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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

In cycling women, the largest quantities of Ig were detected before ovulation

In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors

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

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

Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases

IFN-γ, IL-12, and TNF were allocated to Th1 reactions

IL-4, IL-5, and IL-10 to Th2 responses

antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17

no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.

So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.

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

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

In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity

increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response

secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels

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

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.

E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal

It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation

important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF

low E2 concentrations were demonstrated to have no or even stimulatory effects

This renders a woman in the postmenopausal phase to a more proinflammatory situation

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

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

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

Major Gram-negative bacilli of the human GI-tract, such as the abundant B. fragilis and Escherichia coli (E. coli), are capable of discharging a remarkably complex assortment of pro-inflammatory neurotoxins

(i) bacterial amyloids (10, 21); (ii) endotoxins and exotoxins (5, 12); (iii) LPS (12, 18); and (iv) small non-coding RNAs (sncRNAs)

integral components of the outer leaflet of the outer membrane of Gram-negative bacteria, LPS

LPS, the major molecular component of the outer membrane of Gram-negative bacteria normally serves as a physical barrier providing the bacteria protection from its surroundings

LPS is also recognized by the immune system as a marker for the detection of bacterial pathogen invasion and responsible for the development of inflammatory response is perhaps the most potent stimulator and trigger of inflammation known

AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable

first evidence of a perinuclear association of LPS with AD brain cell nuclei

LPS-mediated stimulation of chronic inflammation, beta-amyloid accumulation, and episodic memory decline in murine models of AD (39, 40) and a biophysical association of LPS with amyloid deposits and blood vessels in human AD patients

Strong adherence of LPS to the nuclear periphery has recently been shown to inhibit nuclear maturation and function that may impair or block export of mRNA signals from brain cell nuclei, a highly active organelle with extremely high rates of transcription, mRNA processing, and export into the cytoplasm

LPS may be further injurious to the nuclear membrane just as LPS contributes to cerebrovascular endothelial cell membrane injury

high intake of dietary fiber is a strong inhibitor of B. fragilis abundance and proliferation in the intact human GI-tract and as such is a potent inhibitor of the neurotoxic B. fragilis-derived amyloids, LPS, enterotoxins, and sncRNAs.

GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to inflammatory degeneration in the AD CNS

LPS has been recently localized to the same anatomical regions involved in AD-type neuropathology

a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation

pro-inflammatory amyloids, endo- and exotoxins, LPSs, and sncRNAs but also serve as potent sources of membrane-disrupting agents

colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable

The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment

The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD

In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal

Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum

We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro

The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic

The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well

Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).

we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.

Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.

In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment

This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.

The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s

Lyme, Connecticut.

Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere

approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6

Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)

‘post-treatment Lyme disease syndrome’ (PTLDS)

host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic

inflammatory responses to residual antigens from dead organisms

residual tissue damage following pathogen clearance;

autoimmune responses, possibly elicited by antigenic mimicry

Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses

Ten male rhesus macaques

half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.

Minimal and focal lymphoplasmacytic inflammation

inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex

Minimal localized lymphoplasmacytic choroiditis

Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces

Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group

For all animals, inflammation was reserved to perineural tissue

The treatment lasted 28 days

Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs

A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal

mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal

three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures

10% to -20% of human patients treated

Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)

and the rapid clearance of dead spirochetes in a murine model

higher doses may be needed to combat neuroborreliosis

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

Niclosamide blocked TNFα-induced IκBα phosphorylation, translocation of p65, and the expression of NF-κB-regulated genes

Niclosamide also inhibited the DNA binding of NF-κB to the promoter of its target genes

niclosamide has two independent effects: NF-kB activation and ROS elevation

The Wnt signaling pathway plays fundamental roles in directing tissue patterning in embryonic development, in maintaining tissue homeostasis in differentiated tissue, and in tumorigenesis

niclosamide is a potent inhibitor of the Wnt/β-catenin pathway

The Notch signaling pathway plays important roles in a variety of cellular processes such as proliferation, differentiation, apoptosis, cell fate decisions, and maintenance of stem cells

niclosamide potently suppresses the luciferase activity of a CBF-1-dependent reporter gene in both a dose-dependent and a time-dependent manners in K562 leukemia cells

niclosamide treatment abrogated the epidermal growth factor (EGF)-stimulated dimerization and nuclear translocation and transcriptional activity of Stat3, and induced cell growth inhibition and apoptosis in several types of cancer cells (e.g. Du145, Hela, A549) that exhibit relatively higher levels of Stat3 constitutive activation

niclosamide can rapidly increase autophagosome formation

niclosamide induced autophagy and inhibited mammalian target of rapamycin complex 1 (mTORC1)

Niclosamide has low toxicity in mammals (oral median lethal dose in rats >5000 mg/kg

Niclosamide is active against cancer cells such as AML and colorectal cancer cells, not only as a monotherapy but also as part of combination therapy, in which it has been found to be synergistic with frontline chemotherapeutic agents (e.g., oxaliplatin, cytarabine, etoposide, and daunorubicin)

Because niclosamide targets multiple signaling pathways (e.g., NF-κB, Wnt/β-catenin, and Notch), most of which are closely involved with cancer stem cells, it holds promise in eradicating cancer stem 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

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

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