Open access peer-reviewed chapter

Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

Written By

Ceren Gezer

Submitted: 27 July 2017 Reviewed: 23 October 2017 Published: 28 February 2018

DOI: 10.5772/intechopen.71867

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The stress responses observed in mammalian cells can be classified as heat shock response, unfolded protein response, autophagic response, deoxyribonucleic acid damage response, antioxidant response, and sirtuin response at the intracellular and molecular levels. Factors that strengthen the hemodynamic structure causing low-level molecular damage and activating one or several stress response pathways are called hormetins. Hormetins can be categorized as physical, physiological, biological, and nutritional hormetins. Nutritional hormetins provide an interesting, comprehensive research topic because of their effects on health and lifespan. Dietary phytochemicals, with their low-level stress-inducing effects, are potential nutritional hormetins. Resveratrol, curcumin, epicatechin, isothiocyanates, ferulic acid, and certain vitamin-minerals can induce a heat shock response, unfolded protein response, autophagic response, deoxyribonucleic acid damage response, antioxidant response, and sirtuin response causing the stimulation of kinases and transcription factors. Studies have shown that these phytochemicals are related to nuclear factor-erythroid 2, sirtuins, nuclear factor-kappa B, and heat shock response pathways. In this chapter, the stress response of dietary phytochemicals will be systematically examined in a hormetic manner for delay of age-related diseases, healthy aging, and longevity based on current data.


  • aging
  • longevity
  • health
  • stress response
  • hormesis
  • nutritional hormetin
  • phytochemical

1. Introduction

The term hormesis, based on toxicology, is described as a biphasic dose response in which environmental factors show a stimulant effect at low doses and a toxic effect at higher doses [1]. A comprehensive current definition of “hormesis” is "chemical and environmental factors having a beneficial effect to cells in an organism at low doses, whereas they are damaging at high doses" [2]. Hemodynamic is the ability of live systems to provide protection against stress, and to maintain adaptation, survival, and continuity of health. Hemodynamic impairment, increased molecular heterogeneity, altered cellular function, and decreased adaptive stress responses are some factors that determine health status and lifespan [3, 4]. The development of adaptive stress response with mild and periodic stress is hormetically related to the strengthening of the hemodynamic structure, the reduction of disease risks, and healthy aging. Hormesis in aging implies that mild stress produces biologically beneficial effects by inducing protective mechanisms in the cells and the organism [5]. Stress response can be defined as the response of cells, tissues, and organisms to physical, chemical, or biological factor(s) affecting adaptation and lifespan by initiating a series of biological events. In terms of hormetic level, stressors at a mild level activate various signaling pathways, maintaining intrinsic changes leading to a high level of stress-adaptive response. Stress response in mammalian cells can be classified into seven basic pathways at the intracellular and molecular levels: (1) heat shock response; (2) unfolded protein response; (3) autophagic response; (4) deoxyribonucleic acid (DNA) repair response; (5) antioxidant response; (6) sirtuin response; and (7) nuclear factor-kappa B (NF-κB) inflammatory response. The conditions and factors identified as hormetic activate the pathway of one or more stress responses by mild molecular impairment and strengthen the hemodynamic structure. Hormetins can be grouped under three categories: (1) physical hormetins (exercise, thermal shock, and irrigation); (2) physiological hormetins (mental interrogation and focusing); (3) biological and nutritional hormetins (infections, micronutrients, phytochemicals, and energy restriction) [4, 6, 7].

Dietary phytochemicals are potential nutritional hormetins with mild stress-inducing effects. In the Greek language “phyto” means plant, so phytochemical means “plant chemical.” Phytochemicals are non-nutrient biologically active compounds produced to protect plants against microbial infections that occur because of environmental factors damaging the plant. Therefore, phytochemicals, which are secondary plant metabolites found primarily to protect their structures and properties in vegetables, fruits, grains, and various plants, may have positive effects on human health when taken in the diet. Phytochemicals are generally classified according to their chemical structure. The main groups with bioactive properties from these groups are phenolic compounds [8, 9]. Ferulic acid, resveratrol, epigallocatechin gallate (EGCG), luteolin, quercetin, and curcumin as phenolic compounds are dose-dependently responsible for the stimulation of kinases and transcription factors and produce a heat shock response, unfolded protein response, autophagic response, DNA repair response, antioxidant response, and sirtuin response [6, 10, 11, 12, 13]. In this chapter, the stress response of dietary phytochemicals will be systematically examined in a hormetic manner for delay of age-related diseases, healthy aging, and longevity based on current data.


2. Dietary Phytochemicals as Nutritional Hormetins

When dietary phytochemicals are invoked in relation to neurodegenerative diseases, cardiovascular diseases, cancer, aging, and longevity, especially in the heat shock response, antioxidant response, NF-κB inflammatory response, and autophagic response were emphasized regarding their hormetic adaptive stress response pathways. The characteristics and importance of these stress response pathways are summarized in what follows.

The major effectors involved in heat shock response are heat shock proteins (HSPs), which are cytoprotective proteins that facilitate cellular protein folding, prevent protein aggregation, and provide protein degradation activation. They also affect the cell survival by interacting with various molecules in the regulation of apoptosis and mitochondrial activities. HSPs are divided into five main groups: the Hsp100 family, Hsp90 family, Hsp70 family, Hsp60 family, and the small Hsp family. Hsp70 regulates protein homeostasis, thereby, it can provide protection against cancer, neurodegeneration, and infections [14, 15]. Hsp90 regulates the stability and intracellular sorting of client proteins found in many oncogenic processes. Thus, Hsp90 inhibition may prevent cancer progression [16]. Hsp27 can protect against neurodegenerative diseases by controlling apoptosis, cytoskeleton regulation, oxidative stress, and protein folding [17]. In general, HSPs provide the survival of cancer cells by overexpression in cancer cells. Thus, the inhibition of Hsp27, Hsp70, and Hsp90 can be targeted in the treatment of cancers in which HSPs are known to be over-expressed [18]. The nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) is the main effective pathway in the formation of antioxidant stress responses. Under basal conditions, Nrf-2 is present in the cell cytoplasm bound to Keap1 protein. However, when combined with oxidative stress and chemo-blocking factors, Nrf2 is released from Keap-1 into the nucleus; it activates the ARE and induces the expression of the antioxidant enzymes including glutathione peroxidase (GPx), catalase, hemoxygenase (HO)-1, and the phase II detoxification enzymes, including glutathione S-transferase (GST). Extracellular signaling protein kinases are responsible for the release of Nrf2 from Keap-1 by phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase C (PKC), and c-Jun N-terminal kinase (JKN). Thus, Nrf2 associated with the cell defense mechanism, may have protective effects against oxidative stress-induced tissue degeneration, premature aging, cancer, neurodegenerative diseases, cardiovascular diseases, acute and chronic lung diseases, and autoimmune and inflammatory diseases [19, 20, 21, 22]. Among the factors that induce Nrf2 in the formation of antioxidant stress responses are isothiocyanates and Michael acceptors. Michael acceptors are susceptible to flavonoids, chalkones, terpenoids, curcumin, cinnamic acid derivatives, and thiophenes, and interact with these phytochemicals to modulate the Nrf-2 pathway [23, 24]. The effector NF-κB protein complex action regulates the expression of genes involved in innate and adaptive immunity, inflammation, cellular stress response, cell survival, and proliferation. Therefore, this pathway can be effective in pathogenesis of inflammatory and autoimmune diseases, septic shock, viral infections, tumorigenesis, and neurodegenerative diseases. Various dietary phytochemicals such as curcumin and resveratrol can suppress NF-κB activation and protect against immunological and inflammatory diseases, cancer, and neurodegenerative diseases [12]. In an autophagic response, hypoxia-inducible factor (HIF)-1 and the activated mammalian target of rapamycin (mTOR) are important. mTOR is involved in cell proliferation and protein synthesis via insulin and insulin-like growth factor (IGF)-1 signaling. It can also cause the suppression of autophagy, and reduced autophagy is associated with decreased longevity. Thus, the increase in autophagy is associated with an increase in inflammatory response, cellular senescence, decreased proteotoxic protein aggregation, and the removal of intracellular pathogens, cumulatively resulting in an increased innate immune response that leads to longevity [25]. HIF-1 regulates genes related to angiogenesis, iron and glucose metabolism, cell proliferation and cell survival. Various dietary phytochemicals, with HIF-1 inhibition, have protective effects against neurodegenerative diseases, cancer, cardiovascular diseases [12, 26]. In this section, hormetic effects of phenolic compounds predominantly expressed as hormetin including ferulic acid, curcumin, resveratrol, EGCG, luteolin, quercetin, and sulforaphane will be discussed in relation to these stress response pathways. The stress pathways, transcription factors, and biological outcomes of these phytochemicals have been summarized in Table 1 .

Phytochemicals Stress pathways Transcription factors Biological outcomes References
Antioxidant response pathway Nrf-2 HO-1↑ [31, 32]
Ferulic acid NFκB inflammatory pathway NFκB NO↓, iNOS↓ [33]
Heat shock response pathway HSF-1 Hsp70↑ [35]
Autophagic response pathway mTOR inhibition [36]
Antioxidant response pathway Nrf2 Glutathione, GR, GST, HO-1, NQO1 [43, 44]
Curcumin NFκB inflammatory pathway NFκB SOD-2↑, Hsp60↑ [42, 45]
Heat shock response pathway HSF-1 Overexpressed Hsp27↓, Hsp70↓, Hsp90↓
Hsp27↑, Hsp70↑
[39, 40]
[41, 42]
Sirtuin response pathway SIRT3↑ [42]
Antioxidant response pathway Nrf2 Glutathione↑, HO-1↑ [49, 50]
Resveratrol NFκB inflammatory pathway NFκB iNOS↓, IL-6↓, TNF-α↓ [54, 55]
Heat shock response pathway HSF-1 Hsp25↑, Hsp70↑ [47, 48]
Autophagic response pathway mTOR inhibition [52, 53]
Sirtuin response pathway SIRT1↑ [47, 48]
Antioxidant response pathway Nrf2 GST↑, NQO1↑, HO-1↑ [59, 60, 62, 64]
EGCG NFκB inflammatory pathway NFκB IL-12p40↓, IL-6↓ [65, 66, 67]
Heat shock response pathway HSF-1 Overexpressed Hsp90↓ [58]
Autophagic response pathway HIF-1α, mTOR inhibition [68, 69]
Antioxidant response pathway Nrf2 HO-1↑, CYP1A1↑, NQO1↑, GST-P1↑, GCLC↑, GCLM↑ [76, 77, 78, 80, 81, 83]
Luteolin NFκB inflammatory pathway NFκB TNF-α↓, NO↓ [73, 74, 75, 81]
Autophagic response pathway HIF-1α inhibition [82]
Sirtuin response pathway SIRT1↑ [81]
Antioxidant response pathway Nrf2 GSH↑, GPx↑, GR↑, GST↑, GCLC↑, GCLM↑, HO-1↑ [89, 90, 91, 92, 93, 94, 95]
Quercetin NFκB inflammatory pathway NFκB COX-2↓ [90, 94]
Heat shock response pathway HSF-1 Overexpressed Hsp27↓, Hsp70↓ [85, 86, 87]
Autophagic response pathway HIF-1, mTOR inhibition [88, 96, 97, 98, 99, 100, 101]
Antioxidant response pathway Nrf2 HO-1↑, SOD-1↑,NQO1↑ [104, 105, 106, 107, 108, 109, 110, 111]
Sulforaphane NFκB inflammatory pathway NFκB TNF- α↓, IL-6↓ [109]
Autophagic response pathway HIF-1α inhibition [114]

Table 1.

Summary of stress pathways, transcription factors, and biological outcomes of phytochemicals.

↑: increased; ↓: decreased.

2.1. Ferulic acid

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a cinnamic acid derivative phenolic compound. It is also the preliminary metabolite for curcumin and lignins. Grain bran, whole grains, artichoke, eggplant, banana, cabbage, and coffee are rich in ferulic acid. Ferulic acid has a positive effect on diseases such as cancer, Alzheimer’s disease, Parkinson disease, and diabetes through various pathways. Among the mechanisms of action of ferulic acid are the antioxidant response, heat shock response, and NF-κB inflammatory response, especially in the adaptive stress response pathways [27, 28, 29]. Ferulic acid showed a protective effect against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 intestinal epithelial cells in a dose-dependent manner in male Sprague-Dawley rats in vitro and in vivo [30]. In a study conducted on the human neuroblastoma cell line SH-SY5Y, ferulic acid increased dose-dependent HO-1 expression through Nrf2 [31]. In a study on PC12 cells, ferulic acid increased HO-1 expression through ERK1/2-Nrf2 signaling pathway and protected against lead acetate-induced neurite outgrowth inhibition [32]. On the other hand, 1-feruloyl glycerol and 1-feruloyl diglycerol predominate in water-soluble forms of ferulic acid in rat primordial astrocytes, suppressing nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) expression by suppressing the NF-κB pathway. Accordingly, these ferulic acid forms may provide a protective effect against neurodegenerative diseases [33]. The tumor necrosis factor (TNF)-α induces endothelial dysfunction by reducing NO bioavailability. Ferulic acid increased tyrosine-dependent NO production and suppressed the NF-κB pathway in TNF-α-stimulated inflammatory human umbilical vein endothelial cells (HUVECs) [34]. Another study showed that ferulic acid demonstrated a cardioprotective effect by increasing Hsp70 through the NO-ERK1/2 pathway in mice cardiomyocytes and suppressing the NF-κB pathway [35]. In another study, HeLa and mouse primary hepatocyte cells activated basal autophagy with an mTOR inhibition almost equivalent to that of rapamycin [36]. As a result, ferulic acid can exert a protective effect against neurodegenerative diseases, cardiovascular diseases, and cancer inflammatory diseases by acting on stress pathways and thus can positively affect longevity.

2.2. Curcumin

Curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also known as diferuloylmethane, is a yellow phenolic compound, found in Curcuma longa (turmeric) a plant of the ginger family. Curcumin is the compound responsible for the chemical and biological properties of this spice, as well as its color and taste. Numerous studies have shown that curcumin is associated with antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer effects, mitigating chronic diseases and increasing longevity [37, 38]. HSPs, HSF1, and histone deacetylase (HDAC) 6 are upregulated in cancer. Expression of Hsp 27, Hsp70, Hsp90, HSF1, and HDAC-6, which are overexpressed in K-562 and HL-60 leukemia cells, was reduced when curcumin was administered [39]. Also, curcumin appeared to reverse the inhibition on Hsp70 induced by the gp120 V3 loop peptide and increased the expression of Hsp70 in primary rat cortical neuronal apoptosis [40]. In addition, curcumin can protect against endosulfan toxicity by decreasing endosulfan-induced apoptosis through increased Hsp 27 expression in human peripheral blood mononuclear cells (PBMCs) [41]. In hyperglycemic HepG2 human hepatoma cells, curcumin increased the expression of NF-κB and Hsp70, sirtuin (SIRT)-3, glutathione peroxidase (GPx)-1, and superoxide dismutase (SOD)-2 in a dose-dependent manner [42]. On the other hand, curcumin may act as an antioxidant in the stress-response pathway. Primary cell cultures of cerebellar granule neurons of rats increased the expression of HO-1, glutathione, glutathione reductase (GR), GST, and SOD through Nrf-2 depending on the dose and duration and thereby protected against hemin-induced toxicity [43]. In mice liver cells with T-cell lymphoma, the expression of GST, GR, and NAD(P)H:quinine oxidoreductase (NQO1) enzymes was increased by activation of curcumin Nrf-2 [44]. Lipopolysaccharide (LPS)-stimulated BV2 mouse microglia cells also inhibited microglial activation by inhibiting the curcumin Hsp60/TLR4/MyD88/NF-κB pathways [45]. As a result, curcumin can show protective effects against cancer, neurodegeneration, and inflammation by acting on stress-response pathways.

2.3. Resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phenolic compound found in some plants such as grapes, berries, peanuts, and Japanese knotweed, with purported medical uses. Several studies have shown that resveratrol affects chronic diseases and longevity through anti-carcinogenic, anti-inflammatory, and antioxidant properties [46]. Resveratrol dose-dependently increased expression of Hsp70 and SIRT-1 in human neuroblastoma SH-SY5Y cells induced by neurotoxicity with high-dose homocysteine [47]. It has been reported that resveratrol induced Hsp25 and Hsp70 proteins in G93A-SOD1 mutant mice cells and can prevent motor neuron losses [48]. Resveratrol dose-dependently increased glutathione expression through the Nrf2 pathway in normal human keratocytes [49]. In the human neuroblastoma cell line SH-SY5Y, resveratrol dose-dependently increased HO-1 expression and HO-1-dependent autophagic flux and prevented rotatone-induced apoptosis [50]. It has been determined that resveratrol dose-dependently reduced the vascular endothelial growth factor (VEGF), leptin, interleukin (IL)-6, and IL-8 expression in hypoxia-induced human adipocytes and prevented adipokine-induced inflammation and angiogenesis [51]. In addition, resveratrol induced autophagy by directly inhibiting mTOR in HeLa cells [52]. Prostate cancer cells induced autophagy through inhibition of the Akt/mTOR pathway in PC3 and DU145 cells [53]. In murine RAW 264.7 macrophages and microglial BV-2 cells, resveratrol also inhibited microglial activation by suppressing the NF-κB pathway [54]. In another study, resveratrol showed anti-inflammatory effect by suppressing the NF-κB pathway in RAW 264.7 murine macrophages in a dose-dependent manner [55]. These studies suggest that resveratrol has anti-inflammatory, antioxidant, anti-carcinogenic effects and can strengthen hemodynamic structure, which in turn can positively affect the aging process and longevity.

2.4. Epigallocatechin gallate

The major catechin EGCG, which is found in green tea at a level of 48–55%, has protective effects against chronic diseases such as neurodegenerative diseases, metabolic syndrome, and cancer by its anti-inflammatory and antioxidant effects [56, 57]. EGCG, with Hsp90 inhibition, showed a protective effect against cancer in a novel human prostate cancer progression model [58]. In primary vascular endothelial cells, GST and NQO1 enzymes were increased dose-dependently by Nrf2 [59]. In another study, EGCG increased the level of HO-1 expression by Nrf-2 activation in endothelial cells, resulting in the passage of caveolin-1 from the plasma membrane to the cytosol, accumulating in the caveolae-regulating signaling pathways associated with vascular disease pathology [60]. Accordingly, EGCG may reduce endothelial inflammation and protect against atherosclerosis [61]. EGCG also showed a protective effect against oxidative stress-induced cerebral ischemia through Nrf2/ARE activation [62]. EGCG suppressed the Nrf-2 pathway in a lethal dose with biphasic dose-response effect in mice hepatocytes [63]. EGCG has been shown to inhibit oxidative stress damage induced by HO-1 through Nrf2 in HUVECs with ambient fine particulate matter (≤2.5 μm in aerodynamic diameter PM2.5) [64]. EGCG dose-dependently suppresses endothelial inflammation through NF-κB inhibition in high glucose-induced HUVECs [65]. It can also suppress NF-κB activation in cardiac fibroblasts and can show a protective effect against cardiac fibrosis [66]. EGCG inhibited lipopolysaccharide-induced inflammation with NF-κB suppression in bone marrow-derived macrophages (BMMs) isolated from ICR mice [67]. EGCG also showed a protective effect against human papillomavirus-16 oncoprotein-induced lung cancer and IGF-1 stimulated lung cancer angiogenesis through HIF-1α inhibition [68, 69]. In addition, primary bovine aortic endothelial cells stimulate autophagy in cells, leading to degradation of lipid droplets. In this way, EGCG may be effective in the prevention of cardiovascular diseases [70]. EGCG regulates ultraviolet B (UVB)-mediated autophagy through the mTOR signaling pathway and significantly alleviates the toxic effects of UVB irradiation in macular retinal pigment epithelial cells. Thus, it may also have a protective effect against macular degeneration [71]. As a result, EGCG can be effective in the prevention of neurodegeneration, cancer, cardiovascular diseases, inflammatory diseases, and macular degeneration through stress pathways.

2.5. Luteolin

Luteolin (3′,4′,5,7-tetrahydroxy flavone) is a phenolic compound found in broccoli, pepper, thyme, celery, lettuce, oregano, artichoke, and carrots; it has antioxidant, anticancer, anti-inflammatory, and neuroprotective effects [72]. Luteolin destabilized the Hsp90 client protein c-Jun and Akt and inhibited LPS-induced production of TNF-α and NO dose-dependently in macrophages [73]. In addition, luteolin prevented TNF-α-induced endolytic monocyte adhesion in mice by suppressing vascular inflammation and the IKBα/NF-κB pathway in HUVECs [74]. In psoriatic skin, luteolin inhibited keratinocyte activation by decreasing NF-κB, which increased dose-dependently [75]. Luteolin and luteolin-7-O-glucoside modulated Nrf2/mitogen-activated protein kinase (MAPK) mediated the HO-1 signaling cascade in RAW 264.7 cells [76]. In wild-type mouse traumatic brain injury models, luteolin showed neuroprotective action by Nrf2/ARE pathway activation [77]. Luteolin inhibited tBHP-induced oxidative stress by increasing ERK2/Nrf2/ARE signaling pathway activation and HO-1, glutamate cysteine ligase catalytic (GCLC), and glutamate cysteine ligase modifier (GCLM) subunit transcription in rat primary hepatocytes [78]. In addition, in HepG2, Hepa1c1c7, and RL-34 HepG2 hepatocytes, it dose-dependently inhibited the expression of phase I enzyme cytochrome P450 1A1 (CYP1A1), and phase II enzymes NQO1 and GST-P1 through an aryl hydrocarbon receptor (AhR) and Nrf2 pathways [79]. In HepG2 human hepatocytes, luteolin also dose-dependently activated the PI3K/Nrf2/ARE system, increased HO-1 expression, and reduced the expression of lipopolysaccharide-induced NO, iNOS, and cytosolic phospholipase A2 (cPLA2) in hepatocytes [80]. Luteolin also reduced acute mercuric chloride-induced hepatotoxicity by anti-inflammatory and antioxidant responses by regulating the SIRT1/Nrf2/TNF-α pathways [81]. The induction of VEGF by oxidative stress has an important role in the pathogenesis of premature retinopathy. Luteolin has shown a protective effect against retinal neovascularization by reducing hypoxia-induced VEGF expression through decreasing HIF-1α expression in human retinal microvascular endothelial cells (HRMECs) [82]. Luteolin reduced 4-hydroxy-2-nonenal-induced cell death of neuronal-like catecholaminergic PC12 cells by regulating unfolded protein response and the MAPK, Nrf2/ARE pathways [83]. As a result, luteolin also affects neurodegeneration, endothelial function, and liver function through stress-response pathways as do other hormetic phytochemicals.

2.6. Quercetin

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is found in many vegetables and fruits. It has anti-inflammatory, anticarcinogenic, and antioxidant effects on cardiovascular diseases, cancer, neurodegenerative diseases, and can reduce aging and positively increase the life span [84]. Quercetin inhibited the growth of A549 and H460 cancer cells with Hsp70 inhibition in lung cancer cells and increased sensitivity to chemotherapy [85]. Quercetin inhibited the t-AUCB-induced autophagy by inhibiting Hsp 27 and Atg 72 in glioblastoma cells [86]. In addition, quercetin inhibited Hsp70 in U937 human monoblastic leukemia cell line [87]. Quercetin inhibited hypoxia-induced AMPK by dramatically inducing apoptosis in hypoxia and reducing the activity of HIF-1 in HCT116 cancer cells [88]. Quercetin dose-dependently increased glutathione, glutamylcysteine synthetase (GSH), GPx, GR, and GST expression in liver HepG2 cells through p38/MAPK and Nrf-2 activation [89]. Quercetin protected against toxicity and inflammation by increasing Nrf-2 expression and decreasing NF-kB and cyclooxygenase (Cox)-2 expression in a time-dependent manner in mycotoxin ochratoxin A-induced liver HepG2 cells [90]. Furthermore, dose-dependently, through p62 and Nrf2-ARE activation, quercetin increased HO-1, GCLC, and GCLM subunit expression and showed a protective effect against hepatotoxicity [91]. Quercetin, depending on the dose, inhibited the production of LPS-induced NO production in BV2 microglial cells, suppressed the NF-κB pathway, and activated the Nrf2-dependent HO-1 pathway [92, 93]. Quercetin showed a protective effect against indomethacin-induced gastrointestinal oxidative stress and inflammation through Nrf-2 activation and NF-kB inhibition in human intestinal Caco-2 cells [94]. In malignant mesothelioma MSTO-211H and H2452 cells, quercetin also inhibited cell growth and showed cytoprotective effect with Nrf-2 activation [95]. In a study on porcine renal proximal tubule cell line LLC-PK1 cells and C57BL/6j mice, quercetin inhibited renal ischemia/reperfusion injury by increasing AMP phosphorylase, inhibiting mTOR phosphorylation, and activating autophagy [96]. A combination of quercetin, resveratrol, and catechin was administered to human metastatic cancer cell lines MDA-MB-231 and MDA-MB-435; quercetin was shown to be the most effective compound for Akt/mTOR inhibition and can prevent breast cancer growth and metastasis [97]. Quercetin inhibited mTOR by expressing SESTIN 2, p53, and activating AMPK in a dose-dependent manner and induced apoptosis via increased intracellular ROS in HCT116 colon cancer cells [98]. The mTOR complex has an important role in cell growth, protein synthesis, and autophagy, with the inhibition of quercetin mTOR/PI3K/Akt in cancer and other diseases where excessive mTOR complex activity is observed [99]. In addition, quercetin, by affecting autophagy with the inhibition of proteasome and mTOR activity, can be both protective and therapeutic against cancer with the death of human breast cancer cell lines MCF7 and MDA-MB-453, the cervical adenocarcinoma cell line HeLa, the ovarian cancer cell line OVCAR3, and the human B-lymphoblastoid cell line IM-9 [100]. Quercetin inhibited tumor growth and angiogenesis by inhibiting VEGF regulated by AKT/mTOR in HUVECs [101]. As a result, quercetin may exert a protective effect against cancer, especially by acting on stress-response pathways.

2.7. Sulforaphane

Sulforaphane (SulR-1-isothiocyanato-4-methylsulfinyl butane) is an isothiocyanate found extensively in cruciferous vegetables. Studies have shown that sulforaphane has a protective effect against cancer, diabetes, cardiovascular diseases, neurodegenerative diseases, and kidney diseases, and is mostly influenced by an Nrf-2-mediated antioxidant response [102, 103]. Sulforaphane may prevent diabetic auric damage and cardiomyopathy by increasing Nrf2 activation in mice [104, 105]. Sulforaphane showed protective effect against ethanol-induced oxidative stresses and apoptosis in neural crest cells by generating an antioxidant response with Nrf2 activation [106]. Sulforaphane activates the Nrf2/ARE pathway and inhibits 3-nitropropionic acid-induced toxicity in striatal cells by inhibiting MAPKs and NF-κB pathways [107]. In MSTO-211H cells administered with sulforaphane, Nrf2-mediated HO-1 expression was regulated by the PI3K/Akt pathway [108]. Sulforaphane inhibited muscle inflammation by inhibiting Nrf-2 and NF-kB in dystrophin-deficient mdx mice [109]. Sulforaphane showed a protective effect against acute alcohol-induced liver steatosis by activation of Nrf2 and synthesis of antioxidant proteins in HepG2 E47 liver cells [110]. Sulforaphane increased Nrf2 expression in TRAMP C1 prostate cancer cells and affected epigenetic regulation [111]. Sulforaphane induced autophagy through ERK activation in immortalized mouse CN1.4 cortical and human SHSY5Y neuronal cells [112]. Huntington’s disease, a neurodegenerative disease, involves damage to the ubiquitin proteasome system. In a mouse study, sulfate inhibited proteasomal and autophagic activation and cytotoxicity resulting from proteasomal impairment [113]. Sulforaphane inhibited HIF-1α expression in HCT116 human colon cancer cells and AGS human gastric cancer cells, but inhibited hypoxia-induced VEGF expression only in HCT116 cells [114]. Sulforaphane affects the stress-response pathways and can show protective effects, especially against neurodegeneration and cancer.


3. Conclusion

Dietary phytochemicals can exert a protective effect against cancer, neurodegenerative diseases, cardiovascular diseases, inflammatory and immune diseases by acting on multiple stress-response pathways. Therefore, healthy aging and longevity can be achieved by preventing the deterioration of hemodynamics. In addition, it is necessary to emphasize that the hormetic stress pathways of each dietary phytochemical is a very wide ranging subject. Therefore, the mechanisms of action of important phytochemicals and stress response pathways in this chapter have been summarized in the light of data obtained in recent years; this may lead to a broader outlook on this subject and to new studies.



AhRaryl hydrocarbon receptor
AREantioxidant response element
BMMsbone marrow-derived macrophages
cPLA2cytosolic phospholipase A2
DNAdeoxyribonucleic acid
EGCGepigallocatechin gallate
ERKextracellular signal-regulated kinase
GCLCglutamate cysteine ligase catalytic
GCLMglutamate cysteine ligase modifier
GPxglutathione peroxidase
HDAChistone deacetylase
HRMECshuman retinal microvascular endothelial cells
HSPheat shock protein
HIF-1:hypoxia-inducible factor-1
HUVECshuman umbilical vein endothelial
IGF-1insulin-like growth factor
iNOSinducible nitric oxide synthase
JKNc-Jun N-terminal kinase
MAPKmitogen-activated protein kinase
mTORmammalian target of rapamycin
NFκBnuclear factor kappa B
NOnitric oxide
Nrf2nuclear factor-erythroid 2-related factor 2
NQO1NAD(P)H:quinine oxidoreductase
PBMCshuman peripheral blood mononuclear cells
PKCprotein kinase C
SODsuperoxide dismutase
TNF-αtumor necrosis factor-α
UVBultraviolet B
VEGFvascular endothelial growth factor


  1. 1. Mattson MP. Hormesis defined. Ageing Research Reviews. 2008;7(1):1-7. DOI: 10.1016/j.arr.2007.08.007
  2. 2. Mattson MP, Calabrese EJ. Hormesis: What it is and why it matters? In: Mattson MP, Calabrese EJ, editors. Hormesis a Revolution in Biology, Toxicology and Medicine. 1st ed. New York: Humana Press; 2010. pp. 1-13. DOI: 10.1007/978-1-60761-495-1_1
  3. 3. Rattan SIS. Biogerontology: From here to where? The Lord Cohen medal Lecture-2011. Biogerontology. 2012;13(1):83-91. DOI: 10.1007/s10522-011-9354-3
  4. 4. Rattan SIS. Rationale and methods of discovering hormetins as drugs for healthy ageing. Expert Opinion on Drug Discovery. 2012;7(5):439-448. DOI: 10.1517/17460441.2012.677430
  5. 5. Rattan SIS. Hormesis in ageing. Ageing Research Reviews. 2008;7(1):63-78. DOI: 10.1016/j.arr.2007.03.002
  6. 6. Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. NeuroMolecular Medicine. 2008;10(4):236-246. DOI: 10.1007/s12017-008-8037-y
  7. 7. Demirovic D, Rattan SIS. Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. Experimental Gerontology. 2013;48(1):98-98. DOI: 10.1016/j.exger.2012.02.005
  8. 8. Somani SJ, Modi KP, Majumdar AS, Sadarani BN. Phytochemicals and their potential usefulness in inflammatory bowel disease. Phytotherapy Research. 2015;29(3):339-350. DOI: 10.1002/ptr.5271
  9. 9. Doughari JH. Phytochemicals: Extraction methods, basic structures and mode of action as potential chemotherapeutic agents, phytochemicals. In: Rao V, editor. A Global Perspective of Their Role in Nutrition and Health. 1st ed. Rijeka: InTech; 2012. pp. 1-32. DOI: 10.5772/26052
  10. 10. Hayes DP. Nutritional hormesis. European Journal of Clinical Nutrition. 2007;61:147-159. DOI: 10.1038/sj.ejcn.1602507
  11. 11. Mattson MP. Dietary factors, hormesis and health. Ageing Research Reviews. 2008;7(1):43-48. DOI: 10.1016/j.arr.2007.08.004
  12. 12. Lee J, Jo DG, Park D, Chung HY, Mattson MP. Adaptive cellular stress pathways as therapeutic targets of dietary phytochemicals: Focus on the nervous system. Pharmacological Reviews. 2014;66(3):815-868. DOI: 10.1124/pr.113.007757
  13. 13. Demirovic D, Rattan SIS. Curcumin induces stress response and hormetically modulates wound healing ability of human skin fibroblasts undergoing ageing in vitro. Biogerontology. 2011;12(5):437-444. DOI: 10.1007/s10522-011-9326-7
  14. 14. Evans CG, Chang L, Gestwicki JE. Heat shock protein 70 (Hsp70) as an emerging drug target. Journal of Medicinal Chemistry. 2010;53:4585-4602. DOI: 10.1021/jm100054f
  15. 15. Gupta SC, Sharma A, Mishra M, Mishra MK, Chowdhuri DK. Heat shock proteins in toxicology: How close and how far? Life Sciences. 2010;86:377-384. DOI: 10.1016/j.lfs.2009.12.015
  16. 16. Hong DS, Banerji U, Tavana B, George GC, Aaron J, Kurzrock R. Targeting the molecular chaperone heat shock protein 90 (HSP90): Lessons learned and future directions. Cancer Treatment Reviews. 2013;39:375-387. DOI: 10.1016/j.ctrv.2012.10.001
  17. 17. Mymrikov EV, Seit-Nebi AS, Gusev NB. Large potentials of small heat shock proteins. Physiological Reviews. 2011;91:1123-1159. DOI: 10.1152/physrev.00023.2010
  18. 18. Jego G, Hazoume A, Seigneuric R, Garrido C. Targeting heat shock proteins in cancer. Cancer Letters. 2013;332(2):275-285. DOI: 10.1016/j.canlet.2010.10.014
  19. 19. Hine CM, Mitchell JR. NRF2 and the phase II response in acute stress resistance induced by dietary restriction. Journal of Clinical and Experimental Pathology. 2012;Suppl 4 (4):7329-7362. DOI: 10.4172/2161-0681.S4-004
  20. 20. Jung KA, Kwak MK. The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules. 2010;15(10):7266-7291. DOI: 10.3390/molecules15107266
  21. 21. Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2(Keap1) signaling in oxidative stress. Free Radical Biology & Medicine. 2009;47(9):1304-1309. DOI: 10.1016/j.freeradbiomed.2009.07.035
  22. 22. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metabolism Reviews. 2006;38(4):769-789. DOI: 10.1080/03602530600971974
  23. 23. Birringer M. Hormetics: Dietary triggers of an adaptive stress response. Pharmaceutical Research. 2011;28:2680-2694. DOI: 10.1007/s11095-011-0551-1
  24. 24. Kumar H, Kim IS, More SV, Kim BW, Choi DK. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Natural Prodcut Reports. 2014;31(1):109-139. DOI: 10.1039/c3np70065h
  25. 25. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nature Cell Biology. 2010;12(9):842-846. DOI: 10.1038/ncb0910-842
  26. 26. Xia Y, Choi HK, Lee K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. European Journal of Medicinal Chemistry. 2012;49:24-40. DOI: 10.1016/j.ejmech.2012.01.033
  27. 27. Barone E, Calabrese V, Mancuso C. Ferulic acid and its therapeutic potential as a hormetin for age related diseases. Biogerontology. 2009;10:97-108. DOI: 10.1007/s10522-008-9160-8
  28. 28. Mancuso C, Santangelo R. Ferulic acid: Pharmacological and toxicological aspects. Food and Chemical Toxicology. 2014;65:185-195. DOI: 10.1016/j.fct.2013.12.024
  29. 29. Ghosh S, Basak P, Dutta S, Chowdhury S, Sil PC. New insights into the ameliorative effects of ferulic acid in pathophysiological conditions. Food and Chemical Toxicology. 2017;103:41-55. DOI: 10.1016/j.fct.2017.02.028
  30. 30. He S, Liu F, Xu L, Yin P, Li D, Mei C, Jiang L, Ma Y, Xu J. Protective effects of ferulic acid against heat stress-induced intestinal epithelial barrier dysfunction in vitro and in vivo. PLoS One. 2016;11(2):e0145236. DOI: 10.1371/journal.pone.0145236
  31. 31. Catino S, Paciello F, Micell F, Rolesi R, Troiani D, Calabrese V, Santangelo R, Mancuso C. Ferulic acid regulates the Nrf2/Heme oxygenase-1 system and counteracts trimethyltin-induced neuronal damage in the human neuroblastoma cell line SH-SY5Y. Frontiers in Pharmacology. 2016;6(305):1-12. DOI: 10.3389/fphar.2015.00305
  32. 32. Yu CL, Zhao XM, Niu YC. Ferulic acid protects against lead acetate-induced inhibition of neurite outgrowth by upregulating HO-1 in PC12 cells: Involvement of ERK1/2-Nrf2 pathway. Molecular Neurobiology. 2016;53(9):6589-6500. DOI: 10.1007/s12035-015-9555-x
  33. 33. Kikugawa M, Ida T, Ihara H, Sakamoto T. Ferulic acid and its water-soluble derivatives inhibit nitric oxide production and inducible nitric oxide synthase expression in rat primary astrocytes. Bioscience, Biotechnology, and Biochemistry. 2017;81(8):1607-1611. DOI: 10.1080/09168451.2017.1336925
  34. 34. Zhao J, Suyama A, Chung H, Fukuda T, Tanaka M, Matsui T. Ferulic acid enhances nitric oxide production through up-regulation of argininosuccinate synthase in inflammatory human endothelial cells. Life Sciences. 2016;145:224-232. DOI: 10.1016/j.lfs.2015.12.044
  35. 35. Liao Z, He H, Zeng G, Liu D, Tang L, Yin D, Chen D, He M. Delayed protection of ferulic acid in isolated hearts and cardiomyocytes: Upregulation of heat-shock protein 70 via NO-ERK1/2 pathway. Journal of Functional Foods. 2017;34:18-27. DOI: 10.1016/j.jff.2017.04.012
  36. 36. Bian Z, Furuya N, Zheng DM, Trejo JAO, Tada N, Ezaki J, Ueno T. Ferulic acid induces mammalian target of rapamycin inactivation in cultured mammalian cells. Biological & Pharmaceutical Bulletin. 2013;36(1):120-124. DOI: 10.1248/bpb.b12-00695
  37. 37. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramires-Tortosa MC. Curcumin and health. Molecules. 2016;21(3):264-286. DOI: 10.3390/molecules21030264
  38. 38. Salem M, Rohani S, Gillies ER. Curcumin, a promising anti-cancer therapeutic: A review of its chemical properties, bioactivity and approaches to cancer cell delivery. RSC Advances. 2014;4:10815-10829. DOI: 10.1039/c3ra46396f
  39. 39. Sarkar R, Mukherjee S, Biswas J. Curcumin augments the efficiency of antitumor drugs used in leukemia by modulation of heat shock proteins via HDAC6. Journal of Enviromental Patology, Toxicology and Oncology. 2014;33(3):247-263. DOI: 10.1615/JEnvironPatholToxicolOncol.2014010913
  40. 40. Xia C, Cai Y, Li S, Yang J, Xiao G. Curcumin increases HSP70 expression in primary rat cortical neuronal apoptosis induced by gp120 V3 loop peptide. Neurochemical Research. 2015;40:1996-2005. DOI: 10.1007/s11064-015-1695-x
  41. 41. Ahmed T, Banerjee BD. HSP27 modulates survival signaling in endosulfan-exposed human peripheral blood mononuclear cells treated with curcumin. Human & Experimental Toxicology. 2016;35(7):695-704. DOI: 10.1177/0960327115597986
  42. 42. Gounden S, Chuturgoon A. Curcumin upregulates antioxidant defense, lon protease, and heat-shock protein 70 under hyperglycemic conditions in human hepatoma cells. Journal of Medicinal Food. 2017;20(5):465-473. DOI: 10.1089/jmf.2016.0146
  43. 43. González-Reyes S, Guzmán-Beltrán S, Medina-Campos ON, Pedraza-Chaverri J. Curcumin pretreatment induces Nrf2 and an antioxidant response and prevents hemin-induced toxicity in primary cultures of cerebellar granule neurons of rats. Oxidative Medicine and Cellular Longevity. 2013;2013:801418. DOI: 10.1155/2013/801418
  44. 44. Das V, Vinayak M. Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of Nrf2 signalling and modulation of inflammation in prevention of cancer. PLoS One. 2015;10(4):e0124000. DOI: 10.1371/journal.pone.0124000
  45. 45. Ding F, Li F, Li Y, Hou X, Ma Y, Zhang N, Ma J, Zhang R, Lang B, Wang H, Wang Y. HSP60 mediates the neuroprotective effects of curcumin by suppressing microglial activation. Experimental and Therapeutic Medicine. 2016;12:823-828. DOI: 10.3892/etm.2016.3413
  46. 46. Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health—A comprehensive review of human clinical trials. Molecular Nutrition & Food Research. 2011;55:1129-1141. DOI: 10.1002/mnfr.201100143
  47. 47. Curro M, Trovato-Salinaro A, Gugliandolo A, Koverech G, Lodato F, Caccamo D, Calabrese V, Ientile R. Resveratrol protects against homocysteine-induced cell damage via cell stress response in neuroblastoma cells. Journal of Neuroscience Research. 2015;93:149-156. DOI: 10.1002/jnr.23453
  48. 48. Han S, Choi JR, Shin KS, Kang SJ. Resveratrol upregulated heat shock proteins and extended the surviva lof G93A-SOD1 mice. Brain Research. 2012;1483:112-117. DOI: 10.1016/j.brainres.2012.09.022
  49. 49. Soueur J, Eilstein J, Léreaux G, Jones C, Marrot L. Skin resistance to oxidative stress induced by resveratrol: From Nrf2 activation to GSH biosynthesis. Free Radical Biology & Medicine. 2015;78:213-223. DOI: 10.1016/j.freeradbiomed.2014.10.510
  50. 50. Lin TK, Chen SD, Chuang YC, Lin HY, Huang CR, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Liou CW. Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. International Journal of Molecular Sciences. 2014;15:1625-1646. DOI: 10.3390/ijms15011625
  51. 51. Cullberg KB, Olholm J, Paulsen SK, Foldager CB, Lind M, Richelsen B, Pedersen SB. Resveratrol has inhibitory effects on the hypoxia-induced inflammation and angiogenesis in human adipose tissue in vitro. European Journal of Pharmaceutical Sciences. 2013;49:251-257. DOI: 10.1016/j.ejps.2013.02.014
  52. 52. Park D, Jeong H, Lee NM, Koh A, Kwon O, Yang YR, Noh J, Suh PG, Park H, Ryu SH. Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Scientific Reports. 2016;6:21772. DOI: 10.1038/srep21772
  53. 53. Selvaraj S, Sun Y, Sukumaran P, Singh BB. Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Molecular Carcinogenesis. 2016;55:818-831. DOI: 10.1002/mc.22324
  54. 54. Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, Marambaud P. Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. Journal of Neurochemistry. 2012;120:461-472. DOI: 10.1111/j.1471-4159.2011.07594.x
  55. 55. Ma C, Wang Y, Dong L, Li M, Cai W. Anti-inflammatory effect of resveratrol through the suppression of NF-κB and JAK/STAT signaling pathways. Acta Biochimica et Biophysica Sinica. 2015;47(3):207-213. DOI: 10.1093/abbs/gmu135
  56. 56. Braicu C, Ladomery MR, Chedea VS, Irimie A, Berindan-Neagoe I. The relationship between the structure and biological actions of green tea catechins. Food Chemistry. 2013;141(3):3282-3289. DOI: 10.1016/j.foodchem.2013.05.122
  57. 57. Legeay S, Rodier M, Fillon L, Faure S, Clere N. Epigallocatechin gallate: A review of its beneficial properties to prevent metabolic syndrome. Nutrients. 2015;7:5443-5468. DOI: 10.3390/nu7075230
  58. 58. Moses MA, Henry EC, Ricke WA, Gasiewicz TA. The heat shock protein 90 inhibitor, (−)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer Prevention Research. 2015;8(3):249-257. DOI: 10.1158/1940-6207.CAPR-14-0224
  59. 59. Han SG, Han SS, Toborek M, Hennig B. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicology and Applied Pharmacology. 2012;261:181-188. DOI: 10.1016/j.taap.2012.03.024
  60. 60. Pullikotil B, Chen H, Muniyappa R, Greenberg CC, Yang S, Reiter CEN, Lee JW, Chung JH, Quon MJ. Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses pro-inflammatory actions of TNF-α. The Journal of Nutritional Biochemistry. 2012;23(9):1134-1145. DOI: 10.1016/j.jnutbio.2011.06.007
  61. 61. Zheng Y, Morris A, Sunkara M, Layne J, Toborek M, Hennig B. Epigallocatechin gallate stimulates NF-E2-related factor and heme oxygenase-1 via calveolin-1 displacement. The Journal of Nutritional Biochemistry. 2012;23:163-168. DOI: 10.1016/j.jnutbio.2010.12.002
  62. 62. Han J, Wang M, Jing X, Shi H, Ren M, Lou H. (−)-Epigallocatechin gallate protects against cerebral ischemia-induced oxidative stress via Nrf2/ARE signaling. Neurochemical Research. 2014;39(7):1292-1299. DOI: 10.1007/s11064-014-1311-5
  63. 63. Wang D, Wang Y, Wan X, Yang CS, Zhang J. Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity inmice: Responses ofmajor antioxidant enzymes and the Nrf2 rescue pathway. Toxicology and Applied Pharmacology. 2015;283:65-74. DOI: 10.1016/j.taap.2014.12.018
  64. 64. Yang GZ, Wang ZJ, Bai F, Qin XJ, Cao J, Lv JY, Zhang MS. Epigallocatechin-3-gallate protects HUVECs from PM2.5-induced oxidative stress injury by activating critical antioxidant pathways. Molecules. 2015;20:6626-6639. DOI: 10.3390/molecules20046626
  65. 65. Yang J, Han Y, Chen C, Sun H, He D, Guo J, Jiang B, Zhou L, Zeng C. EGCG attenuates high glucose-induced endothelial cell inflammation by suppression of PKC and NF-κB signaling in human umbilical vein endothelial cells. Life Sciences. 2013;92:589-597. DOI: 10.1016/j.lfs.2013.01.025
  66. 66. Cai Y, Yu SS, Chen TT, Gao S, Geng B, Yu Y, Ye JT, Liu PQ. EGCG inhibits CTGF expression via blocking NF-κB activation in cardiac fibroblast. Phytomedicine. 2013;20:106-113. DOI: 10.1016/j.phymed.2012.10.002
  67. 67. Joo SY, Song Y, Park YL, Myung E, Chung CY, Park KJ, Cho SB, Lee WS, Kim HS, Rew JS, Kim NS, Joo YE. Epigallocatechin-3-gallate inhibits LPS-induced NF-κB and MAPK signaling pathways in bone marrow-derived macrophages. Gut and Liver. 2012;6(2):188-196. DOI: 10.5009/gnl.2012.6.2.188
  68. 68. He L, Zhang E, Shi J, Li X, Zhou K, Zhang Q, Lee AD, Tang X. (2)-Epigallocatechin-3-gallate inhibits human papillomavirus (HPV)-16 oncoprotein-induced angiogenesis in non-small cell lung cancer cells by targeting HIF-1a. Cancer Chemotherapy and Pharmacology. 2013;71:713-725. DOI: 10.1007/s00280-012-2063-z
  69. 69. Li X, Feng Y, Liu J, Feng X, Zhou K, Tang X. Epigallocatechin-3-gallate inhibits IGF-1-stimulated lung cancer angiogenesis through downregulation of HIF-1α and VEGF expression. Journal of Nutrigenetica and Nutrigenomics. 2013;6:169-178. DOI: 10.1159/000354402
  70. 70. Kim HS, Montana V, Jang HJ, Parpura V, Kim J. Epigallocatechin gallate (EGCG) stimulates autophagy in vascular endothelial cells. The Journal of Biological Chemistry. 2013;288(31):22693-22705. DOI: 10.1074/jbc.M113.477505
  71. 71. Li CP, Yao J, Tao ZF, Li XM, Jiang Q, Yan B. Epigallocatechin gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: A potential role for reducing UVB light-induced retinal damage. Biochemical and Biophysical Research Communications. 2013;438:739-745. DOI: 10.1016/j.bbrc.2013.07.097
  72. 72. Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Wozniak K, Nabavi SM. Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Research Bulletin. 2015;119(Pt A):1-11. DOI: 10.1016/j.brainresbull.2015.09.002
  73. 73. Chen D, Bi A, Dong X, Jiang Y, Rui B, Liı J, Yin Z, Luo L. Luteolin exhibits anti-inflammatory effects by blocking the activity of heat shock protein 90 in macrophages. Biochemical and Biophysical Research Communications. 2014;443:326-332. DOI: 10.1016/j.bbrc.2013.11.122
  74. 74. Jia Z, Nallasamy P, Liu D, Shah H, Li JZ, Rojin C, Si H, McCormickJ ZH, Zhen W, Li Y. Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway. Journal of Nutritional Biohemistry. 2015;26(3):293-302. DOI: 10.1016/j.jnutbio.2014.11.008
  75. 75. Weng Z, Patel AB, Vasiadi M, Therianou A, Theoharides TC. Luteolin inhibits human keratinocyte activation and decreases NF-kB induction that is increased in psoriatic skin. PLoS One. 2014;9(2):e90739. DOI: 10.1371/journal.pone.0090739
  76. 76. Song YS, Park CM. Luteolin and luteolin-7-O-glucoside strengthen antioxidative. Food and Chemical Toxicology. 2013;65:70-75. DOI: 10.1016/j.fct.2013.12.017
  77. 77. Xu J, Wang H, Ding K, Zhang L, Wang C, Li T, Wei W, Lu X. Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2–ARE pathway. Free Radical Biology & Medicine. 2014;71:186-195. DOI: 10.1016/j.freeradbiomed.2014.03.009
  78. 78. Huang CS, Lii CK, Lin AH, Yeh YW, Yao HT, Li CC, Wang TS, Chen HW. Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Archives of Toxicology. 2013;87:167-178. DOI: 10.1007/s00204-012-0913-4
  79. 79. Zhang T, Kimura Y, Jiang S, Harada K, Yamashita Y, Ashida H. Luteolin modulates expression of drug-metabolizing enzymes through the AhR and Nrf2 pathways in hepatic cells. Archives of Biochemistry and Biophysics. 2014;557:36-46. DOI: 10.1016/
  80. 80. Paredes-Gonzalez X, Fuentes F, Jeffery S, Saw CLL, Shu L, ZY S, Kong ANT. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharmaceutics & Drug Disposition. 2015;36:440-451. DOI: 10.1002/bdd.1956
  81. 81. Yang D, Tan X, Lv Z, Liu B, Baiyun B, Lu J, Zhang Z. Regulation of SIRT1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Scientific Reports. 2016;6:37157. DOI: 10.1038/srep37157
  82. 82. Park SW, Cho CS, Jun HO, Ryu NH, Kim JH, YS Y, Kim JS, Kim JH. Anti-angiogenic effect of luteolin on retinal neovascularization via blockade of reactive oxygen species production. Investigative Ophthalmology & Visual Science. 2012;53:7718-7726. DOI: 10.1167/iovs.11-8790
  83. 83. Wu PS, Yen JH, Kou MC, Wu MJ. Luteolin and apigenin attenuate 4-hydroxy-2-nonenal-mediated cell death through modulation of UPR, Nrf2-ARE and MAPK pathways in PC12 cells. PLoS One. 2015;10(6):e0130599. DOI: 10.1371/journal.pone.0130599
  84. 84. Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: Facts and fancies. Biochemical Pharmacology. 2012;83:6-15. DOI: 10.1016/j.bcp.2011.08.010
  85. 85. Lee SH, Lee EJ, Min KH, Hur GY, Lee SH, Lee SY, Kim JH, Shin C, Shim JJ, In KH, Kang KH, Lee SY. Quercetin enhances chemosensitivity to gemcitabine in lung cancer cells by inhibiting heat shock protein 70 expression. Clinical Lung Cancer. 2015;16(6):e235-e243. DOI: 10.1016/j.cllc.2015.05.006
  86. 86. Li J, Tang C, Li L, Li R, Fan Y. Quercetin blocks t-AUCB-induced autophagy by Hsp27 and Atg7 inhibition in glioblastoma cells in vitro. Journal of Neuro-Oncology. 2016;129(1):39-45. DOI: 10.1007/s11060-016-2149-2
  87. 87. Storniolo A, Raciti M, Cucina A, Bizzarri M, Di Renzo L. Quercetin affects Hsp70/IRE1α mediated protection from death induced by endoplasmic reticulum stress. Oxidative Medicine and Cellular Longevity. 2015;2015:645157. DOI: 10.1155/2015/645157
  88. 88. Kim HS, Wannatung T, Lee S, Yang WK, Chung SH, Lim JS, Choe W, Kang I, Kim SS, Ha J. Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer. Apoptosis. 2012;17:938-949. DOI: 10.1007/s10495-012-0719-0
  89. 89. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. Chemico-Biological Interactions. 2012;195:154-164. DOI: 10.1016/j.cbi.2011.12.005
  90. 90. Ramyaa P, Krishnaswamy R, Padma PP. Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells—Up regulation of Nrf2 expression and down regulation of NF-κB and COX-2. Biochimica et Biophysica Acta. 2014;1840:681-692. DOI: 10.1016/j.bbagen.2013.10.024
  91. 91. Ji LL, Sheng YC, Zheng ZY, Shi L, Wang ZT. The involvement of p62–Keap1–Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity. Free Radical Biology & Medicine. 2015;85:12-23. DOI: 10.1016/j.freeradbiomed.2015.03.035
  92. 92. Kang CH, Choi YH, Moon SK, Kim WJ, Ki GY. Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κBpathway andactivating the Nrf2-dependent HO-1 pathway. International Immunopharmacology. 2013;17:808-813. DOI: 10.1016/j.intimp.2013.09.009
  93. 93. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A. Quercetin attenuates inflammatory responses in BV-2 microglial cells: Role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One. 2015;10(10):e0141509. DOI: 10.1371/journal.pone.0141509
  94. 94. Carrasco-Pozo C, Castillo RL, Beltrán C, Miranda A, Fuentes J, Gotteland M. Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: Role of NF-κB and Nrf2. The Journal of Nutritional Biochemistry. 2016;27:289-298. DOI: 10.1016/j.jnutbio.2015.09.016
  95. 95. Lee YJ, Lee DM, Lee SH. Nrf2 expression and apoptosis in quercetin-treated malignant mesothelioma cells. Molecules and Cells. 2015;38(5):416-425. DOI: 10.14348/molcells.2015.2268
  96. 96. Chen BL, Wang LT, Huang KH, Wang CC, Chiang CK, Liu SH. Quercetin attenuates renal ischemia/reperfusion injury via an activation of AMP-activated protein kinase-regulated autophagy pathway. The Journal of Nutritional Biochemistry. 2014;25:1226-1234. DOI: 10.1016/j.jnutbio.2014.05.013
  97. 97. Rivera AR, Castillo-Pichardo L, Gerena Y, Dharmawardhane S. Anti-breast cancer potential of quercetin via the Akt/AMPK/mammalian target of rapamycin (mTOR) signaling cascade. PLoS One. 2016;11(6):e0157251. DOI: 10.1371/journal.pone.0157251
  98. 98. Kim GT, Lee SH, Kim YM. Quercetin regulates sestrin 2-AMPK-mTOR signaling pathway and induces apoptosis via increased intracellular ROS in HCT116 colon cancer cells. Journal of Cancer Prevention. 2013;18(3):264-270. DOI: 10.15430/JCP.2013.18.3.264
  99. 99. Bruning A. Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anti-Cancer Agents in Medical Chemistry. 2013;13(7):1025-1031
  100. 100. Klappan AK, Hones S, Mylonas I, Bruning A. Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity. Histochemistry and Cell Biology. 2012;137:25-36. DOI: 10.1007/s00418-011-0869-0
  101. 101. Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways. PLoS One. 2012;7(10):e47516. DOI: 10.1371/journal.pone.0047516
  102. 102. Elbarbry F, Elrody N. Potential health benefits of sulforaphane: A review of the experimental, clinical and epidemiological evidences and underlying mechanisms. Journal of Medicinal Plant Research. 2011;5(4):473-484
  103. 103. Dinkova-Kostova AT, Kostov RV. Glucosinolates and isothiocyanates in health and disease. Trends in Molecular Medicine. 2012;18(6):337-347. DOI: 10.1016/j.molmed.2012.04.003
  104. 104. Miao X, Bai Y, Sun W, Cui W, Xin Y, Wang Y, Tan Y, Miao L, Fu Y, Su G, Cai L. Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants. Nutrition and Metabolism. 2012;9(84):1-9. DOI: 10.1186/1743-7075-9-84
  105. 105. Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, Chen Q, Tan Y, Cui T, Zheng Y, Cai L. Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation. Journal of Molecular and Cellular Cardiology. 2013;57:82-95. DOI: 10.1016/j.yjmcc.2013.01.008
  106. 106. Chen X, Liu J, Chen SY. Sulforaphane protects against ethanol-induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2-mediated antioxidant response. British Journal of Pharmacology. 2013;169:437-448. DOI: 10.1111/bph.12133
  107. 107. Jang M, Cho IH. Sulforaphane ameliorates 3-nitropropionic acid-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-κB pathways. Molecular Neurobiology. 2016;53:2619-2635. DOI: 10.1007/s12035-015-9230-2
  108. 108. Lee YJ, Jeong HY, Kim YB, Lee YJ, Won SY, Shim JH, Cho MK, Nam HS, Lee SH. Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells. Food and Chemical Toxicology. 2012;50:116-123. DOI: 10.1016/j.fct.2011.10.035
  109. 109. Sun CC, Li SJ, Yang CL, Xue RL, Xi YY, Wang L, Zhao QL, Li DJ. Sulforaphane attenuates muscle inflammation in dystrophin-deficient mdx mice via NF-E2-related factor 2 (Nrf2)-mediated inhibition of NF-κB signaling pathway. The Journal of Biological Chemistry. 2015;290(29):17784-17795. DOI: 10.1074/jbc.M115.655019
  110. 110. Zhou R, Lin J, Wu D. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochimica et Biophysica Acta. 2014;1840:209-218. DOI: 10.1016/j.bbagen.2013.09.018
  111. 111. Zhang C, Su ZY, Khor TO, Shu L, Kong ANT. Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation. Biochemical Pharmacology. 2013;85:1398-1404. DOI: 10.1016/j.bcp.2013.02.010
  112. 112. Jo C, Kim S, Cho SJ, Choi KJ, Yun SM, Koh YH, Johnson YVW, Park SI. Sulforaphane induces autophagy through ERK activation in neuronal cells. FEBS Letters. 2014;588:3081-3088. DOI: 10.1016/j.febslet.2014.06.036
  113. 113. Liu H, Talalay P. Relevance of anti-inflammatory and antioxidant activities of exemestane and synergism with sulforaphane for disease prevention. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(47):19065-19070. DOI: 10.1073/pnas.1318247110
  114. 114. Kim DH, Sung B, Kang YJ, Hwang SY, Kim MJ, Yoon JH, Im E, Kim ND. Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells. International Journal of Oncology. 2015;47:2226-2232. DOI: 10.3892/ijo.2015.3200

Written By

Ceren Gezer

Submitted: 27 July 2017 Reviewed: 23 October 2017 Published: 28 February 2018