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Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids

a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)

Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase

there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes

To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases

intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers

intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging

dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain

mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment

Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways

unfolded protein response (UPR) machinery

ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases

brain ER stress underlies neurodegenerative diseases

under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival

intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance

prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging

TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense

Most hypothalamic cell types including neurons and glia cells express TLRs

overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs

Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition

hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding

overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain

these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.

circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors

significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components

entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension

Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions

both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.

In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein

IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity

Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition

it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic

this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension

evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition

In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging

intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation

overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved

excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC

oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging

central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations

overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders

chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases

recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations

when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect

autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)

The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases

Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome

Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway

TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase

these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response

TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus

central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.

cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation

central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain

the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance

the hypothalamus, is the central regulator of energy and body weight balance [

pharmacologic inhibition of NF-κB was effective in killing AML cells

High NF-κB expression is found in primitive human AML blast cells

niclosamide inhibited the TNF-induced NF-κB reporter activity in a dose- and time-dependent manner

niclosamide inhibiting TNF-induced IKK phosphorylation (Fig. 2A), niclosamide may exert its inhibitory effect at the TAK1 step

Pretreatment with niclosamide completely blocked the time- and dose-dependent TNFα-induced alteration of the NF-κB–DNA complex

niclosamide inhibited constitutively active NF-κB binding to DNA in U266 cells

niclosamide completely abolished the TNFα-induced phosphorylation of IKKα/β and IκBα

Accordingly, the TNFα-induced degradation of IκBα was abrogated by niclosamide

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

In this study, we found that curcumin down-regulated DNMT1 expression in AML cells. This occurred, at least in part, through down-modulation of two positive regulators of DNMT1: Sp1 and the NF-κB component, p65. We also found that curcumin-mediated down-regulation of DNMT1 was associated with reactivation of TSGs and tumor suppression, both in vivo and in vitro.

curcumin may selectively downregulate DNMT1 expression in tumor cells, but not in normal cells

DNMT1 expression is positively regulated by Sp1 and the NF-κB signaling component

indicating that curcumin may have significant anti-tumor activity in AML

We found that, compared to the vehicle control, curcumin treatment reduced tumor weight by 70%

Surprisingly, although curcumin significantly inhibited tumor growth in these mice, we were unable to find any obvious toxicity associated with curcumin treatment

Consistent with our observations regarding curcumin’s ability to inhibit tumor growth in vivo (Figure 4) and down-regulate DNMT1 expression in vitro and ex vivo (Figure 1), we found that decreased levels of DNMT1 protein and mRNA were expressed by tumor cells isolated from curcumin-treated mice

we identified curcumin as a substance which acts as an inhibitor of DNA methyltransferase enzymatic activity and induces significant global DNA hypomethylation in AML cells

In this study, we first demonstrated that curcumin decreases DNMT1 mRNA and protein expression levels, most likely through inhibiting expression of positive regulators of DNMT1, such as Sp1 and the p65 component of NF-κB component, and/or altering their ability to bind to the promoter region of DNMT1

(SOCS)-3. A member of a protein family originally characterized as negative feedback regulators of inflammation (13, 37), SOCS3 inhibits insulin and leptin signaling

IKKβ signaling in discrete neuronal subsets appears to be required for both hypothalamic inflammation and excess weight gain to occur during HF feeding

the paradoxical observation that hyperphagia and weight gain occur when hypothalamic inflammation is induced by HF feeding, yet when it occurs in response to systemic or local inflammatory processes (e.g. administration of endotoxin), anorexia and weight loss are the rule

, serves as a circulating signal of energy stores in part by providing feedback inhibition of hypothalamic orexigenic pathways [e.g. neurons that express neuropeptide Y and agouti-related peptide (AgRP)]

and stimulating anorexigenic neurons

signals from Toll-like receptors (TLRs), evolutionarily conserved pattern recognition molecules critical for detecting pathogens, amplified through signaling intermediates such as MyD88 activate the inhibitor of κB-kinase-β (IKKβ)/nuclear factor-κB (NF-κB), c-Jun N-terminal kinase (Jnk) and other intracellular inflammatory signals in response to stimulation by circulating saturated fatty acids

Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells

adipose tissue macrophage (ATM)

Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).

increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).

The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ

well-known regulators of lipid metabolism and mitochondrial activity

Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).

inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)

Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass

JNK, TLR4, ER stress)

NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells

Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity

DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)

saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)

Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)

Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)

Placental inflammation is a characteristic of maternal obesity

a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74

Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB

Nod-like receptor (NLR) family of PRRs

ceramides and sphingolipids

The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.

adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate

Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)

NF-κB, obesity also activates JNK in insulin-responsive tissues

Activation of NF-κB can also be blocked by several other thiol-containing antioxidants including N-acetyl-l-cysteine (NAC)

Other clinically available antioxidants reported to have antiinflammatory, antioncogenic, and/or antiatherogenic properties that have been shown to block the activation of NF-κB include resveratrol (115, 116), (-)-epicatechin-3-gallate (117), pycnogenol (118), silymarin (119), and curcumin (120)

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

however, 100 mg/kg of niclosamide could suppress the growth of the relatively slow-growing tumor (CRC039) to the same level

niclosamide was confirmed to inhibit the growth of human CRCs in NOD/SCID mice

niclosamide can inhibit Wnt pathway activation in CRC

The mechanism of action of the niclosamide in our studies is thought to be through internalization of Fzd1 and downregulation of Wnt pathway intermediaries

Recently, Jin et al. (26) reported that niclosamide inhibited the NF-κB pathway and increased reactive oxygen species levels to induce apoptosis in AML cells. In contrast, we did not observe any inhibitory effect of niclosamide on NF-κB signaling in our CRC model

One potential concern for the use of niclosamide as an anticancer therapy is the poor absorption of this drug

we required higher doses (100 ~ 200 mg/kg body weight) of niclosamide in order to demonstrate significant inhibition of tumor growth in NOD/SCID mice

niclosamide concentrations in tumor tissue showed good correlation with those in plasma, suggesting the efficient distribution of niclosamide from blood to tumor tissue

we observed downregulation of Dvl2 and ß-catenin cytosolic expression in niclosamide-treated tumor cells in vivo

oral administration of niclosamide does result in sufficient distribution of the drug into tumor tissue, to prove a prolonged inhibitory effect on Wnt/ß-catenin signaling, resulting in tumor growth inhibition

The Wnt signaling pathway, fundamental to embryonic tissue patterning, is also activated in stem-like cells

The canonical Wnt pathway is activated in approximately 80% of sporadic CRC primarily due to mutations in the APC gene

recent observations reveal that Wnt ligands or inhibitors may affect the growth and survival of colon cancer cells in spite of the presence of APC or CTNNB1 mutations