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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens have a variety of beneficial effects in vivo including protection against osteoporosis, coronary heart disease, Alzheimer's disease, and stroke. Similarly, antiestrogens have been shown to be effective both in treating breast cancer as well as preventing this disease. Despite the health benefits of these drugs adverse side effects have been reported including increased risk for developing certain hormone dependent cancers. Although an estrogenic mechanism likely contributes to mechanism of estrogen/antiestrogen carcinogenesis there is substantial evidence to suggest that metabolism to reactive intermediates is also involved. Both estrogens and antiestrogens can be metabolized to phenoxyl radicals, o-quinones, and semiquinone radicals, all of which could cause damage in cells either through alkylation or oxidation of cellular macromolecules including DNA. In contrast, there are several reports that estrogens and antiestrogens can act as antioxidants which could protect cells against free radical mediated damage and contribute to the beneficial effects of these compounds discussed above. The focus of this review is the role of quinoids, quinoid radicals, and phenoxyl radicals in the biological effects of estrogens and antiestrogens.
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PMID:Quinoids, quinoid radicals, and phenoxyl radicals formed from estrogens and antiestrogens. 1212 95

Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-kappaB, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1(-/-) mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumor-bearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1(-/-) mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-kappaB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-kappaB activation and induction kappaB-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-kappaB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.
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PMID:Crosstalk between PARP-1 and NF-kappaB modulates the promotion of skin neoplasia. 1507 72

We previously showed that sunlight-mimicking light induces genotoxic damage not only in skin but also even in lung, bone marrow, and peripheral blood of hairless mice. Moreover, light and smoke acted synergically in the respiratory tract. To clarify the mechanisms involved, we investigated by cDNA-arrays the expression of 746 toxicologically relevant genes in skin and lungs of mice exposed for 28 days to light and/or environmental cigarette smoke. Glutathione-S-transferase-Pi and catalase were overexpressed in the lungs of mice exposed to light only. Moreover, the light induced in skin the expression of genes involved in carcinogenesis, photoaging, and production of genotoxic and oxidizing derivatives traveling at a distance. Smoke induced the expression of multiple genes in both skin and lung, which reflect adaptive responses and mechanisms related to cancer and, possibly, to emphysema and stroke. As shown in mice exposed to both light and smoke, the light tended to increase smoke-induced gene expression in lungs, while smoke tended to attenuate light-induced gene expression in skin. The oral administration of the nonsteroidal anti-inflammatory drug sulindac inhibited the light-induced overexpression of cyclooxygenase-2 and oxidative stress-related genes in skin, and down-regulated smoke-induced genes involved in oxidative stress, removal of damaged proteins, inflammation, and immune response in lung. These results provide a mechanistic insight explaining the systemic alterations induced by both light and smoke in mouse skin and lungs.
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PMID:Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke. 1528 47

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
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PMID:Glutathione transferases. 1582 71

Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However,coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP),which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum,and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.
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PMID:Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: a review and report of personal experience. 1655 98

The generation of free radicals is a cause of many pathological conditions like diabetes mellitus, cancer, stroke, etc. Free radicals cause damage to cellular DNA and initiate carcinogenesis. Free radicals also bring about proliferation of cells via cell signaling. An inverse relationship between the consumption of vegetable diets and the risk of cancer has been established. In the present study, Star anise (Illicium verum), which is a commonly used condiment in Indian cuisine, was assessed for its anti-carcinogenic potential in N-nitrosodiethylamine (NDEA) initiated and phenobarbital (PB) promoted hepato-carcinogenesis. Rats were randomly selected for eight experimental groups. The carcinogenesis was induced by injecting the rats, with a single dose of NDEA (200mg/kg body weight) intraperitoneally as initiator, followed by promotion with PB (0.05%) in drinking water for 14 consecutive weeks. The treatment with NDEA increased liver weight, while Star anise (Star) treatment reduced the liver weight of rats. The treatment with Star throughout for 20 weeks or during the promotion stage (6-20 weeks) significantly reduced the nodule incidence and nodule multiplicity in the rats, while the treatment with Star at the initiation phase (first 4 weeks) only could not reduce these parameters. The treatment with Star for 20 consecutive weeks significantly reduced the nodule size and nodule volume. The treatment with Star throughout as well as at the promotion stage lowered the lipid peroxidation (LPO) in liver and erythrocytes, while the LPO was not lowered, when Star was administered during initiation stage only. The treatment with Star restored the liver and erythrocyte super-oxide dismutase (SOD) activities to normal in the carcinogenesis-induced rats. The liver catalase (CAT) activity increased in all the treated groups. The erythrocyte CAT activity increased in the rats treated with Star during initiation and promotion stage only. The liver glutathione (GSH) level increased significantly in the groups treated with Star. The erythrocyte GSH level was lowered in the rats treated with NDEA and PB, however, Star treatment helped in increasing the erythrocyte GSH level to some extent. The liver and erythrocyte glutathione-S-transferase (GST) activity increased in all the groups treated with NDEA and PB. The treatment with Star decreased GST level significantly. These results indicate that the treatment with Star reduces the tumor burden, lowers oxidative stress and increases the level of phase II enzymes, which may contribute to its anti-carcinogenic potential.
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PMID:Chemo-preventive effect of Star anise in N-nitrosodiethylamine initiated and phenobarbital promoted hepato-carcinogenesis. 1765 3

Aquaporins have multiple distinct roles in mammalian physiology. Phenotype analysis of aquaporin-knockout mice has confirmed the predicted role of aquaporins in osmotically driven transepithelial fluid transport, as occurs in the urinary concentrating mechanism and glandular fluid secretion. Aquaporins also facilitate water movement into and out of the brain in various pathologies such as stroke, tumour, infection and hydrocephalus. A major, unexpected cellular role of aquaporins was revealed by analysis of knockout mice: aquaporins facilitate cell migration, as occurs in angiogenesis, tumour metastasis, wound healing, and glial scar formation. Another unexpected role of aquaporins is in neural function - in sensory signalling and seizure activity. The water-transporting function of aquaporins is likely responsible for these roles. A subset of aquaporins that transport both water and glycerol, the 'aquaglyceroporins', regulate glycerol content in epidermal, fat and other tissues. Mice lacking various aquaglyceroporins have several interesting phenotypes, including dry skin, resistance to skin carcinogenesis, impaired cell proliferation, and altered fat metabolism. The various roles of aquaporins might be exploited clinically by development of drugs to alter aquaporin expression or function, which could serve as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
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PMID:Mammalian aquaporins: diverse physiological roles and potential clinical significance. 1848 62

Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer.
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PMID:Knock-out models reveal new aquaporin functions. 1909 87

It is well known that human papillomaviruses (HPVs) involve in the pathogenesis of some specific carcinomas such as cervical cancer. Experimental and clinical studies have shown that early proteins E6 and E7 played the most important role in the cervical carcinogenesis. Early proteins E6 and E7 of HPV both are oncoproteins for they disable specific tumor suppressor proteins, p53 and pRb, and disturb apoptosis against carcinogenesis. Both p53 and pRb play an important role in regulating apoptosis and preventing cell immortalization, but they also mediate ischemia/reperfusion-associated apoptosis and give rise to ischemia-reperfusion injury (IRI). Several studies showed inhibition of apoptosis may provide promising approaches to ameliorating IRI in ischemia/reperfusion. Both small-molecule chemical inhibitor and siRNA against p53 block p53-dependent apoptosis and protect organ function from IRI. Similarly, inhibiting pRb can restrain ischemia/reperfusion-associated apoptosis. Based on these studies, we propose a novel hypothesis that early proteins E6 and E7 of HPV attenuate ischemia-reperfusion injury by inhibiting apoptosis and inactivating p53 and pRb. It is possible that the two oncoproteins can be used to protect organ function from ischemia-reperfusion injury in special clinical conditions such as organ transplant, stroke, cardiopulmonary bypass, and myocardial infarction.
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PMID:Early proteins E6 and E7 of human papillomavirus may attenuate ischemia-reperfusion injury. 2127 88

Part 2 of this review concerns the application of melatonin (Mt) to the treatment of aged patients with cardiovascular diseases and other pathology with reference to its genoprotective and anticarcinogenic action. Effects of Mt on the cardiovascular system are underlain by its antioxidative, vasodilating, and sedative activities, the ability to regulate the heart rate and inhibit platelet aggregation. Certain authors report negative correlation between Mt production and blood cholesterol level. Mt was shown to protect from cardiac lesions associated with ischemia and reperfusion. Mt inhibits carcinogenesis and is active at systemic, tissue, cellular and subcellular levels. At the systemic level, Mt decreases hormonal production, stimulates immune activity, and prevents the development of metabolic syndrome. It inhibits cell proliferation and promotes apoptosis of tumour cells but suppresses it the nervous tissue. Mt activates telomerase. It decreases expression of oncogens and interferes with the action of mutagens and clastogens at the genetic level. Extensive studies of Mt protective action in nervous diseases are underway with special reference to spinal cord, brain, neuron and glial cell lesions; experimental cerebral stroke, Parkinson's and Alzheimer's diseases. Similar studies concern the role of Mt in the protection against ionizing radiation, the development of renal pathology, and ophthalmology (glaucoma, cataract). Mt is shown to influence practically all organ systems by inhibiting mutagenesis and maintaining correlation between circadian rhythms of different biological processes throughout human evolution.
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PMID:[Melatonin: its role in the system of neurohumoral regulation in man. Part 2]. 2157 34


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