Effect of Cigarette Smoke Exposure and Mutant Kras Overexpression on Pancreatic Cell Proliferation

Pancreatic cancer is the fourth leading cause of cancer‑associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRasG12D) in the pancreas as well as wild‑type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure decreased cell proliferation in pancreatic ductal and acinar cells, and had no effect in islet cells. Cigarette smoke did not affect pancreatic protein levels of tumor necrosis factor (TNF)α, p53, or cyclin D1, but mutant Kras overexpression slightly decreased TNFα and p53 protein levels. Therefore, pancreatic cell proliferation in mice overexpressing mutant Kras is associated with the later development of pancreatic tumors, but effects of cigarette smoke on pancreatic cell proliferation do not provide a good model for human pancreatic carcinogenesis

The Role of NF-κB in PPARα-Mediated Hepatocarcinogenesis

In this review, the role of NF-κB in the induction of hepatocarcinogenesis by peroxisome proliferators is examined. The administration of peroxisome proliferators for more than a three-day period leads to the activation of NF-κB in the livers of rats and mice. On the other hand, peroxisome proliferator activated receptor-α (PPARα) activation in non-hepatic tissues can lead to the inhibition of NF-κB activation. Several lines of evidence support the hypothesis that the activation of NF-κB by peroxisome proliferators in the liver is mediated by oxidative stress. The role of NF-κB in peroxisome proliferator-induced hepatocarcinogenesis has been examined using NF-κB knockout models. Specifically, the induction of cell proliferation and the promotion of liver carcinogenesis are inhibited in mice lacking the p50 subunit of NF-κB. Overall, the activation of NF-κB appears to be important in the carcinogenic activity of peroxisome proliferators

Suppression of Peroxisomal Enzyme Activities and Cytochrome P450 4A Isozyme Expression by Congeneric Polybrominated and Polychlorinated Biphenyls

The purpose of this study was to determine the effects of PCBs and PBBs on peroxisome proliferator-activated receptor-α-(PPARα-) associated enzyme activities or protein levels. Male Sprague-Dawley rats were administered a single IP injection (150 μ mol/kg) of either 3,3′,4,4′-tetrabromobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, 3,3′,5,5′-tetrabromobiphenyl, 2′,3,3′,4,5-pentachlorobiphenyl, 3,3′,4,4′,5-pentachlorobiphenyl, 2,2′,3,3′,5,5′-hexachlorobiphenyl, or 3,3′,4,4′,5,5′-hexabromobiphenyl in corn oil (10 ml/kg). One week later, the activities of catalase, peroxisomal fatty acyl-CoA oxidase, and peroxisomal beta-oxidation as well as cytochrome P450 4A (CYP4A) protein content were determined in subcellular liver fractions. None of the peroxisomal enzyme activities were significantly increased by any of the halogenated biphenyl congeners tested. Except for minor (approx. 25%) increases in the total CYP4A content following treatment with 2,2′,3,3′,5,5′-hexachlorobiphenyl and 3,3′,5,5′-tetrabromobiphenyl, CYP4A protein contents were not increased by any treatment. The two Ah receptor agonists, 3,3′,4,4′-tetrabromobiphenyl and 3,3′,4,4′,5-pentachlorobiphenyl, significantly diminished the liver content of CYP4A proteins and activities of the peroxisomal enzymes studied. Since a range of congeners with different biologic and toxicologic activities were selected for this study, it may be concluded that the polyhalogenated biphenyls do not induce peroxisome proliferation in the male rat, but rather certain members of this class of compounds down regulate peroxisome-associated enzymes. Since PCBs and PBBs do not increase enzyme activities and expression of proteins associated with PPARα, these agents are therefore exerting their carcinogenic and promoting activities by some other mechanism

Effect of Dietary Selenium and Cigarette Smoke on Pulmonary Cell Proliferation in Mice

The objective of this study was to determine if dietary selenium could inhibit pulmonary cell proliferation in control and cigarette smoke-exposed female A/J mice. Selenium in the form of sodium selenite was supplemented to purified diets similar to the AIN-93M diet to yield 0.15, 0.5, or 2.0 mg selenium/kg diet. After 3 weeks, mice in each dietary group were divided into two subgroups; one used as control, whereas the other was exposed to cigarette smoke for five consecutive days. Mice from both groups were euthanized 3 days later. Mice were administered bromodeoxyuridine in the drinking water starting 5 days before the initiation of the smoke exposure and continuing until they were euthanized. After euthanasia, the left lung lobe was processed for histology and cell proliferation analysis. Cigarette smoke increased cell proliferation in the terminal bronchioles and large airways, but not in alveoli. High-selenium diets inhibited cell proliferation in the alveoli, terminal bronchioles and large airways areas in both control and smoke-exposed mice. Increasing the dietary selenium level led to increased selenium levels in the blood and lung, and increased glutathione peroxidase (GPx) activity in the lung. Cytochrome P-450 1A1 protein levels in the lung were increased by cigarette smoke but were not affected by dietary selenium. It is concluded that dietary selenium inhibits pulmonary cell proliferation in both control and cigarette smoke-exposed mice, indicating that selenium is inhibiting cell proliferation independently of smoke exposure, and that this inhibition may be related to selenium concentration and GPx activity in the lung

The effect of dietary glycine on the hepatic tumor promoting activity of polychlorinated biphenyls (PCBs) in rats

The wall inside the arcade of the sahn (courtyard), showing a doorway; Ahmed's mosque (also known as the Blue Mosque) was placed in the heart of the city on a site containing the ruins of the Byzantine Great Palace and facing the Hippodrome to the west. It confronted at a distance of some 200 m to the north the most venerated and important mosque in the capital, the converted church of Hagia Sophia. With its six minarets and its semi-domes cascading on four axes, the mosque represents the ultimate evolution of the imperial Ottoman mosque after two centuries of linear development. The exterior arcading of the mosque and courtyard walls, the massing of semi-domes and the four tall and two shorter minarets provide an indelible architectural impression, which marks growing Ottoman architectural self-confidence vis-à-vis Hagia Sophia and contrasts strikingly with the Byzantine church. Source: Grove Art Online; http://www.groveart.com/ (accessed 1/22/2008