animal study finds that cocaine binge use associated with decreased eNOS expression in the penis. This is consistent with the other very limited studies that show that cocaine decreases eNOS protein expression and thus NO.
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
Testosterone has beneficial
effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves
cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart
failure.
testosterone is an L-calcium channel blocker and induces potassium
channel activation in vascular smooth muscle cells
Animal studies have consistently demonstrated that testosterone is atheroprotective,
whereas testosterone deficiency promotes the early stages of atherogenesis
there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes
adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
bidirectional effect between decreased testosterone
concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and
insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular
risk factors
Achieving a normal physiological testosterone concentration through the administration
of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central
adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory
profiles and vascular function
It is well known that impaired erectile function and CVD are closely
related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5
years
no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
free testosterone
levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated
brachial artery vasodilation in men with CAD
Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects
when testosterone is replaced within normal physiological limits in humans
Endothelium-independent mechanisms of testosterone
are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
Testosterone shares the same molecular binding site as nifedipine
Testosterone increases the expression of endothelial nitric oxide synthase (eNOS)
and enhances nitric oxide (NO) production
Testosterone also inhibited
the Ca2+ influx response to PGF2α
one of the major actions of testosterone is on NO and its signalling pathways
In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult
to delineate and may be dependent upon the stage of plaque development
Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate
with serum testosterone
t long-term testosterone treatment reduced CIMT in men with low testosterone levels
and angina
neither intracellular nor membrane-associated
ARs are required for the rapid vasodilator effect
acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described,
primarily in the context of vascular tone regulation via the modulation of gene transcription
Testosterone and DHT increased the expression of eNOS in HUVECs
oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase
inhibition
non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated
human umbilical vein endothelial cells
Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure
in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis
factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM
and/or hypogonadism
patients with the
highest IL1β concentrations had lower endogenous testosterone levels
TRT has been reported to significantly
reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
testosterone treatment to normalise levels in hypogonadal men with the MetS
resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly
men
Higher levels of serum adiponectin have been shown to lower cardiovascular risk
Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ
(IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types
including human endothelial cells
decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in
human endothelial cells when treated with DHT
The key to unravelling the link between testosterone
and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors
and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
testosterone
functions through the AR to modulate adhesion molecule expression
pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
DHT inhibited NFκB activation
DHT could inhibit an LPS-induced upregulation of MCP1
Both NFκB and
AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory
agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis
may reduce or alter any potentially protective effects of testosterone
DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional
level, suggesting that androgens down-regulate IFN-induced genes
(Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT
3β-derivative, 3β-Adiol
TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly
reduced by a pre-incubation with 3β-Adiol in HUVECs
3β-Adiol also reduced LPS-induced gene expression
of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory
effects that are mediated by ER activation.
The authors suggest that DHT differentially
effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and
via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated
an increased risk of adverse cardiovascular events or mortality
The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely
as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase
in either cardiovascular events or mortality in studies up to 12 months
Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse
effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect
or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors,
there may possibly be a cardioprotective action
The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen
and/or disease status.
the majority of studies suggest that testosterone may display both acute and
chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via
endothelium-dependent and -independent mechanisms
5-MTHF increases BH4 which increases eNOS activity and NO production providing improved endothelial function and thereby providing a mechanism to reduce atherosclerosis. Interesting that the MTHFR A1298C decreases BH4 in contrast to the 677T.
IV Vitamin C improves endothelial vasodilation in essential hypertension. The Vitamin C reduces the oxygen free radicals which allowed eNOS to increase NO production. Two take homes: oxygen free radicals may be responsible for the endothelial dysfunction that leads to essential hypertension and vitamin C, particularly IV, can be used to counter this process. Other studies have shown IV vitamin C to be anti-hypertensive in its action.
Tetrahydrobiopterin is a critical cofactor for the NO synthases
at hypertension produces a cascade involving production of ROSs from the NADPH oxidase leading to oxidation of tetrahydrobiopterin and uncoupling of endothelial NO synthase (eNOS). This decreases NO production and increases ROS production from eNOS
Tetrahydrobiopterin oxidation may represent an important abnormality in hypertension
Treatment strategies that increase tetrahydrobiopterin or prevent its oxidation may prove useful in preventing vascular complications of this common disease.
Chronic stress increases cardiovascular disease. Of note, chronic stress reduces eNOS activity and NO bioavailability, increased lipid oxidation (oxLDL) via a reduction in antioxidant protection, increased pro-inflammatory cytokines, increased thrombosis and clotting risk, increased blood pressure and reduced HRV.
IV vitamin C and BH4 shown to resolve blood flow restriction in Sepsis rat model. Again, revealing the benefits of not only vitamin C, but IV vitamin C.
This is the perfect study to compare synthetic, unnatural hormones with bioidentical hormones. Premarin was compared with bioidentical estradiol. Premarin reduced the endothelial NO synthase transcription and activity by 30-50% compared to Estradiol. Thus, premarin results in a lower NO production and thus greater endothelial dysfunction compared to Estradiol.
beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity
Great review of the redox system in cancer cells. Everybody focus' on the ROS, but forget about the RNS from NO. The current marketing pushes NO for CVD.
Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
NO from eNOS in cancer cells can travel through membranes and over long distances in the body
NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
Inhibition of inducible Nitric Oxide Synthase (iNOS)
NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
tolerance in the immune system that decreases the immune response to antigens on the tumors
Freund’s adjuvant
increase in kinases in these cells which phosphorylate serine, and tyrosine
responsible for activation of many growth factors and enzymes
phosphorylated amino acids suppress iNOS activity
Hexokinase II
Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10. IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
cGMP is increased by NO
NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
the greater the malignancies and the greater the metastatic potential of these tumors
The greater the NO production in many types of tumors,
gynecological
elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells. Histamine alone stimulates many tumor cells.
The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
COX 2 inhibitors or all trans-retinoic acid
Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
some steroid hormone-induced nuclear events can occur in minutes
the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
Further, ER activates IGF-IR pathways including MAPK
GPER is involved in the transactivation of the EGFR independent of classical ER
tight interconnection between genomic and non-genomic effects of NRs.
non-genomic pathways can also lead to genomic effects
androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
extranuclear steroid hormone actions can potentially reprogram nuclear NR events
estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells