The anti-aging role of telomerase has been demonstrated to be largely mediated by its canonical role in elongating telomeres, which prevents the accumulation of critically short telomeres and loss of tissue homeostasis
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Basic properties and molecular mechanisms of exogenous chemical carcinogens. (2010) | L... - 0 views
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Telomerase at the intersection of cancer and aging - 0 views
www.ncbi.nlm.nih.gov/...PMC3896987
telomere telomeres telomerase telomerase activator aging disease cancer
shared by Nathan Goodyear on 18 May 16
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increased abundance of short telomeres correlates with higher genomic instability and decreased longevity in various organisms, including mice, zebrafish, and yeast
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mice deficient for telomerase or for telomere binding proteins are characterized by accelerated age-related defects
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In humans, short telomeres are considered good indicators of an individual’s health status and correlate with both genetic and environmental factors
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Although recent findings strongly support the idea that short telomeres drive several age-related diseases 38 we cannot exclude the possibility that in some situations short telomeres may be a consequence of the disease itself.
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the current view is that telomerase deficiency may contribute to the early steps of cancer development by fueling chromosomal instability, while subsequent activation of telomerase may be necessary to allow tumor growth and tumor progression towards more malignant states
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telomerase can stimulate tumor progression by ensuring maintenance of telomeres above a critically short length, thus preventing induction of cellular senescence or apoptosis
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Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells
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recent evidence demonstrated that short telomeres alone could lead to genomic instability and cancer
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Getting rid of telomerase can also be problematic; the lack of telomerase could lead to increased chromosomal instability, which in turn could be at the basis for cancer initiation when tumor suppressor barriers are bypassed
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telomerase activation in adult or old mice by means of a gene therapy strategy was shown to be sufficient to improve metabolic fitness, neuromuscular capacity, and prevent bone loss, as well as significantly increase both median and maximum longevity, without increased cancer incidence
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These studies suggest that telomerase expression could be considered a feasible approach to reverse tissue dysfunction and extend healthy lifespan without increasing cancer incidence
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a change of paradigm seems to be occurring in telomerase biology, with a switch from viewing telomerase as fueling cancer to reversing aging
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Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor
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Telomerase activity and longer telomere length is shown to correlated inversely with many chronic diseases of aging. In contrast, telomerase activity is found to be involved in carcinogenesis. Increased carcinogenic potential of telomerase activity has not borne out in studies. In addition, increased CD8 cell activity as a result of telomerase activation will actually decrease carcinogenic potential via NK activation.
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Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views
www.ncbi.nlm.nih.gov/...PMC154104
progesterone metabolites breast cancer 5alpha-reductase 5-alpha pregnene 5-alpha pregnenes 4-pregnene 4-pregnenes
shared by Nathan Goodyear on 30 Jan 14
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Exposure of human breast cell lines (MCF-7, MCF-10A, and ZR-75-1) to 5α-pregnanes results in changes associated with neoplasia, including increased proliferation and decreased attachment [1], depolymerization of F-actin [2] and decreases in adhesion plaque-associated vinculin
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The 5α-pregnanes:4-pregnenes ratio was about 8-fold higher in tumorous than in nontumorous breast tissue after an 8-hour incubation with [14C]progesterone
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Studies with breast cell lines, showing that 5α-pregnanes stimulate proliferation and decrease attachment of cells
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both tissue and breast cell line studies suggest that an elevated level of progesterone 5α-reductase activity may be an indicator of breast tumorigenesis, regardless of presence or absence of ER and/or PR
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5αR1 is the main isoform expressed in human breast carcinomas [29] and that 5αR2 may not be associated with risk of breast cancer
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the differences in 5α-pregnane production between the cells is due primarily to a difference in 5αR1 expression
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As in the case of 5α-reductase activity, the presence or absence of ER and PR do not appear to be related to 5α-reductase expression.
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the conversion of progesterone to the cancer promoting 5α-pregnanes is significantly higher in the human tumorigenic breast cell lines
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lthough both 5αR1 and 5αR2 are expressed by these cells, the elevated 5α-reductase activity appears to be the result of significantly greater expression of 5αR1
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Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for promoting breast cancer progression due to increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes
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balance of enzyme production between 5alpha-reductase and 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductase play role in carcinogenesis and proliferation in the balance of production of progesterone metabolites. The 5alpha pregnenes are pro carcinogenic and the 4-pregnenes are anti carcinogenic.
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Potential Mechanisms of Estrogen Quinone Carcinogenesis - 0 views
www.ncbi.nlm.nih.gov/...PMC2556295
estrogen metabolites estrogen quinones 4-OH-estrone cancer hormones
shared by Nathan Goodyear on 19 Sep 15
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4-hydroxyestrone/estradiol was found to be carcinogenic in the male Syrian golden hamster kidney tumor model, whereas, 2-hydroxylated metabolites were without activity
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4-hydroxyestradiol induced uterine tumors in 66% of CD-1 mice; whereas, mice treated with 2-hydroxyestradiol or 17β-estradiol had much lower uterine tumor incidence
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DNA adducts of catechol estrogen quinones have been detected in the mammary glands of ACI rats treated with 4-hydroxyestradiol or it’s quinone
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PLOS ONE: Caramel Color in Soft Drinks and Exposure to 4-Methylimidazole: A Quantitativ... - 0 views
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Melatonin inhibits both ER alpha activation and... [J Pineal Res. 2006] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...16635015
Cadmium CD estrogen receptor alpha estrogen receptor estrogen receptor melatonin hormones ER alpha
shared by Nathan Goodyear on 19 Jan 13
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Circadian Rhythm Disruption Promotes Lung Tumorigenesis: Cell Metabolism - 0 views
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DNA methylation and cancer. - PubMed - NCBI - 0 views
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Progesterone metabolites in breast cancer - 1 views
erc.endocrinology-journals.org/...717.full
progesterone metabolism tumor tumorigenesis cancer risk growth hormone hormones 5-beta-pregnanediol 5-alpha-pregnanediol 4-pregnenediol 5-alpha reductase
shared by Nathan Goodyear on 20 Feb 12
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P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
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these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
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only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
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P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
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These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
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Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
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The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
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the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
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In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
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The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
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he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
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The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
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altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
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In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
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Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
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The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
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Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
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Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
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αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
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The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
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The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
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separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
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The studies thus provided the first demonstration of the existence of specific P metabolite receptors
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the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
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Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
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In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
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The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
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current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
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http://eu-acme.org/europeanurology/upload_articles/Bonkhoff.pdf - 0 views
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Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate C... - 0 views
cebp.aacrjournals.org/...1055-9965.EPI-13-1126.abstract
inflammation prostate cancer prostatitis infection
shared by Nathan Goodyear on 22 Apr 14
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Chronic prostattis in men associated with prostate cancer. Even more concerning, is the increase in high Gleasons score prostate cancer. This is no surprise as inflammation will increase aromatase activity in the prostate which will increase estrogen production which has been shown to be carcinogenic.
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Coffee and cancer risk: a summary overview - 0 views
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2017 meta-analysis finds no increase relative risk (RR) of cancer with coffee consumption. First, this must consider all the "other" junk put in coffee these days. Second, and most important, this study looked at RR which tells us nothing about risk. Studies like this don't do much more than confuse the general public, doctors, and judges--recent judge ruling in California that coffee needs a carcinogenic lable. Third, epigenetis will tell us about individual risk. I am growing more concerned that the majority of studies published today are merely statistical dances to ensure publication. Is it good that no RR was found? yes, does that give any indication of absolute risk? No. Take home: enjoy your morning cup of joe as nature prescribed--no additives.
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Substantial contribution of extrinsic risk factors to cancer development - 0 views
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Here we provide evidence that intrinsic risk factors contribute only modestly (<10~30%) to cancer development
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we conclude that cancer risk is heavily influenced by extrinsic factors. These results carry immense consequences for strategizing cancer prevention
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cancers are proposed to originate from the malignant transformation of normal tissue progenitor and stem cells
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“Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens
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intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions
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if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case)
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Particularly, for breast and prostate cancers, it has long been observed that large international geographical variations exist in their incidences (5-fold for breast cancer, 25-fold for prostate cancer)14, and immigrants moving from countries with lower cancer incidence to countries with higher cancer rates soon acquire the higher risk of their new country
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Colorectal cancer is another high-incidence cancer that is widely considered to be an environmental disease17, with an estimated 75% or more colorectal cancer risk attributable to diet
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HPV may cause ~90% cases in cervical cancer23, ~90% cases in anal cancer24, and ~70% in oropharyngeal cancer
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While a few cancers have relatively large proportions of intrinsic mutations (>50%), the majority of cancers have large proportions of extrinsic mutations, for example, ~100% for Myeloma, Lung and Thyroid cancers and ~80–90% for Bladder, Colorectal and Uterine cancers, indicating substantial contributions of carcinogen exposures in the development of most cancers
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onsistent estimate of contribution of extrinsic factors of >70–90% in most common cancer types. This concordance lends significant credibility to the overall conclusion on the role of extrinsic factors in cancer development
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Inhibition of human carcinoma cell growth and DNA ... [Cancer Lett. 1999] - PubMed result - 0 views
www.ncbi.nlm.nih.gov/...10660092
milk thistle silymarin prostate cervical breast cancer inhibition anti-cancer
shared by Nathan Goodyear on 15 Feb 11
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Several studies from our laboratory have shown the cancer chemopreventive and anti-carcinogenic effects of silymarin, a flavonoid antioxidant isolated from milk thistle, in long-term tumorigenesis models and in human prostate, breast and cervical carcinoma cells
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Implications of free radicals and antioxidant levels in carcinoma of the breast: A neve... - 0 views
www.indianjcancer.com/article.asp
SOD superoxide disumutase catalase antioxidants antioxidant breast cancer cancer malondialdehyde MDA lipid peroxides oxidative stress inflammation
shared by Nathan Goodyear on 10 Nov 14
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Experimental investigations as well as clinical and epidemiological findings have provided evidence supporting the role of reactive oxygen metabolites or free radicals such as singlet oxygen O 2 - , superoxide anions (O 2 ), hydrogen peroxide (H2 O2 ) and hydroxyl radical in the etiology of cancer.
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Certain aldehydes such as Malonyldialdehyde (MDA), the end product of lipid peroxidation arising from free radical degeneration of polyunsaturated fatty acids can cause cross linking in lipids, proteins and nucleic acids leading to cellular damage.
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In this study, patients with cancer exhibited higher levels of MDA, both in tissues and serum (p<0.001) compared to the control group [Table 1]. In tissue, the MDA level in stage IV was significantly higher as compared to stage I indicating increased free radical activity with increasing severity of cancer
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From these observations, it can be concluded that MDA levels play an important role in assessing the outcome of cancer
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SOD and CAT are considered primary antioxidant enzymes, since they are involved in direct elimination of reactive oxygen metabolites. [13-16] They also act as anti-carcinogens and inhibitors at initiation and promotion/transformation stage in carcinogenesis
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In our study, SOD and CAT levels were found to be low in all cancer patients as compared to controls
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Fridovich and Tayarani have demonstrated in their respective studies that the reduction in SOD activity increases the toxic effects of O2 - and this might lead to severe cellular damage.
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Mehrotra et al. in their study also observed high levels of MDA and low levels of SOD and CAT in patients of cancer cervix which is in sync with our observations.
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This study finds a strong correlation between advancing breast cancer, decreased catalase and SOD with increasing MDA. The authors of this study conclude this is a key factor in carcinogenesis and not a by-product of cancer. This flies in the face of traditional medicines fear of antioxidant therapy in cancer.
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Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skelet... - 0 views
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The induction of DNA methylation changes after 5 days of HFO supports the growing awareness of DNA methylation as a dynamic signal that is possibly relevant to short-term day-to-day metabolic adaptations, including acute exercise
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Diverging DNA methylation levels between elderly, but not young, genetically identical twins indicate that environmental exposures throughout life may permanently influence DNA methylation, suggesting some preservation of de novo DNA methylation in adults
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our finding of a slow reversibility rate indicates the demethylation process may be somewhat impeded compared with the induction of methylation changes by diet, which could have implications for the preservation or build-up of CpG methylation over time
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A slow reversibility of DNA methylation induced by carcinogenic agents has likewise been observed due to ingestion of high-fat diets in rodents
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Redox regulation in cancer - 0 views
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Mitochondrial electron-transport chain and other oxidizing agents are the prime pathways that generate excess ROS in vivo
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Permanent modification of genetic material resulting from the oxidative damage is one of the vital steps involved in mutagenesis that leads to carcinogenesi
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The most frequent DNA mutations caused during oxidative stress, initiated by ionizing radiation and other environmental carcinogens are 7,8-dihydro-8-oxoguanine (8-Oxo-G) and Thymine Glycol (TG)
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High Fat High Calories Diet (HFD) Increase Gut Susceptibility to Carcinogens by Alterin... - 0 views
www.jcancer.org/v11p4091.htm
diet high fat diet high calorie diet excess calorie cancer nutrition colorectal cancer
shared by Nathan Goodyear on 22 Aug 21
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