More on telemores.
All this begs the question if oestrogen (telemore protector anti-inflamatory? see below) is indeed the bady?? -- Or is it something else lack of omega three blocking of pathways and vast excess (in evolutionary terms) of omega six consequent oxidative stress self fuelling unbreakable cycle as oestrogen tries to moderate inflamation via omega three??????????
Interesting article linking to inflamatory pathways oxidative stress etc.(below)
Inflamatory pathways - See posts on omega six and Greek diet re COX 2 inflamatory pathways and cancer.
The comments on oestrogen as an anti inflamatory are interesting, and something I had not seen before.
I post these conjectures as a wandering true amateur with very limited knowledge in case thought provoking for those who may be able to make better sense of it.
IF oestrogen is an anti inflamatory (see below) and one role is to mitigate the omega six AA eicosanid pathways then the body may produce oestrogen in response to series 2 inflamatory agents.
PGE2 has been reported as uprating p450 which uprates oestrogen which uprates growth factors.
In a situation of excess omega six / AA it may not be possible to damp down the inflamation leading to a self fuelling cycle as oestrogen tries to damp down the inflamation and AA keeps upgrading it PGE2 etc.
If one mechanism of damping is production of series three eicosanoids, could a role of oestrogen be to uprate FAS and preferentially omega three (pregnanacy lactation DHA required by infant.)
In the absence of adequate supply of ALA the omega three percussor - or blockage of the FAS pathways by excess omega six, trans fats etc - no DHA EPA would be produced so no moderating series three eicosanoid.
At the same time "permenantly" high oestrogen casued by excess inflamatory factors PGE2 etc would possibly partially activate pregnancy implatation / breast activation type activity in the breast as well as uterous.
Pregnacy produces increased demand for DHA production.
Could this combination of factors with high oxidation stress due to constant inflamatory pressure, combined with a self-fuelling cycle of forcing oestrogen levels up as the body tries to activate the FAS pathway to make DHA both for milk provision and series three eicosanoid inflamatory damping have implications fro some tyes of breast cancers?.
Trials I have seen suggest the same growth factors are involved in attachement in the placenta etc. (see below)
Interesting growth factors were higher in the placenta in pre-eclampsia and DHA has been reported as moderating the condition.
My searches did not find much on pregnancy and HEr 2 growth factors - should their be more corss exchange of ideas - or have I not searched with the right words.
Clearly from what I have seen the derivates of omega six AA have very fundamental roles in the body and reproduction what ever link they have to inflamatory disease and BC. The complexity is truly wonderous.
Thanks for the post Tom that lead on on this latest wander.
RB
http://72.14.221.104/search?q=cache:...ient=firefox-a
Increased adiposity is associated with a rise in systemic inflammation (1-4) and oxidative stress (5,6).
Both processes may accelerate telomere erosion in leukocytes, because inflammation enhances the
turnover rate of leukocytes and oxidative stress heightens the loss of telomeric repeat per cell replication (7). Such mechanisms provide a potential explanation for findings of accelerated leukocyte telomere attrition with a rise in insulin resistance and a gain in the body mass index (BMI) in a
longitudinal study (8), and the inverse correlations of leukocyte telomere length with insulin resistance (unpublished data), serum leptin and BMI (9) in cross-sectional analyses of relatively large populations. What’s more, it appears that leukocyte telomere dynamics (telomere length and attrition rate) are influenced not by the body mass per se, but by mechanisms linked to obesity, expressed in elevated insulin resistance and leptin levels........
......Another alternative explaining the absent association between leukocyte telomere length and insulin resistance in postmenopausal women is the dramatic decline in overian steroid hormones— particularly estrogen—during the postmenopausal period. Estrogen may be linked to leukocyte Page 10
10 telomere dynamics through its anti-inflammatory and anti-oxidant attributes and by its ability to stimulate telomerase, a reverse transcriptase that elongates telomere ends (24). Estrogen is a potent anti-inflammatory agent, because it lowers the production of cytokines, including
the pro-inflammatory, tumor necrosis factor-α (TNF-α) (25-28). Depending on tissues examined, insulin resistance may arise from or be caused by oxidative stress (29-32). One of the factors that defend against oxidative stress is estrogen (32-34). The anti-oxidant activity of estrogen may also mediate its anti-diabetic property (35). Estrogen serves as an anti-oxidant by mechanisms that are not fully elucidated, but appear to be exerted via membrane/cytoplasmic receptors (36). Estrogen stimulates the mitochondrial superoxide dismutase (Mn-SOD) and glutathione peroxidase (Gpx) (32),
two powerful enzymes engaged in the metabolism of reactive oxygen species. Since neither Mn-SOD nor Gpx have an estrogen responsive element in their promoter regions, a direct genomic effect in
this stimulation is unlikely................
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_DocSum
1: J Endocrinol. 2000 May;165(2):443-56.Click here to read Links
Placental lactogen-I gene activation in differentiating trophoblast cells: extrinsic and intrinsic regulation involving mitogen-activated protein kinase signaling pathways.
* Peters TJ,
* Chapman BM,
* Wolfe MW,
* Soares MJ.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Trophoblast giant cells are one of the primary endocrine cell types of the rodent placenta. Placental lactogen-I (PL-I) is the initial prolactin (PRL) family member expressed as trophoblast giant cells differentiate. In this report, we use the Rcho-1 trophoblast cell line as a model for studying the regulation of PL-I gene expression during trophoblast giant cell differentiation. Evidence is provided for trophoblast cell expression of epidermal growth factor receptor (EGFR), ErbB2, fibroblast growth factor receptor 1 (FGFR1), transforming growth factor-alpha, and heparin-binding EGF. EGF and FGF-2 stimulated PL-I mRNA and protein accumulation and PL-I promoter activity in a concentration-dependent manner. These latter growth factor actions on PL-I promoter activities were specifically inhibited by cotransfection with dominant negative constructs for EGFR and FGFRs respectively. Utilization of the mitogen-activated protein kinase (MAPK) pathway by EGF and FGF-2 in trophoblast cells was demonstrated by growth factor stimulation of a Gal4 DNA binding/Elk1 transactivational domain fusion construct, and more specifically by activation of extracellular signal regulated kinase and p38 MAPK. PL-I gene activation was also sensitive to disruption of MAPK and activation protein-1 (AP-1) signaling pathways. In conclusion, autocrine/paracrine pathways involving EGFR and FGFR1, MAPK and AP-1 are shown to participate in the regulation of the PL-I gene in differentiating trophoblast cells.
PMID: 10810308 [PubMed - indexed for MEDLINE]
1: J Neurosci. 1999 Nov 15;19(22):9913-27.Click here to read Links
Neuregulins signaling via a glial erbB-2-erbB-4 receptor complex contribute to the neuroendocrine control of mammalian sexual development.
* Ma YJ,
* Hill DF,
* Creswick KE,
* Costa ME,
* Cornea A,
* Lioubin MN,
* Plowman GD,
* Ojeda SR.
Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton, Oregon 97006, USA.
Activation of erbB-1 receptors by glial TGFalpha has been shown to be a component of the developmental program by which the neuroendocrine brain controls mammalian sexual development. The participation of other members of the erbB family may be required, however, for full signaling capacity. Here, we show that activation of astrocytic erbB-2/erbB-4 receptors plays a significant role in the process by which the hypothalamus controls the advent of mammalian sexual maturation. Hypothalamic astrocytes express both the erbB-2 and erbB-4 genes, but no erbB-3, and respond to neuregulins (NRGs) by releasing prostaglandin E(2) (PGE(2)), which acts on neurosecretory neurons to stimulate secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual development. The actions of TGFalpha and NRGs in glia are synergistic and involve recruitment of erbB-2 as a coreceptor, via erbB-1 and erbB-4, respectively. Hypothalamic expression of both erbB-2 and erbB-4 increases first in a gonad-independent manner before the onset of puberty, and then, at the time of puberty, in a sex steroid-dependent manner. Disruption of erbB-2 synthesis in hypothalamic astrocytes by treatment with an antisense oligodeoxynucleotide inhibited the astrocytic response to NRGs and, to a lesser extent, that to TGFalpha and blocked the erbB-dependent, glia-mediated, stimulation of LHRH release. Intracerebral administration of the oligodeoxynucleotide to developing animals delayed the initiation of puberty. Thus, activation of the erbB-2-erbB-4 receptor complex appears to be a critical component of the signaling process by which astrocytes facilitate the acquisition of female reproductive capacity in mammals.
PMID: 10559400 [PubMed - indexed for MEDLINE]
Related Links
http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_DocSum
Glia-to-neuron signaling and the neuroendocrine control of female puberty. [Recent Prog Horm Res. 2000] PMID: 11036938
Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. [J Neurosci. 2003] PMID: 12514220
Glial-neuronal interactions in the neuroendocrine control of mammalian puberty: facilitatory effects of gonadal steroids. [J Neurobiol. 1999] PMID: 10453054
Epidermal growth factor tyrosine kinase receptors and the neuroendocrine control of mammalian puberty. [Mol Cell Endocrinol. 1998] PMID: 9722176
Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain. [J Neurosci. 2003] PMID: 12574420
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