good article on the biochemistry of COX2 in inflammation. Particularily with AGE and it the receptors RAGE. COX2 has been shown to decrease insulin secretion through inhibition of islet cell production, but in the presence of disease level inflammation, COX2 can be a part of a very dangerous autocrine/paracrine loop.
Cox-2 found to increase prolactin expression to increase metastatic spread of cancer cells. Cox-2 may work here more in the autocrine/paracrine prolactin signaling. This is an animal study.
Cox II inhibition helps to slow surgical induced metastatic and local recurrence of cancer. Surgery does cause metastasis and local recurrence and cox II inhibition stops spread.
COX-2 is overexpressed in a variety of human cancers i.e. colorectal, prostate, lung adenocarcinoma. This study hightlights the increased tumor metastatic potential via upregulation of VEGF-C via EP1 and HER-2 dependent pathways. This upregulation was correlated with survival and mets.
Rat model induced inflammatory reaction in brain via LPS injection. The result was impaired memory. RG3 from panax ginseng was shown to reduce inflammation, TNF-alpha, IL-1beta, cox-2, thus improving memory and cognitive function.
O2-O3 triggers tumoricidal immune response after application of a repetitive highly oxidative stimulus by insufflation of a medical O3/O2 gas mixture into the peritoneal cavity in animal model. O3/O2-PP treatment, indicates an enhanced activation of the innate and adaptive arms of the immune system, implicating a role of activated TILs In the anti cancer effects of the O3. Interestingly, COX2 expression was decreased.
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
secretion of MCP-1,
resistin, and other proinflammatory cytokines is increased by
obesity, the adipose secretion of the anti-inflammatory protein
adiponectin is decreased
the
peroxisome proliferators- activated receptor (PPAR) family are
involved in the regulation of inflammation and energy homestasis
natural agonists, including unsaturated fatty acids and
eicosanoids
PPARα also
regulates inflammatory processes, mainly by inhibiting
inflammatory gene expression
upregulation of COX-2 is seen in alcoholic
steatohepatitis and nonalcoholic steatohepatitis and has been
directly linked to the progression of steatosis to
steatohepatitis, the inhibitory effect of PPARα on COX-2
may reduce steatohepatitis
PPARα agonists have a clear anorexic
effect resulting in decreased food intake, evidence is
accumulating that PPARα may also directly influence
adipose tissue function, including its inflammatory
status.
PPARα may govern adipose tissue inflammation in three
different ways: (1) by decreasing adipocyte hypertrophy, which is
known to be connected with a higher inflammatory status of the
tissue [3, 11, 59], (2) by direct regulation of inflammatory
gene expression via locally expressed PPARα, or (3) by
systemic events likely originating from liver
PPARγ is considered the master regulator of adipogenesis
Unsaturated fatty acids and several
eicosanoids serve as endogenous agonists of PPARγ
PPARγ2, which is
adipose-tissue specific
two different molecular mechanisms have been proposed by which
anti-inflammatory actions of PPARγ are effectuated: (1)
via interference with proinflammatory transcription factors
including STAT, NF-κB, and AP-1
and (2) by preventing removal of corepressor complexes from gene promoter
regions resulting in suppression of inflammatory gene
transcription
diet-induced obesity is associated with increased inflammatory
gene expression in adipose tissue via adipocyte hypertrophy and
macrophage infiltration
PPARγ is
able to reverse macrophage infiltration, and subsequently reduces
inflammatory gene expression
Inflammatory adipokines mainly originate from macrophages which
are part of the stromal vascular fraction of adipose tissue
[18, 19], and accordingly, the downregulation of inflammatory
adipokines in WAT by PPARγ probably occurs via effects on
macrophages
By interfering with NF-κB signaling pathways,
PPARγ is known to decrease inflammation in activated
macrophages
Recent data suggest that activation of PPARγ in
fatty liver may protect against inflammation
PPARs may influence the inflammatory response either by direct
transcriptional downregulation of proinflammatory genes
anti-inflammatory
properties of PPARs in human obesity
PPARs play pivotal in obesity. PPARs appear to reduce the inflammatory cascade associated with obesity. Downregulation of PPARs are associated with increased inflammation. Natural PPARs include unsaturated fats and eicosanoids.
Progesterone receptor (PR) shown to provide an important anti-inflammatory role in breast cancer in this study. PR shown to increase NF-kappaB inhibitor IkBalpha, shown to inhibit aromatase activity, shown to inhibit COX-2 expression and shown to inhibit HER-2/neu expression.