P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting
or -inhibiting regulatory agents
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shared by Nathan Goodyear on 28 Oct 12
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Arthritis Research & Therapy | Abstract | Restoration of regulatory and effector T cell... - 0 views
arthritis-research.com/...abstract
lupus SLE vitamin D D3 vitamin D Th1 Th17 inflammation autoimmune disease autoimmunity arthritis
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Vitamin D supplementation in those individuals with SLE found to benefit these patients. Vitamin D found to reduce TH1 and Th17 activity. It also was found to decrease memory B cells and auto-antibodies. Also of note is the level of vitamin D after therapy-only at 51.4 at 2 months and 41.5 at 6 months.
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shared by Nathan Goodyear on 19 Mar 14
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Regulatory effects of estriol on T cell migra... [J Neuroimmunol. 2002] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...11958828
Estriol E3 inflammation NF-kappaB Th2 T-cells rheumatoid arthritis RA MS multiple
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shared by Nathan Goodyear on 20 Feb 12
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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
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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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shared by Nathan Goodyear on 03 Jan 12
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Regulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice - 0 views
diabetes.diabetesjournals.org/...2574.full
obesity overweight weight-loss M1 macrophage M2 ATM inflammation TNF-alpha IL-6
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M1 macrophages (and a high M1/M2 ratio) promote inflammation and insulin resistance in obese individuals; This is in contrast to M2 macrophages. Obese individuals will see a shift in M2 to M1. The exact mechanism is yet unknown. But M2 macrophages have been shown to resolve insulin resistance in this obese mice model
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Obesity - Inducible Toll-like Receptor and NF-[kappa]B Regulatory Pathway Expression in... - 0 views
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TLRs are functionally inducible and associated with downstream NF-B activation and proinflammatory cytokine production.
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TLRs represent a family of receptors that are critical to the innate immune response against foreign pathogens and microorganisms
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LPS has been shown to induce proinflammatory chemokine gene expression in differentiated human adipocytes through TLR and NF-B action
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Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.
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Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models
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The Complex Role of Estrogens in Inflammation - 0 views
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up-regulation of ERβ relative to ERα under hypoxic conditions, which might lead to a preponderance of signaling through ERβ pathways
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it seems that E2 at periovulatory to pregnancy levels inhibited proinflammatory cytokines from PBMCs
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it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells
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E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors
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In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life
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Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases
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antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17
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Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation
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in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells
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In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity
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increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response
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secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels
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The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations
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experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.
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E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal
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It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation
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important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF
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most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels
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E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy
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Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat
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Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How ca... - 0 views
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shared by Nathan Goodyear on 28 Jan 14
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Progesterone metabolites regulate induction, growth, and suppression of estrogen- and p... - 0 views
www.ncbi.nlm.nih.gov/...PMC3706910
progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen
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in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
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Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
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When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
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Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
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Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
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The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
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hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
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Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure (Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
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The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
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In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
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the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
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Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
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The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
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The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
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In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
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When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
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The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
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Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
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ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
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3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
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the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
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Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
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Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
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The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
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Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
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in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
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the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
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because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
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The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
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Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms - 0 views
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The imbalance between regulatory and IL-17-se... [Clin Rheumatol. 2010] - PubMed - NCBI - 0 views
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shared by Nathan Goodyear on 31 Jul 13
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Restoration of regulatory and effector T cell balance and B cell homeostasis in systemi... - 0 views
www.ncbi.nlm.nih.gov/...PMC3580532
vitamin d vitamin D T reg Th17 inflammation autoimmune disease lupus SLE
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Sympathetic overactivity precedes metabolic dysfunction in a fructose model of glucose ... - 0 views
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shared by Nathan Goodyear on 28 Apr 15
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Diet-induced obesity and low testosterone increase neuroinflammation and impair neural ... - 0 views
www.ncbi.nlm.nih.gov/...PMC4190446
Testosterone neuroinflammation glia insulin resistance obesity diabetes brain CNS PNS inflammation low T low Testosterone TNF-alpha IL-1beta
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both obesity and low testosterone are also risk factors for neural dysfunction, including cognitive impairment [58–61] and development of AD
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diet-induced obesity causes significant metabolic disturbances and impairs central and peripheral nervous systems.
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both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems
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In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation
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fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet
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testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation
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fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.
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testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis
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Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone
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it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth
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Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β
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many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression
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neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation
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testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions
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Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group
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testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions
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Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration
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a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS
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Study points to obesity and low Testosterone contribution of neuroinflammation. No effect of body weight was seen with TRT. This animal model found similar positive effects of TRT in insulin sensitivity. Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line. Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol. Testosterone's effect on glial survival was positive but not significant. Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta. Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.
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shared by Nathan Goodyear on 22 Jun 15
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Salivary Testosterone and a Trinucleotide (CAG) Length Polymorphism in the Androgen Rec... - 0 views
www.ncbi.nlm.nih.gov/...PMC2825741
CAG androgen receptors AR androgen receptor Testosterone hormone hormones male men
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Testosterone correlated inversely with participant age (r = −0.39, p = 0.012) and positively with number of CAG repeats
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transactivation potential of the AR appears to decline in graded relation to an increasing number of CAG repeats, which are distributed over a normative range of 11–37 and, in Caucasian populations, commonly average 21–22 repeats
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When activated by androgens, ARs translocate to the cell nucleus, where they exert transcriptional control of androgen-dependent genes by binding to androgen response elements within gene regulatory sequences
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androgens (like other steroid hormones) promote or repress the expression of genes specifying an array of cellular proteins
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salivary testosterone correlated negatively with participant age and positively with CAG length variation in the AR gene
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CAG repeat number varied inversely with reactivity of the ventral amygdala to facial expressions of negative affect
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Because circulating testosterone is regulated via negative feedback through the hypothalamic-pituitary-gonadal axis, diminished androgen sensitivity at higher CAG repeat lengths may reduce feedback suppression of luteinizing hormone (LH). LH would then be maintained at higher levels, in turn promoting higher testosterone production
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Oxytocin exerts an inhibitory influence on AVP expression in the central amygdala, and the synthesis of oxytocin is mediated by estrogen and estrogen receptors
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Does experimental pain response vary across the menstrual cycle? A methodological revie... - 0 views
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