Interferon therapy in men with hepatitis C was found to decrease total Testosterone and Free Androgen index at the level of the gonads; this was independent of the HPA in this study.
Study of men with hepatitis C and interferon therapy found decrease in free and total Testosterone levels in men. The study results suggest a non-HPA effect, which suggests more of a peripheral effect at the level of the TEsticles.
Exercise is not just for calories out. Exercise increases growth hormone, IGF-1, glucagon-like peptide 1, IL-6, and IL-1ra. The effect is to GH increases beta islet cell mass and protects beta cell lines against IL-1beta, Interferon-gamma and TNF-alhpa induced apoptosis. IL-6 increased production increases GLP-1 and IL-1ra which counters IL-1beta. Interleukin-1beta induces islet cell apoptosis and thus IL-1ra counters this pro-inflammatory signal.
EGCG found to reduce cytokine production in animal model of MS, experimental autoimmune encephalomyelitis. Specifically, EGCG reduced interferon gamma, IL017, IL-6, IL-1beta, TNF-alpha and decreased Th1 and Th17 cells with an increase in Treg cells.
Estradiol in mice predisposed to Lupus have increased inflammation and characteristics of Lupus. In contrast, Estradiol in those without predisposition, do not. Clearly this is an inflammatory signaling problem. Studies have shown an Interferon gamma signaling deficit in those with Lupus.
Testosterone decreases the above inflammation signaling.
hepatitis associated with a decline in total Testosterone. This was a positive correlation with worsening hepatitis. Free Testosterone was not effected. Interesting, SHBG increased.
Study found that viral oncolytic therapy improved efficacy of PD-1 check point inhibitors by 62%. Increased CD8 expression, interferon-gamma...Interesting, starting CD8 levels played no role in predicting outcome.
only abstract available here. Great review and discussion of the research behind Germanium Sesquioxide and its immune effects in the fight against cancer. Primary effects are via increase in Interferon gamma and increase in NK cell activity; but it also inhibits tumor growth and metastatic potential. The germanium compound is specific to the sesquioxide compound.
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
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.
IV antioxidant mixture of vitamin C, glutathione, glycyrrhiza, and B-complex reduces liver enzymes. Arm taking only oral shows no decline in liver enzymes.
anti-depressants inhibit inflammatory IL-6 production from microglial cells in brain, suggesting anti-inflammatory effects of antidepressants as role in improving depression symptoms