged ≥ 40 years. Negative binomial regression modelling was used to estimate rate ratios for country/region, gender and age differences and general trends over time. Results: Mortality rates per 10 000 population ranged 6.4–9.2 in men, 2.1–3.5 in women and 3.7–5.3 overall in 2003. Corresponding ranges for morbidity were 32.6–334.7, 21.2–129 and 28.1–207.3 per 10 000. Trend analysis of data since 1997 produced annual percentage changes in mortality versus hospitalization of ?4.4% versus ?0.7% in Australia, ?3.6% versus 7.5% in Pacific Canada (British Columbia), ?7.15% versus ?5.6% in Hong Kong and ?2.9% versus ?4.2% in Taiwan. Conclusions: In Asia‐Pacific, overall mortality and morbidity rates are high and trends in mortality and morbidity vary between countries/regions. Differences in rates and trends for men and women most likely reflect the different trends in historical and prevalent smoking profiles for COPD in the different countries and regions.     

Self‐other resonance,its control and prosocial inclinations: Brain–behavior relationships

Humans seem to place a positive reward value on prosocial behavior. Evidence suggests that this prosocial inclination is driven by our reflexive tendency to share in the observed sensations, emotions and behavior of others, or “self‐other resonance”. In this study, we examine how neural correlates of self‐other resonance relate to prosocial decision‐making. Subjects performed two tasks while undergoing fMRI: observation of a human hand pierced by a needle, and observation and imitation of emotional facial expressions. Outside the scanner, subjects played the Dictator Game with players of low or high income (represented by neutral‐expression headshots). Subjects’ offers in the Dictator Game were correlated with activity in neural systems associated with self‐other resonance and anticorrelated with activity in systems implicated in the control of pain, affect, and imitation. Functional connectivity between areas involved in self‐other resonance and top‐down control was negatively correlated with subjects’ offers. This study suggests that the interaction between self‐other resonance and top‐down control processes are an important component of prosocial inclinations towards others, even when biological stimuli associated with self‐other resonance are limited. These findings support a view of prosocial decision‐making grounded in embodied cognition. Hum Brain Mapp 37:1544‐1558, 2016. © 2016 Wiley Periodicals, Inc.