Testosterone modulates dopaminergic pathways in the the brain. This was a rat model. This points to some of the euphoria experienced by men on Testosterone likely occurs through dopamine.
our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer. Indeed our results are more suggestive of an increase in risk, rather than a decrease, with higher levels of 2-OHE1
women with a higher 2-OHE1 : 16α-OHE1 ratio did not have a decreased risk of endometrial cancer as compared with women with a lower ratio
The findings from this first prospective epidemiological study of oestrogen metabolites and endometrial cancer are in line with results from prospective studies on breast cancer, another oestrogen-related cancer. None of the seven studies on breast cancer reported significant associations overall
On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers
Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors
the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens
a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours
both 2- and 4-catechol estrogen metabolites bind to the ER with affinities comparable
with estradiol, 4-catechol estrogen metabolites have lower dissociation rates than estradiol and an enhanced ability to upregulate
ER-dependent processes
2-catechol estrogen metabolites act as either weak mitogens (39) or weak inhibitors of cell proliferation
While 16α-hydroxyestrone binds to the ER with lower affinity than estradiol, it binds covalently (41) and leads to a constitutively activated ER
4-hydroxyestradiol
and 16α-hydroxyestrone increasing proliferation and decreasing apoptosis in a manner similar to estradiol; however, these
effects were achieved only at concentrations 10-fold higher than estradiol (39). In contrast, 2-hydroxyestradiol did not have substantial proliferative or antiapoptotic effects
In our study, the associations with both 2-hydroxyestrone and 16α-hydroxyestrone were nonsignificantly inverse and
we did not observe a consistent trend or significant associations between the 2-hydroxyestrone:16α-hydroxyestrone ratio and
breast cancer risk
Ratios of the 3 hydroxylation pathways
were not significantly associated with risk although the 2:16-pathway and 4:16-pathway ratios were suggestively inversely
associated
a significant inverse association with the ratio of parent estrogens to estrogen metabolites
several potentially estrogenic and genotoxic mechanisms
Estrogen metabolites also can be genotoxic
Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly
via redox cycling and generation of reactive oxygen species
the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized
2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination
and mutations
2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative
DNA damage
act independently from the ER
16α-Hydroxyestrone also may be genotoxic
While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol
estrogens with one hydroxyl group methylated, have been hypothesized to lower the risk of breast cancer
The suggested mechanisms
are indirect, by decreasing circulating levels of catechol estrogens and thereby the opportunity for catechols to exert genotoxic
or proliferative effects, or direct, by inhibiting tumor growth and inducing apoptosis
the balance between phase I (oxidation) and phase II (methylation) metabolism of estrogen may be important in hormonally
related cancer development.
Despite the estrogenic and genotoxic potential of many of the estrogen metabolites, we only observed a significantly increased
breast cancer risk with one estrogen metabolite, 17-epiestriol, which has particularly strong estrogenic activity and binds
to both ERα and ERβ with an affinity comparable with estradiol
A number of the
catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of
central nervous system inflammation is well documented.
We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP
of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
transient receptor potential cation channel subfamily V, member 1
orphan G protein–coupled receptor 55
Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
two major cannabinoid-specific receptors—cb1 and cb2
cardiovascular tone, energy metabolism, immunity, and reproduction
cannabinoids are well known to exert palliative effects in cancer patients
best-established use is the inhibition of chemotherapy-induced nausea and vomiting
thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
pharmacologic activation of cannabinoid receptors decreases tumour growth
endocannabinoid signalling can also have a tumour-suppressive role
pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
impair tumour angiogenesis and block invasion and metastasis
thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
autophagy is important for cannabinoid antineoplastic activity
autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
The activation of each of them leads to an inhibition of adenylyl cyclase via G proteins (Gi/o), which in turn activates many metabolic pathways such as mitogen‐activated protein kinase pathway (MAPK), phosphoinositide 3‐kinase pathway (PI3K), cyclooxygenase‐2 pathway (COX‐2), accumulation of ceramide, modulation of protein kinase B (Akt), and ion channels
phytocannabinoids, endocannabinoids, and synthetic cannabinoids
Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids
The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells (skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma)
concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer
CB2 receptor contributes to human epidermal growth factor receptor (HER2) pro‐oncogenic signaling and an overexpression of CB2 increases susceptibility for leukemia development after leukemia viral infection
endocannabinoid‐degrading enzymes are upregulated in cancer cell lines and in human tumors
Many cannabinoids, ranging from phytocannabinoids (THC, CBD), endocannabinoids (2‐arachidonoylglycerol, anandamide), to synthetic cannabinoids (JWH‐133, WIN‐55,212‐2), have shown ability to inhibit proliferation, metastasis, and angiogenesis in a variety of models of cancer
Despite some inconsistent data, the main effect of cannabinoids in a tumor is the inhibition of cancer cells’ proliferation and induction of cancer cell death by apoptosis
CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells by induction of de novo synthesis of ceramide, sphingolipid with proapoptotic activity
process of autophagy is upstream of apoptosis in mechanism of cell death induced by cannabinoids
Niclosamide (trade name Niclocide) is a teniacide in the antihelmintic family that is especially effective against cestodes, which infects humans. Niclosamide has been FDA approved for such indications and has been used in humans for nearly 50 years
We demonstrated for the first time that niclosamide can inhibit Wnt/β-catenin signaling by inducing LRP6 degradation, and that this activity is closely associated with its antiproliferative and apoptosis inducing activity.
Niclosamide, an old anti-parasitic drug, found to inhibit the Wnt/B-catenin pathways so critical to cancer growth. This triggers apoptosis of the cancer cell.
IL‐6 increases PSA and androgen receptor expression through a STAT3‐dependent pathway in the absence of androgen in LNCaP cells. Our results agreed with those of an earlier study that indicated that IL‐6 induced expression of the androgen receptor, which up‐regulated PSA promoter activity in the androgen‐independent pathway. Moreover, curcumin blocked stimulation of IL‐6 on the androgen receptor, which attenuated PSA gene expression in a ligand‐independent manner.
Although currently no drugs that specifically target mitochondrial biogenesis in HF are available, acceleration of this process through adenosine monophosphate–activated kinase (AMPK), endothelial nitric oxide synthase (eNOS), and other pathways may represent a promising therapeutic approach
Mitochondrial biogenesis can be enhanced therapeutically with the use of adenosine monophosphate kinase (AMPK) agonists, stimulants of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway (including phosphodiesteraes type 5 inhibitors), or resveratrol
metformin, a commonly used antidiabetic drug that activates AMPK signaling
Recent evidence suggests that the eNOS/NO/cGMP pathway is an important activator of mitochondrial biogenesis
BH4 (tetrahydrobiopterin) supplementation can prevent eNOS uncoupling and was found to reduce left ventricular hypertrophy
folic acid is known to replenish reduced BH4 and has been shown to protect the heart through increased eNOS activity
Both folate deficiency and inhibition of BH4 synthesis were associated with reduced mitochondrial number and function
Resveratrol, a polyphenol compound responsible for the cardioprotective properties of red wine, was recently identified as a potent stimulator of mitochondrial biogenesis
epidemiological studies reveal a reduced risk of cardiovascular disease in premenopausal, but not post-menopausal, women compared with men
I would hypothesis that a change in the predominance of ER expression is one of ER beta to ER alpha: creating a more pro-inflammatory signal.
The majority of ROS in the heart appear to come from uncoupling of mitochondrial electron transport chain at the level of complexes I and III
Because the majority of ROS in HF comes from mitochondria, these organelles are the primary target of oxidative damage.
cardioprotective therapies such as angiotensin-converting enzyme inhibitors and ATII receptor blockers were shown to possess antioxidant properties, although it is not known whether they target mitochondrial ROS directly or indirectly
NK cells have been the cells most extensively studied, primarily because they constitute the predominant
leukocyte population present in the endometrium at the time of implantation and in early pregnancy
In summary, in vivo animal experiments have shown an inhibitory role of estrogen on peripheral NK cell lytic activity, which is partly due to
suppression of NK cell output by the bone marrow and partly due to suppression of individual NK cell cytotoxicity. However,
in vitro studies so far have failed to show conclusively a direct effect of estrogen on NK cells.
At the progesterone
concentrations believed to be present in the uterus [up to 10−5 m at the maternal-fetal interface (35)], studies consistently show inhibition of lymphocyte proliferation (33) and inhibition of NK cytolytic activity in vitro
The exact role of prolactin in NK cell regulation is unknown.
The overall effects of estrogen on NK cells are likely multifactorial, therefore, and depend on the type of cell affected
as well as the kind of ER expressed by that cell.
It is known that progesterone can directly affect T cell differentiation in vitro, suppressing development of the Th1 pathway and enhancing differentiation along the Th2 pathway (44)
Th1 cells predominantly produce interferon-γ (IFN-γ), IL-2, and TNF-β and are involved in cell-mediated immunity. Th2 cells
produce IL-4, IL-5, IL-6, IL-10, and IL-13 and stimulate humoral immunity
Furthermore, in response to progesterone, γδ T cells produce progesterone-induced blocking factor (PIBF) (54
A defining characteristic of NK cells is their ability to lyse target cells without prior sensitization and without restriction
by HLA antigens.
NK cell function is mainly regulated by IL-2 and IFN-γ
IL-2 causes both NK cell proliferation and enhanced cytotoxicity.
IFN-γ augments NK cytolytic activity, but does not cause NK proliferation. The two cytokines act synergistically to augment
NK cytotoxicity (6).
The largest leukocyte population in the endometrium consists of NK cells named large granulated lymphocytes
there is a significant increase
in the number of uNK cells throughout the secretory phase, which peaks in early pregnancy when uNK cells comprise about 75%
of uterine leukocytes (62)
Second, uNK cell phenotype changes during the normal menstrual cycle and early pregnancy (68)
general proinflammatory effect of estrogen, causing an influx of macrophages and neutrophils, which is
antagonized by progesterone through its receptor (70, 71).
The mechanism of such a progesterone-induced local immunosuppression is unclear.
progesterone plays an important role in proliferation and differentiation of uNK cells (32).
Through promotion of a uterine Th2 environment, progesterone could indirectly affect uNK cell function
The mechanism of this increase in uNK cell numbers has been addressed
in both human and mouse models, and is likely the result of: 1) recruitment of peripheral NK cells to the uterus, and 2) proliferation
of existing uNK cells
prolactin system plays an important role in implantation and the maintenance of pregnancy
the exact pathways of hormonal regulation of NK cells remain to be delineated.
The exact function of uNK cells has not yet been unequivocally determined
uNK cells express a different cytokine profile, compared with resting peripheral NK cells. mRNAs for granulocyte
CSF, M-CSF, GM-CSF, TNF-α, IFN-γ, TGF-β, and leukemia inhibitory factor (LIF) have been found in decidual CD56+ cells
Their increased numbers in early pregnancy, their hormonal dependence, and their close proximity
to the infiltrating trophoblast all suggest that they play an important role in the regulation of the maternal immune response
to the fetal allograft and the control of trophoblast growth and invasion during human pregnancy
role of
uNK cell-derived cytokines on trophoblast growth and differentiation (114, 115, 116, 117).
Th1 immunity to trophoblast is associated with RPL, whereas Th2 immunity is associated
with a successful pregnancy
RPL is associated with Th1 immunity, for which NK cells are partly responsible.
statin therapy shown to decrease genetic expression of the ubiquitin proteasome pathway. Not only do statins damage mitochondria through CoQ10 depletion, but this study shows a new component of the damage statins do: they actually change the human genetic expression. This should startle you.
NF-kappaB and the associated inflammatory pathways are associated with tumor growth, vascular growth within the tumor, and increased migration of macrophages--thus more inflammation. When NF-kappaB inhibition was achieved, tumor macrophages and new tumor blood vessel growth was decreased. Reduced blood vessel growth to the tumor has implications on metastasis of the tumor.
elevated FFA (free-fatty acids) shown to produce inflammation and insulin resistance through endoplasmic reticulum stress. The main target in this pathway is IKK-Beta overexpression.