Live or let die: Neuroprotective and anti-cancer effects of nutraceutical
antioxidants

Xiao-Yuan Mao, Ming-Zhu Jin, Jin-Fei Chen, Hong-Hao Zhou, Wei-Lin

Jin

PII: S0163-7258(17)30262-0
DOI: doi:10.1016/j.pharmthera.2017.10.012
Reference: JPT 7140

To appear in: Pharmacology and Therapeutics

Please cite this article as: Mao, X.-Y., Jin, M.-Z., Chen, J.-F., Zhou, H.-H. & Jin, W.-
L., Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants,
Pharmacology and Therapeutics (2017), doi:10.1016/j.pharmthera.2017.10.012

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P&T 23206

Title: Live or let die: Neuroprotective and anti-cancer effects of

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nutraceutical antioxidants

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Running Title: Nutraceutical antioxidants in neuroprotection and anti-cancer therapy

Authors and affiliations:

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Xiao-Yuan Maoa,b,#, *, Ming-Zhu Jinc,#, Jin-Fei Chend,e,*, Hong-Hao Zhoua,b, and

Wei-Lin Jinf,g,h,*
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a
Department of Clinical Pharmacology, Xiangya Hospital, Central South University,
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Changsha 410008, P. R. China

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b
Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory
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of Pharmacogenetics, Changsha 410078, P. R. China

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c
Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.

d
Department of Oncology, Nanjing First Hospital, Nanjing Medical University,

Nanjing, 210006, China

e
Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment,

Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical

University, Nanjing, 211166, China

f
Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for

Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science

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and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of

Ministry of Education, School of Electronic Information and Electronic Engineering,

Shanghai Jiao Tong University, Shanghai 200240, China

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National Center for Translational Medicine, Collaborative Innovational Center for

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System Biology, Shanghai Jiao Tong University, Shanghai 200240, PR China

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College of Clinical Medicine & Institute of Basic and Translational Medicine,

Shaanxi Key Laboratory of Central Nervous System Disease and School of Basic

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Medical Sciences, Xi'an Medical University, Xi'an 710021, China
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# These authors have equal contributions to this work.

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*To whom correspondence should be addressed:

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Dr. Xiao-Yuan Mao, Department of Clinical Pharmacology, Xiangya Hospital, Central

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South University, Changsha 410008, P. R. China and Institute of Clinical

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Pharmacology, Central South University; Hunan Key Laboratory of

Pharmacogenetics, Changsha 410078, P. R. China

E-mail: maoxiaoyuan2011@163.com

Dr. Jin-Fei Chen, Department of Oncology, Nanjing First Hospital, Nanjing Medical

University, Nanjing, 210006, China; Jiangsu Key Laboratory of Cancer Biomarkers,

Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized

Medicine, Nanjing Medical University, Nanjing, 211166, China.

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E-mail: jinfeichen@sohu.com

Dr. Wei-Lin Jin, Institute of Nano Biomedicine and Engineering, Department of

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Instrument Science and Engineering, Key Lab. for Thin Film and Microfabrication

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Technology of Ministry of Education, School of Electronic Information and

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Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R.

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China

E-mail: weilinjin@yahoo.com or weilinjin@sjtu.edu.cn.

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Abstract

Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric

disorders and cancers, in addition to inherited factors. Currently, natural products or

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nutraceuticals (commonly called medical foods) are increasingly employed for

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adjunctive therapy of these patients. However, the potential molecular mechanisms of

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the nutrient efficacy remain elusive. In this review, we summarized the

neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that

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the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly
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through the differential modulations of redox homeostasis. In addition, the balance

between reactive oxygen species (ROS) production and ROS elimination was
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manipulated by multiple molecular mechanisms, including cell signaling pathways,

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inflammation, transcriptional regulation and epigenetic modulation, which were

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involved in the therapeutic potential of nutraceutical antioxidants against neurological

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diseases and cancers. We specifically proposed that ROS scavenging was integral in
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the neuroprotective potential of nutraceuticals, while alternation of ROS level (either

increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted

the anti-cancer property of these compounds. We also hypothesized that

ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death,

was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting

ferroptosis is advantageous to develop new nutraceuticals with more effective and

lower adverse reactions for curing patients with neuropsychiatric diseases or

carcinomas.

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Keywords: nutraceuticals; neuroprotection; anti-cancer; ROS addiction; ferroptosis;

oxidative stress

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Table of Contents

1. Introduction

2. Classifications of nutraceuticals

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3. Neuroprotective and anti-cancer mechanisms of nutraceuticals

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3.1. Involvement of ROS-mediated cellular signaling

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3.2. Involvement of ROS-regulated inflammation

3.3. Involvement of ROS-associated epigenetics

3.4. Involvement of ROS-mediated apoptosis

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4. ROS-associated ferroptosis is speculated to serve as an important mechanism for

the neuroprotective and anti-cancer activities of nutraceuticals

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4.1. Suppressing ROS-associated ferroptosis as a neuroprotective mechanism of

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nutraceuticals
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4.2. Modulation of ROS-associated ferroptosis is likely to serve as an important

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mechanism for the anti-cancer potential of nutraceuticals

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5. Neuroprotective and anti-cancer properties of nutraceuticals: Merits and challenges

6. Concluding remarks and perspectives

Conflict of interest statement

Acknowledgments

References

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Abbreviations:

PD, Parkinson’s disease; AD, Alzheimer's disease; EGCG,

(-)-Epigallocatechin-3-gallate; NRF2, NF-E2-related factor 2; ROS, reactive oxygen

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species; H2O2, hydrogen peroxide; ER, endoplasmic reticulum; GPX,

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glutathione-peroxidase; NOX, NADPH oxidases (NOXs); LOX, lipoxygenases; ERK,

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extracellular signal-regulated kinase; JNK, c-Jun amino-terminal kinase; MAPK,

mitogen-activated protein kinase; HNE, 4-hydroxy-2-nonenol; ARE, antioxidant

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responsive element; GST, glutathione S-transferase; IFNγ, interferon-γ; LPS,
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lipopolysaccharide; SOD, superoxide dismutase; TNF-α, tumor necrosis factor-α; APP,

β-amyloid precursor protein; SAM, S-adenosylmethionine; MAT, methionine

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adenosyltransferase; SAH, Sadenosyl homocysteine; MT, methyltransferases; BDNF,

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brain-derived neurotrophic factor

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1. Introduction

Plant-derived foods exert great beneficial effects on human health, according to a

broad combination of epidemiology and experimental data (Winer et al., 2009).

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Except for inherited factors, many human diseases, including cardiovascular diseases,

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diabetes, neurological diseases and cancers, are also influenced by nutraceuticals to

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varying degrees (Yu, Fu, & Wang, 2012). In addition, multiple neuropsychiatric

disorders, such as epilepsy, ischemic stroke, Parkinson’s disease (PD), Alzheimer's

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disease (AD), spinal cord injury, depression, schizophrenia, etc., have been greatly
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improved after the sustained intake of nutraceuticals. Several nutraceuticals have been

evaluated for their clinical efficacy, as listed in Table 1. Specifically, green tea
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polyphenols (-)-Epigallocatechin-3-gallate (EGCG) with the daily oral dose of 400

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mg are currently tested for Phase 3 clinical trials for traumatic brain injury. Similarly,
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Phase 2 clinical trials have also been performed to determine the therapeutic potential
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of the non-flavonoid polyphenol resveratrol (250 mg/day) on the elderly (Kelsey,

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Wilkins, & Linseman, 2010). Moreover, in cancer therapy, some diets or

plants-derived compounds have been successfully utilized in clinical practice. For

instance, paclitaxel (60 mg/cm2), a component extracted from the bark of the Pacific

yew Taxusbrevifolia, and vincristine (135 mg/cm2), which is obtained from

catharanthus roseus, have been used in the treatment of multiple types of cancers

(Armstrong et al., 2006; Ihde, 1992; Rowinsky & Donehower, 1995). Vitamin C has

been in Phase 2 clinical trial for treating diverse cancers including pancreatic

neoplasms (75 g of Vitamin C), non-small cell lung cancer (75g of Vitamin C) and

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glioblastoma multiforme (87.5 g of Vitamin C) (Table 1). In fact, it is estimated that

nearly 50% of anti-cancer drugs in clinical applications constitute natural compounds

or derivatives (Diederich & Cerella, 2016). Taken together, nutraceuticals offer

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tremendous promise to produce major benefits for patients suffering from

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neurological diseases or cancers.

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2. Classifications of nutraceuticals

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No accurate definition currently exists for “nutraceuticals”. However, a nutraceutical
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is generally understood to be a food, or a part of food, that produces substantial

benefits for the prevention and treatment of diseases. Under this definition,
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nutraceuticals at least comprise medical foods, functional foods, and dietary

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ingredients. Medical foods are usually administered under the supervision of a

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physician for the management of a disease. Functional foods and medical foods are
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actually not distinct, except that functional foods provide additional benefits for
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decreasing the risk of disease or ensuring optimal health. Lastly, another type of

nutraceutical, dietary supplements, often include multiple forms of ingredients, such

as vitamins, minerals, herbs, amino acids, and other substances that are administered

for health. Nutraceuticals are frequently present in large quantities in numerous sorts

of foods, such as fresh fruit, root vegetables, and fruiting vegetables, and possess

potent antioxidative properties (Agudo et al., 2007).

According to distinct chemical structures, antioxidative nutraceuticals are divided

into four different categories, as previously reported (Kelsey et al., 2010): (1)

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flavonoid polyphenols; (2) non-flavonoid polyphenols; (3) phenolic acids and

phenolic diterpenes; and (4) organosulfur compounds. Representative nutraceuticals

of each type are displayed in Table 2. Among them, dietary polyphenols have recently

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been extensively investigated on the neuroprotective and anticancer properties. It is

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estimated that polyphenols are one of the most common types of natural agents across

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the plant kingdom, among which more than 4000 flavonoids have been isolated and

identified. High amounts of polyphenols are contained in fruits, vegetables and other

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kinds of foods and beverages, such as tea and chocolate. As the most abundant
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biologically active ingredient in tea polyphenols, EGCG (2 mg/kg) has been shown to

promote neuroprotection against various neurological disorders and inhibit the

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pathogenesis of cancer (Lambert & Elias, 2010; Lee et al., 2013; Singh, Mandal, &
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Khan, 2016). Other important flavonoid polyphenols, such as Quercetin (0.5 mg/kg)
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(Costa, Garrick, Roque, & Pellacani, 2016), apigenin (40 mg/kg) (Mao, Yu, Liu, &
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Zhou, 2015), Genistein (1 mg/kg) (Li et al., 2011; Wang et al., 2013), Baicalein (40
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mg/kg) (Choi et al., 2016; Mao et al., 2014), Chrysin (12 μM) (Kanwal, Datt, Liu, &

Gupta, 2016; Zhang et al., 2015), Kaempferol (100 nM) (Ebrahimi & Schluesener,

2012; Huang et al., 2013), and Wogonin (Cho & Lee, 2004; Tsai, Yeh, Huang, Tan, &

Lu, 2012) are also reported to be beneficial for protecting against glutamate-induced

neuronal injuries (143.3 μg/ml of Wogonin) and preventing cancer cell growth (25 μM

of Wogonin).

Additionally, there are several non-flavonoid polyphenols found in foods that are

advantageous for human health. For instance, Curcumin (100 mg/kg) serves as a

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potent antioxidant from turmeric (Kiasalari, Roghani, Khalili, Rahmati, &

Baluchnejadmojarad, 2013) and Resveratrol (30 mg/kg), abundant in grapes and red

wine, can prevent or slow the progression of cancer and ischemic injuries (Jang et al.,

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1997; Wang et al., 2002). In addition, phenolic acids and phenolic diterpenes, which

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are found in rosemary, constitute another member of anti-oxidative nutraceuticals,

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with rosmarinic acid and carnosic acid being representative antioxidants in this herb.

A prior work determined that rosmarinic acid (56 μM) functioned as a potent

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free-radical scavenger and protected human neuroblastoma cells SH-SY5Y against
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hydrogen peroxide (H2O2)-induced oxidative stress and cell death (Lee et al., 2008;

Qiao et al., 2005). Similar to the polyphenols mentioned above, rosmarinic acid (0.25
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mg/kg) also exhibited neuroprotective effects against memory deficits in a mouse AD

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model (Alkam, Nitta, Mizoguchi, Itoh, & Nabeshima, 2007). As a major member of
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phenolic diterpenes, carnosic acid (1 μM) was reported to prevent

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6-hydroxydopamine-induced cell death in SH-SY5Y cells and defend neurons from

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oxidative stress (Lin & Tsai, 2016; Satoh et al., 2008).

The final type of nutraceutical antioxidants discussed in our review is organosulfur

compounds, including L-sulforaphane and allicin. L-sulforaphane belongs to an

isothiocyanate compound, and is highly abundant in broccoli and other cruciferous

vegetables. It is also a neuroprotectant, as evidenced by the fact that

6-OHDA-induced dopaminergic neuronal toxicity was significantly suppressed after

treatment with L-sulforaphane (5 mg/kg) (Morroni et al., 2013). In an in vivo model

of murine oral cancer induced by the carcinogen 4-nitroquinoline-1-oxide,

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L-sulforaphane treatment exerted an evident anti-cancer role via NF-E2-related factor

2 (NRF2) activation of antioxidant enzymes (Bauman et al., 2016). Moreover, another

compound highly enriched in garlic and garlic extract, allicin has nearly two-fold

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more neuroprotective effects than pure allicin, probably due to its strong antioxidant

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properties (Chauhan, 2005). In terms of the anti-cancer aspect, allicin (5mg/kg) was

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found to promote cytotoxicity in hepatocellular carcinoma via the reactive oxygen

species (ROS)-mediated mitochondrial pathway (Zou et al., 2016). Taken together,

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four different types of nutraceutical antioxidants have evident neuroprotective and
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anti-cancer effects. Determining the corresponding potential molecular mechanisms is

essential to elucidate the novel therapeutic targets for neuropsychiatric diseases and
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carcinomas.
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3. Neuroprotective and anti-cancer mechanisms of nutraceuticals

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3.1. Involvement of ROS-mediated cellular signaling

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It is well-known that basal amounts of ROS are indispensible for the normal

metabolism and have critical physiological functions, including signaling transduction

and transcription. Usually, ROS is defined as a highly reactive oxygen-containing

species. There are three different sorts of ROS, i.e., superoxide radical, hydroxyl

radical (HO) and non-radical molecule H2O2, all of which confer different reactivities

to biological targets (Figure 1A) (Gorrini, Harris, & Mak, 2013). These molecules

often arise from the product of oxygen consumption during metabolic reactions in

diverse cellular locations, with mitochondria, endoplasmic reticulum (ER), and

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peroxisomes constituting the dominant sites. Mitochondria is a important source of

cellular ROS, as nearly 2% of molecular oxygen is consumed in mitochondria via the

electron transport chain during respiration and finally generates superoxide (Handy &

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Loscalzo, 2012). ER provides an oxidizing environment that forms disulfide bonds,

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corrects protein folding, and triggers the accumulation of ROS via protein oxidation

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(Malhotra & Kaufman, 2007). Peroxisomes are responsible for both ROS production

(through the generation of H2O2 by peroxisomal oxidases, which are involved in the

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β-oxidation of fatty acids) and ROS elimination (through the decomposition of H2O2
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by catalase and glutathione-peroxidase (GPX)) (Schrader & Fahimi, 2006). The

modulation of ROS is essential for maintaining normal physiological and metabolic

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functions, as different ROS levels lead to distinct biological processes (Cairns, Harris,
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& Mak, 2011; Sena & Chandel, 2012). Physically, the basal cellular ROS level is
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strictly maintained by ROS scavengers (such as dietary antioxidants, tumor

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suppressors, glutathione, NADPH, and NRF2) and ROS inducers (such as Aβ,
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hypoxia, ER stress, oncogenes, and metabolic defects) (Figure 1B). Substantial

evidence has supported that hypoxia can augment the activity of NADPH oxidases

(NOXs) and subsequently aggregate ROS accumulation via targeting PKCε signaling

in pulmonary artery smooth muscle cells (Rathore et al., 2008). The redox

homeostasis is vital to cell survival. Decreased ROS content by stress stimulators

makes cells cytostatic, while elevated ROS level exacerbates cell death (for example,

apoptosis, ferroptosis, and necrosis) (Figure 1C). In fact, ROS is involved in multiple

facets relating to functional regulations, such as inflammation, apoptosis, DNA

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damage, niche maintenance, mitochondrial regulation, cell reprogramming,

antioxidant response, cell proliferation and survival, iron homeostasis, and metabolic

remodeling (Figure 1D). In neurons, the basal cellular ROS level is tightly balanced

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by antioxidant defense (including some anti-oxidative enzymes, such as superoxide

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dismutase, catalase, glutathione peroxidase, glutathione disulfide reductase and

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glutathione-S-transferase, as well as non-enzymatic sources, such as the antioxidant

molecule glutathione, ascorbic acid, and α-tocopherol) and pro-oxidant systems

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(Figure 2). The pro-oxidant system that dictates ROS production is often divided into
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endogenous factors, such as mitochondrial electron transport chain, NOXs and

lipoxygenases (LOXs), as well as exogenous factors, such as ultraviolet radiation,

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drugs, and heavy metals (Figure 2) (Prasad, Gupta, & Tyagi, 2017). When the cellular
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redox homeostasis is disturbed, an imbalanced regulation between antioxidant defense

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and pro-oxidant systems occurs and results in oxidative stress. ROS-mediated

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oxidative stress can frequently react with biological macromolecules, including DNA,
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RNA, proteins and lipids, and exacerbate oxidative damage. In particular, DNA

oxidation induced by ROS leads to DNA mutation and genetic instability, which are

involved in the etiology of neurological disorders and cancer development (Lin &

Beal, 2006; Mi et al., 2012; Toyokuni, Okamoto, Yodoi, & Hiai, 1995). It is worth

noting that the brain, especially the neurons, is more vulnerable to oxidative stress

because the brain (Halliwell, 2001; Olanow, 1993), which accounts for only 2% of

body weight, requires one-fifth of the total oxygen. High oxygen consumption, a

destroyed anti-oxidative defense system, or reduced regenerative capacity navigates

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the brain to oxidative damage in the brain tissue (Barnham, Masters, & Bush, 2004).

In addition, neurons possess a non-reproductive property, and oxidative injury to the

brain is cumulative over time. A large body of extant literature has demonstrated the

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excessive production of ROS, which caused oxidative impairments in epilepsy, AD,

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PD, ischemic stroke, and schizophrenia (Boskovic, Vovk, Kores Plesnicar, & Grabnar,

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2011; Coyle & Puttfarcken, 1993; El Kossi & Zakhary, 2000; Frantseva et al., 2000).

These findings imply that targeting oxidative stress is beneficial for curing these

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neurological disorders. As mentioned previously, most nutraceuticals possess potent
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anti-oxidative properties, and thus have great potential for exerting neuroprotective

effects through recovering redox homeostasis in the brain. In fact, our prior work
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proved that the flavones Baicalein (40 mg/kg) and Baicalin (200 mg/kg) remarkably
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attenuated epileptic seizures and global cerebral ischemia, respectively, via

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suppressing oxidative stress (Cao et al., 2011; Mao et al., 2014). Activated
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extracellular signal-regulated kinase (ERK) and suppressions of c-Jun amino-terminal

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kinase (JNK), as well as mitogen-activated protein kinase (MAPK), may be involved

in baicalein’s neuroprotection against epileptogenesis. In fact, ROS production can be

found to trigger various alterations of cellular signaling in aging. It is revealed that

ERK has a pro-survival effect, while JNK and p38 MAPK are detrimental to neurons

in response to oxidative damage (Finkel & Holbrook, 2000), indicating that ROS is

likely to cause alterations in the MAPK signaling pathway during the neuroprotection

of dietary agents. The ROS scavenging effect was also found in our laboratory in the

attenuation of the flavonoid polyphenol apigenin (40 mg/kg) on diabetes-associated

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memory deficits in rats (Mao et al., 2015). Oxidative impairment is complicated, and

often leads to the occurrence of DNA adduct, protein modification, and lipid

peroxidation due to the detrimental effects of high ROS levels on biomolecules,

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including DNA, lipoproteins, and lipids (Perry et al., 2000). Thus, it is of vital

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importance to identify the appropriate gene that controls the expressions of the many

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genes involved in suppressing not only the production of oxygen radicals, but also

products of oxidation, as mentioned above. NRF2 is most probably the candidate, as it

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can drive the transcription of multiple genes that are important in oxygen free radical
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scavenging and products of oxidation (Calkins et al., 2009). One clear example is that

NRF2 can detoxify and inhibit the generation of 4-hydroxy-2-nonenol (HNE), a

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highly reactive byproduct of lipid perioxidation (Calkins et al., 2009). NRF2 is a

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transcription factor, which inhibits oxidative stress through coordinated binding to the
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antioxidant responsive element (ARE) in the nucleus and dictating the expression of
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detoxification enzymes, such as glutathione S-transferase (GST) (Gan & Johnson,

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2014; Lastres-Becker et al., 2012), oxidative stress-inducible proteins, such as heme

oxygenase-1 and system Xc- activity (Ishii et al., 2000).The repressed activity of

NRF2 relies on Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm (Itoh

et al., 1999). Cytoplasmic Keap1 functions as an adaptor of ubiquitin E3 ligase and

dictates NRF2 degradation (Kobayashi et al., 2004). Extensive evidence has

demonstrated that many nutraceuticals possess potent antioxidant potentials against

various pathological conditions in CNS through targeting NRF2 activity. Specifically,

the non-flavonoid polyphenol curcumin (100 mg/kg) was previously reported to

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remarkably attenuate oxidative damage in cerebral ischemia-reperfusion injury and

multiple neurotoxic insult in vitro via activating NRF2 activity (Cui, Li, & Zhu, 2016;

Wu et al., 2013). In this pathogenic condition, Akt phosphorylation induced by

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curcumin (100 mg/kg) promotes translocation of NRF2 into nucleus and the binding

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of ARE, combating the generation of oxidative stress following neurotoxic insult

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(Figure 2) (Cui et al., 2016; Lee & Johnson, 2004; Wu et al., 2013).

In cancer cells, redox homeostasis regulation seems to be more complex (Figure

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3). Traditionally, it is thought that cell malignancy simply relies on the activation of
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oncogenes or inactivation of tumor suppressors, which is usually referred to as

“oncogene addiction” (Weinstein & Joe, 2008). However, recent investigations have
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demonstrated that cancer cells can experience metabolic adaptations to defend against
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moderate ROS content (Hanahan & Weinberg, 2011). Generally, the malignant cell
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type usually has a higher ROS level to maintain its survival than normal cells. A
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previous investigation determined that cancer cells had a nearly two-fold lower rate to
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remove H2O2, a strong oxidant, than normal cell lines (Doskey et al., 2016),

supporting intrinsically higher ROS content in carcinomas (Figure 3).

Cancer cells at an advanced stage often exhibit genomic instability, especially

in the mitochondria genome, which further contributes to metabolic malfunctions and

augmented production of ROS. They can frequently adapt to survive under a

moderate increase of ROS stress (ROS adaptation). The redox adaptation in cancers

can be maintained by activating ROS scavenging enzymes, such as GSH, to combat

enhanced ROS generation. In addition, redox-sensitive transcription factors, including

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NRF2 and HIF-1, have also been activated to improve the activities of antioxidant

enzymes, such as SOD and catalase, as well as trigger the elevation of cell-survival

molecules (Bcl-2 and Akt). These ROS adaptive mechanisms allow cancer cells to

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escape from oxidative impairment under ROS-mediated genetic mutations. Mounting

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evidence has shown that a slight accumulation of ROS promotes the proliferation of

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cancer cells, indicating the dependence on ROS for survival (ROS addiction). ROS

addiction has been found to be involved in malignant transformation, metastasis, and

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therapeutic resistance (Chen et al., 2007; Martinez-Sanchez & Giuliani, 2007;
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Schneider & Kulesz-Martin, 2004). Further altering ROS adaptation through either

enhancing ROS level or decreasing the originally enhanced ROS content for cancer
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cell survival by drug treatment is likely to constitute a therapeutic strategy that can
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specifically kill cancer cells (Sies, Berndt, &Jones, 2017). Large-scale

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epidemiological data also supported an evidently reduced liver cancer incidence after
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treatment with vitamin E (no accurate dose) in China (Zhang et al., 2012). Likewise,
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the natural diterpenoid isoforretin A (15 μM) could also be found to inhibit

thioredoxin 1, a critical antioxidant protein, and result in ROS accumulation, finally

suppressing the growth of hepatocellular carcinoma (Sun et al., 2017). Apigenin (25

mg/kg) was also shown to prevent hepatocellular carcinogenesis via decreasing

oxidative stress (Jeyabal, Syed, Venkataraman, Sambandham, & Sakthisekaran, 2005).

Recent investigations also revealed that the antioxidant dietary supplement

chlorogenic acid (1 μM) could suppress glioma growth via facilitating M1-polarized

macrophage and inhibiting M2 phenotypic macrophage (Xue et al., 2017). Of special

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interest, curcumin (25 μM) was found to inhibit the self-renewal property of

glioblastoma stem cell via inducing ROS (Gersey et al., 2017). Combinations of

curcumin (0.5 μM) and thioridazine (10 μM) evidently induced apoptotic cell death in

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glioma via NOX4-mediated ROS accumulation (Seo, Kim, Kim, Min, &Kwon, 2017).

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What’s more, Vitamin C treatment was also reported to exert anti-cancer effects

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against non-small-cell lung cancer (2 mM of Vitamin C) and glioblastoma (5 mM of

Vitamin C) via increasing redox-active labile iron (Schoenfeld et al., 2017).

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Nevertheless, the results were contradictory in another two investigations showing
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that vitamin A (25000 IU) supplement triggered an increased risk of lung cancer

(Omenn et al., 1996), implying differential redox homeostasis states in different

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cancer cell types (Table 3, Figure 2 and Figure 3). Moreover, several other
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investigations have demonstrated that anti-oxidant nutraceuticals accelerate the

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progression of cancer cells (Chandel & Tuveson, 2014; Kaiser, 2014; Sayin et al.,
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2014; Stebbing & Hart, 2011). Collectively, dietary compounds seem to constitute a
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“double-edged sword” in cancer treatment, as they can either kill the cancer cells or

protect them. As far as I am concerned, the detrimental or effective role of dietary

compounds is possibly related to the redox state in the cellular or tissue context,

especially in carcinomas. As the tumor heterogeneity is very common and enormous

responsive variation often occurs following intake of nutraceuticals. Additionally, the

mechanisms by which nutraceuticals exert harmful or effective roles are not clear,

dietary compounds are likely to have non-redox functions as similarly, the antioxidant

enzyme GPX4 can function as a structure protein in sperm in addition to its

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antioxidant property (Lei et al., 2016). Besides, many other facets are required to be

considered such as the pharmacodynamics and the concentration of the target organ

for nutraceuticals. Further research is indispensible to elucidate this critical issue.

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3.2. Involvement of ROS-regulated inflammation

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It seems that ROS and inflammation are modulated by each other. ROS is produced in

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the inflammatory microenvironment in phagocytes either within mitochondria or via

NADPH oxidase-mediated oxidative burst (Leavy, 2014; Noubade et al., 2014).

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Ouyang and colleagues claimed that the negative regulator of ROS could block ROS
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production, and this phenomenon was prevented when treating with interferon-γ

(IFNγ) or lipopolysaccharide (LPS), the classical inflammatory stimulator, indicating

D

the causative role of inflammation in ROS generation. Conversely, accumulation of

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ROS was also found to limit T helper type 17 cell differentiation and ROS scavenger
P

N-acetyl cysteine treatment boosted cell differentiation, finally exacerbating severity

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of inflammation-associated autoimmune diseases (Fu et al., 2017). In addition,

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inflammation in the CNS is a research focus due to well-established crosstalk between

the nervous and immune systems. Astrocyte and microglia are often conceived of as

the major inflammation responsive cells and modulate inflammation-mediated cell

death in the brain. A transgenic mouse model with a superoxide dismutase (SOD1)

mutation exhibited glial cell activation, and the up-regulation of inflammation-related

genes, including tumor necrosis factor-α (TNF-α) and motor neurodegeneration

(Yoshihara et al., 2002). In addition, during chronic neuroinflammation, ROS

accumulation could exacerbate inflammation -induced cellular impairment in

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microglia through activating multiple signaling molecules, such as JNK, p38 MAPK,

and NF-κB (Bauer & Bauer, 2002). Aromatic (ar)-turmerone (20 μM), a major

component isolated from Curcuma longa, was reported to significantly suppress

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Aβ-induced neuroinflammation of microglial cells and ROS accumulation (Park, Jin,

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Kim, Kim, & Lee, 2012). Furthermore, it has been shown that the interaction of ROS

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and inflammation is involved the development of cancers. For instance, it was

previously revealed that the production of ROS during inflammatory conditions

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contributed to DNA damage, which was of central importance in carcinogenesis
MA
(Ohnishi et al., 2013). On the other hand, excessive ROS level has also been found to

promote the release of inflammatory cytokines, leading to tumorigenesis. Valavanid

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and colleagues observed that ROS could exacerbate pulmonary inflammation and
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mediate the initiation of carcinogenesis in the respiratory system (Valavanidis,

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Vlachogianni, Fiotakis, & Loridas, 2013). Additionally, excessive ROS was also
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found to activate NF-κB-mediated inflammatory reactions, inducing melanoma cell

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angiogenesis (Schaafhausen et al., 2013). Collectively, these findings indicate that

targeting the interaction of ROS and inflammation is likely to protect neural cells

from injury and inhibit the pathogenesis of carcinomas. In fact, a previous

investigation showed that ethanol exposure induced the production of ROS, which

further induced inflammatory factors, including TNF-α, NF-κB, and p65 in animals

(Ye et al., 2013).

3.3 Involvement of ROS-associated epigenetics

In addition to genetic alterations, epigenetic modulations also occur during oxidative

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stress. Targeting epigenetic regulations may underlie the neuroprotective and

anti-cancer effects of nutraceuticals. It has been well-established that epigenetic

modifications mainly include DNA methylation, histone modification, and non-coding

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RNAs (Costa, 2008). In AD, the sustainable hypomethylation of β-amyloid precursor

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protein (APP) promoter has been shown to drive the overproduction of APP and Aβ

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level (Zawia, Lahiri, & Cardozo-Pelaez, 2009). The enhanced Aβ content

subsequently contributes to excessive ROS level, and causes DNA damage. This

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implies that DNA methylation patterns are involved in the etiology of neurological
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diseases via manipulating ROS production. Moreover, excessive production of ROS

can also induce epigenetic alterations in numerous human carcinomas (Lim et al.,
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2008; Quan, Lim, & Jung, 2011). In particular, there exists a close relationship
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between ROS and DNA methylation patterns (Donkena, Young, & Tindall, 2010;
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Ziech et al., 2010). It has been demonstrated that induction of ROS by zinc oxide
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nanoparticles promotes global hypomethylation in cells by triggering the expression

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of TET-enzymes (Choudhury et al., 2017). In addition, ROS-triggered oxidative stress

is increasingly considered to act as a catalyst of DNA methylation and improve

unusual hypermethylation of the tumor suppressor gene promoter region that is linked

with gene silencing, leading to a malignant transformation. One representative

example is that H2O2 treatment augmented the hypermethylation of the E-cadherin

gene promoter by increasing the expression of the transcription factor Snail in

hepatocellular carcinoma cells (Ziech et al., 2010). Furthermore, ROS can also

promote site-specific hypermethylation via either increasing the expression of

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DNMTs or forming a new DNMT-containing complex. In addition, elevated levels of

superoxide radical, one of the ROS family members, is shown to be positively

correlated with the upregulation of DNMT1 and DNMT3B (Wu & Ni, 2015). In

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colorectal cancer, it is revealed that H2O2 results in reduced RUNX3 expression via

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augmenting its promoter, methylation (Kang, Zhang, Kim, Bae, & Hyun, 2012). H2O2

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treatment is also observed to accelerate the formation of a large complex containing

DNMT1 and Sirt1, a common histone deacetylase, in breast cancer in vitro (O'Hagan,

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Mohammad, & Baylin, 2008). What’s more, GSH, a commonly anti-oxidant molecule,
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is considered to serve as a post-translational modifier of the histone code

(García-Giménez, Romá-Mateo, Pérez-Machado, Peiró-Chova, &Pallardó, 2017).

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Specially, GSH depletion was found to induce global DNA hypomethylation in vitro,
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which was likely because of depletion of S-adenosylmethionine (SAM), which often

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functioned as a methyl donor for DNA through DNA methyltransferases. During GSH
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synthesis, SAM is catalyzed by methionine adenosyltransferases (MATs) while

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Sadenosyl homocysteine (SAH) is generated by methyltransferases (MTs). Therefore,

decreased MAT activity contributes to diminished GSH content and low ratio of SAM

and SAH can destroy DNA methylation. The anti-oxidative transcriptional factor

NRF2 has also been shown to be regulated by various microRNAs, resulting in

tumorigenesis (Zhang, Shu, & Kong, 2015). In the human breast cancer cell line

MCF-7, microRNA-218 was reported to decrease NRF2 stability via promoting its

degradation, finally enhancing tumor cell growth (Yang, Yao, Eades, Zhang, & Zhou,

2011). These findings suggest that the modulation of epigenetic factors induced by

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ROS may be beneficial for combating carcinogenesis. Indeed, in prostate cancer cell

line PC3, it was reported that ascorbic acid (also termed vitamin C, 3.96mM)

suppressed the expression of NF-κB transcription factor RelB and subsequently

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inhibited Sirt3, as well as the powerful antioxidant MnSOD. This ultimately increased

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oxidative impairments in cancer cells, which indicated the vital role of epigenetic

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factor regulation in the anti-cancer effects of dietary agents (Wei et al., 2017).

3.4 Involvement of ROS-mediated apoptosis

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Production of oxidative stress following neuronal insult ultimately activates cell
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apoptosis. Caspase-3 is regarded as an executioner of apoptosis (Cao et al., 2011).

Accumulative evidence has demonstrated that the up-regulation of caspase-3 is

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observed after diverse neurological disorders. Our previous investigation showed that
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the brain-derived neurotrophic factor (BDNF) was involved in the suppression of

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caspase-3 after global cerebral ischemia in gerbils, and that the flavone baicalin (100
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mg/kg) could confer neuroprotection against ischemic insult via upregulating BDNF
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and inhibiting caspase-3 activity (Cao et al., 2011). Similarly, huperzine A (0.05

mg/kg), a Lycopodium alkaloid extracted from Huperzia serrate, was also found to

effectively improve cognitive deficits after diabetes, transient global ischemia, and

AD via ablating apoptotic cascades (Mao et al., 2014; Wang, Yan, & Tang, 2006;

Zhou, Zhang, & Tang, 2001). In aging-related disorders, activations of JNK and p38

MAPK are more susceptible to causing ROS-mediated apoptosis. Specifically, under

normal circumstances, the redox regulatory protein thioredoxin has been found to

bind to apoptosis signal-regulating kinase (ASK1), which acts as the upstream

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activator of both JNK and p38, and blocks its activity (Saitoh et al., 1998).

Nevertheless, oxidative stress promotes the disassociation of ASK1-JNK or p38

complex, and contributes to the activation of JNK and p38, finally augmenting

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caspase-3 activity and triggering apoptotic cascades (Kadowaki et al., 2005; Tobiume

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et al., 2001). Phosphoinositide 3-kinase (PI3K)/Akt pathway activation has also been

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shown to suppress ROS-regulated apoptosis following ischemic insult (Yao et al.,

2012). Targeting this pathway may protect neurons from oxidative impairment. In fact,

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our previous study unequivocally proved that huperzine A (10 μM) attenuated
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glutamate-induced oxidative damage in HT22 neurons via activating the PI3K/Akt

signaling pathway (Mao, Zhou, Li, & Liu, 2016). Similarly, the protection of
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glutamate-triggered oxidative stress in HT22 cells was also found to be significantly

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resisted by resveratrol via PI3K/Akt-dependent induction of SOD2, a classical

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antioxidant enzyme (Fukui, Choi, & Zhu, 2010). These findings imply that targeting
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cell apoptosis may promote neuronal survival after treatment with nutraceuticals. Of
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course, this apoptotic phenomenon is also present in cancer cells, and is considered to

constitute a critical step in tumorigenesis and drug resistance (Hanahan & Weinberg,

2000; Watson, 2013). Therefore, apoptotic pathways also serve as relevant drug

targets for killing cancer cells (Fesik, 2005). In fact, many bioactive compounds have

been extracted from natural plants in the past decade, and some reagents, such as

paclitaxel (60 mg/cm2) and vincristine (135 mg/cm2), have been successfully applied

in anti-cancer therapy in clinical practice via apoptosis induction (Marks, Baltimore,

& McCaffrey, 1978; Rowinsky & Donehower, 1995). Dietary compounds also have

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attracted attention due to their activations of apoptosis in cancer cells. For instance,

Baicalein (25 μM) is found to trigger the occurrence of apoptosis in multiple cancer

cells via modulating ROS level (Choi et al., 2016; Li, Lu et al., 2017). Taken together,

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apoptosis constitutes a common phenomenon in neurological diseases and cancers.

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Suppressing the apoptotic pathway or inducing cell apoptosis functions as a critical

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mechanism for the neuroprotective or anti-cancer effects of nutraceuticals,

respectively.

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Nutraceutical antioxidants play multiple biological roles via diverse molecular
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targets, as listed in Table 4. These roles are either directly correlated with ROS or

indirectly involved in the modulation of ROS level.

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4. ROS-associated ferroptosis is anticipated to serve as an essential mechanism

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for the neuroprotective and anti-cancer activities of nutraceuticals

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As mentioned above, ROS is produced by multiple factors. One of the most important
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factors is that high levels of ferrous iron (Fe2+) in cells could disturb the balance of

ROS scavenging and ROS production systems, and subsequently change the cell from

redox homeostasis into oxidative stress due to excessively augmented generation of

hydroxyl radicals via the Fenton reaction (Radi, Formichi, Battisti, & Federico, 2014;

Torti & Torti, 2013). In fact, high content of Fe2+- induced oxidative stress can trigger

ferroptosis, a recently discovered form of iron- and lipid peroxidation-dependent

regulated cell death (RCD) that is distinct from other forms of RCD, including

apoptosis, necroptosis, and autophagy at the morphological, biochemical, and genetic

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levels (Dixon et al., 2012). It is characterized morphologically by the presence of cell

volume shrinkage and increased mitochondrial membrane density. Additionally,

excessive accumulation of lipid peroxidation products and lethal ROS are also found

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following ferroptotic cell death (Angeli, Shah, Pratt, & Conrad, 2017). It is well-

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known that ferroptosis is triggered either by experimental compounds (including

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erastin, glutamate, buthionine sulfoximine (BSO), and RAS-selective lethal small

molecule 3 (RSL3)) or clinical drugs (sulfasalazine (SAS) and sorafenib).

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Iron metabolism and lipid peroxidation signaling are regarded as the two key
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regulators of ferroptosis (Dixon, &Stockwell, 2014). There is ample evidence

supporting that iron overload exacerbates ferroptotic cell death. Blunting iron
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accumulation by iron chelators (including deferoxamine) suppresses erastin-induced

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ferroptosis while elevated exogenous iron resources such as ferric ammonium citrate
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and ferric citrate augment erastin-associated cell death (Dixon et al., 2012; Yang,
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&Stockwell, 2008). In fact, iron excession contributes to ROS production by Fenton

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reaction, finally triggering lipid peroxidation, which is a critical feature of ferroptosis.

Additionally, NADPH-mediated lipid peroxidation and GSH depletion also lead to the

generation of ferroptosis (Dixon et al., 2012; Yang et al., 2014). A previous

investigation revealed that GSH depletion could induce GPX4 inactivation and

subsequently the occurrence of ferroptosis via lipid ROS accumulation (Yang et al.,

2014). Moreover, during ferroptosis, the lethal signal from GPX4 knockout cells were

found to occur outside the mitochondrial matrix, suggesting that ferroptosis was

caused by extra-mitochondrial lipid peroxidation (Friedmann Angeli et al., 2014).

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GPX4 was also observed to attenuate mitochondria-mediated apoptosis via decreasing

levels of lipid hydroperoxides and membrane permeability in mitochondria (Loscalzo,

2008), suggesting its diverse roles in modulating cell death.

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In the following, we present a comprehensive description of the relationship

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between ROS-related ferroptosis and neuroprotection or anti-cancer effects of

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nutraceuticals and the potential regulatory mechanisms. Additionally, the proposed

nutraceutical antioxidants are also listed in Figure 4.

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4.1. Suppressing ROS-associated ferroptosis as a neuroprotective mechanism of
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nutraceuticals

Abnormal generation of oxidative stress has been observed in multiple

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neuropsychiatric diseases. Several by-products of lipid peroxidation, a well-known

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marker for evaluating oxidative stress, have been found to be obviously enhanced
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following insult in CNS. Several lipid peroxidation by-products, including HNE,

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acrolein, malondialdehyde, and F2-isoprostanes are often produced during the chain
AC

reaction which is initiated by highly reactive lipid peroxy radicals. It was previously

reported that augmented HNE levels were found in AD and PD brain tissue (Dexter et

al., 1989; Selley, Close, & Stern, 2002). Additionally, elevated HNE levels were also

observed in the hippocampal tissue of epilepsy (Pecorelli et al., 2015).

Malondialdehyde level was also found to be remarkably elevated in PD and epileptic

brains (Dexter et al., 1989; Mao et al., 2014). In addition, there were great elevations

of acrolein and F2-isoprostanesin in AD brains (Selley et al., 2002). These findings

emphasize the positive correlation of reactive lipid peroxides and the etiology of

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neuropsychiatric disorders. As the accumulation of lipid-based reactive ROS is also

considered to be a vital index for assessing the presence of ferroptotic cell death

(Gaschler & Stockwell, 2017), we expect that ferroptosis plays a crucial role in the

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pathogenesis of diverse neuropsychiatric diseases. Targeting ferroptosis may provide a

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novel therapeutic approach for treating these disorders. In fact, previous evidence

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supported the assertion that the inhibition of GPX4 could result in motor

neurondegeneration characterized by ferroptosis, indicating that GPX4 served as a

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critical ferroptosis inhibitor and dictated neuronal survival (Chen, Hambright, Na, &
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Ran, 2015). Similarly, in an in vivo mouse model, GPX4 deletion in forebrain neurons

contributed to serious learning and memory deficits, as well as hippocampal

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neurodegeneration. Treatment with liproxstatin-1, a small ferroptosis inhibitor that

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prevented lipid peroxidation, evidently ameliorated deficient cognition in a GPX4

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knockout mouse model (Hambright, Fonseca, Chen, Na, & Ran, 2017), which further
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confirmed the critical role of ferroptosis in maintaining normal function and survival
AC

of neurons in CNS. Additionally, ferroptotic cell death was also reported to be

involved in the etiologies of hemorrhagic stroke and PD (Guiney, Adlard, Bush,

Finkelstein, & Ayton, 2017; Zille et al., 2017). In particular, a previous investigation

confirmed that the 5-Lipoxygenase inhibitor zileuton at the concentration of 10 μM

conferred remarkable neuroprotection against glutamate-induced HT22 damage via

blocking ferroptosis (Liu et al., 2015). Ferroptotic cell death in the immortalized

hippocampal neuron HT22 subjected to glutamate was also significantly reversed by

the inhibition of receptor tyrosine kinase Flt3 and the signaling molecule

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phosphoinositide 3-kinase α (PI3Kα) (Kang, Tiziani, Park, Kaul, & Paternostro, 2014).

More importantly, the nutraceutical vitamin E with the dose of 1000 IU/kg in the diet

has been shown to be a ferroptosis inhibitor, and attenuated neuronal cell death after

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GPX4 ablation (Chen et al., 2015), indicating a critical role of ferroptosis in the

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neuroprotection of this dietary compound.

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4.2. Modulation of ROS-associated ferroptosisis is likely to act as an important

mechanism for the anti-cancer potential of nutraceuticals

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Ferroptosis, a new form of regulatory cell death, is also widespread in cancers. As
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early as 2003, Stockwell’s laboratory identified a new chemical compound, i.e.,

erastin, that exhibited remarkable killing effects on RAS-mutant tumor cells in a

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manner that was distinct from well-known programmed cell death, apoptosis, via
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large-scale screening experiments (Dolma, Lessnick, Hahn, & Stockwell, 2003).

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Thereafter, Stockwell’s research group also reported that two novel compounds, Ras
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Selective Lethal 3 (RSL3) and Ras Selective Lethal 5 (RSL5), had equivalent effects
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to erastin (Yang & Stockwell, 2008). Several genes, including NADPH oxidase 4

(NOX4) (Poursaitidis et al., 2017), RAS (Yagoda et al., 2007), (Jiang et al., 2015),

acyl-CoA synthase 4 (ACSL4) (Doll et al., 2017), BID (Neitemeier et al., 2017),

transferrin receptor 1 (TFR1) (Gao, Monian, Quadri, Ramasamy, & Jiang, 2015) and

nuclear receptor coactivator 4 (NCOA4) (Hou et al., 2016) have the capacity to

induce ferroptosis, while others, such as Metallothionein-1G (MT-1G) (Sun, Niu et al.,

2016), GPX4 (Hambright et al., 2017; Yang et al., 2014), System Xc- (Dixon et al.,

2014) and heat shock 70kDa protein 5 (Zhu et al., 2017) suppress ferroptotic cell

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death in diverse carcinomas. Specifically, MT-1G was found to promote sorafenib

resistance in hepatocellular carcinoma (HCC) via inhibiting ferroptosis (Sun, Niu et

al., 2016), suggesting that suppressing this gene could enhance sorafenib (5 μM)

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chemosensitivity. It is also noted that facilitating the generation of ROS in HCC by

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ultrasmall nanoparticles causes an induction of ferroptosis, and finally inhibits tumor

SC
growth (Kim et al., 2016), implicating the positive correlation of ROS and ferroptosis.

Indeed, a previous investigation also showed that the activated antioxidant NRF2

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signaling pathway protects against ferroptotic cell death in HCC cells in vitro (Sun,
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Ou et al., 2016). Currently, diverse drugs have been identified to induce or suppress

ferroptosis in distinct cancers. It is interesting to note that a nutraceutical, Baicalein

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(10 μM), is found to obviously inhibit ferroptosis and increase the proliferation of the
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human pancreatic cancer cell line PANC1 via natural product screening (Xie et al.,
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2016). This is possibly attributed to its antioxidant property and inhibition of ROS
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level in carcinoma. However, inhibiting ROS in cancers can also exert anti-cancer
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effects, as mentioned above. Further research may focus on the accurate regulatory

mechanisms of ferroptosis and the effects of other nutrateuticals on this novel RCD in

cancers. In any case, modulation of ROS-associated ferroptosis is still likely to be a

critical mechanism for the anti-cancer effects of nutraceuticals.

5. Neuroprotective and anti-cancer properties: Merits and challenges

Nutraceutical antioxidants possess numerous advantages regarding neuroprotection

and anti-cancer properties. Firstly, dietary agents are widely distributed in various

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kinds of foods, plants, and minerals. Thus, it is relatively easy to obtain effective

elements from these sources. Secondly, in order to improve neural cell survival

following pathogenic states, the drugs should penetrate a specific and unique structure,

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i.e., the blood brain barrier. Most dietary agents can easily enter this barrier and exert

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evident protections in CNS (Cai et al., 2015; Campos-Bedolla, Walter, Veszelka, &

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Deli, 2014). Although some nutraceuticals, such as curcumin, present a challenge of

solubility in water due to their hydrophobic nature and are poorly absorbed in the

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human body (Anand, Kunnumakkara, Newman, & Aggarwal, 2007), employing
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nanoparticle encapsule technology readily overcomes this limitation. Previous studies

revealed that curcumin-loaded lactic-coglycolicacid nanoparticle remarkably

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increased its biodistribution and bioavailability, finally protecting cells against AD

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and acrolein toxicity (Doggui et al., 2013; Mathew et al., 2012).

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Moreover, as discussed above, multiple nutraceuticals exert potent anti-oxidative

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actions, which are involved in the occurrence of many disorders. It is easy for them to
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kill cancer cells due to altering the ROS addiction/adaptation state in carcinomas,

enhancing immunity, and subsequently increasing the survival of cancer patients and

improving their quality of life. Suppression of ROS level by dietary agents was also

previously reported to inhibit the formation of metastatic colonies (Kunnumakkara,

Anand, & Aggarwal, 2008).

Nutraceutical antioxidants also exert neuroprotections against various neurological

disorders. As previously discussed, enormous productions of ROS exacerbate cell

damage in neuropsychiatric diseases, including epilepsy, stroke, AD, and PD.

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However, the dietary compounds can remarkably protect neural cells from these

disorders, as a consequence of reducing ROS. In fact, compelling evidence has

supported the protective roles of the nutraceuticals zileuton (10 μM) against

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glutamate-induced HT22 neuronal damage via inhibiting lipid ROS-dependent

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ferroptosis (Liu et al., 2015), indicating that suppressing ROS-regulated ferroptosis

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possibly serves as an essential mechanism of nutraceuticals’ neuroprotection, as

mentioned above.

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It is worth noting that some challenges exist for the dietary agents. One obvious
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example is that the binding receptor is not clear for most of this kind of compound.

Actually, the unknown molecular targets for dietary compounds can frequently result
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in contradictory results. For instance, Nelson’s research group found no therapeutic

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benefits in several diseases including colon cancer, pancreatic cancer and AD (Baker,
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2017; Nelson et al., 2017). On the other hand, in a curcumin double-blind

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placebo-controlled clinical trial with 49 entries, 17 recent trials exhibited efficacy

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(Kimmelman & Federico, 2017). Further high-throughout screening techniques, such

as proteome analysis (including quantitative chemical proteomics and tandem mass

spectrometry) (Wang et al., 2016), gene expression profile array, and next-generation

sequencing approaches should be employed to identify the accurate molecular target

and corresponding regulatory signaling pathway, and probe the potential molecular

mechanisms of the nutraceuticals, which can preclude the promising drug candidates

in clinics. One representative example is that the cellular targets of the dietary

flavonoid, apigenin, has been enriched in three categories, including GTPase

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activation, membrane transport, and mRNA alternative splicing via combinations of

phage display with second-generation sequencing strategies (Arango et al., 2013). In

particular, the heterogeneous nuclear ribonucleo protein A2 (hnRNPA2), which

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belongs to the mRNA alternative splicing type, has been identified to be an accurate

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cellular target of apigenin (10 μM). In addition, this nutraceutical prevents hnRNPA2

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from forming homodimers and disturbs the mRNA alternative splicing of

hnRNPA2-related targets via binding to the C-terminal glycine-rich domain of

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hnRNPA2. Additionally, the bioactivity of food bioactive constituents has been
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extensively explored in animal studies and in vitro investigations, whereas clinical

trials in humans are scarce and inclusive. Moreover, the bioavailability, metabolism,
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dose/response, and toxicity of nutraceuticals have not been well-established in human

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clinical trials. It is thus critical to verify the bioactivity and pharmacodynamics of

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nutraceuticals in clinical practice settings.

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6. Concluding remarks and perspectives

It is clear that traditional chemical drugs possess limited therapeutic capacity for

the treatment of patients with neurological disorders or cancers due to the occurrence

of resistance. In addition, serious side effects often appear in these patients.

Nutraceutical antioxidants, which have a wide distribution in diverse sorts of foods,

fruits, vegetables and minerals, may constitute good candidates in clinical applications,

as we have shown above that nutraceutical antioxidants exhibit potent neuroprotection

and anti-cancer properties in vivo and in vitro. Following protecting neural cells or

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killing cancer cells, a large body of extant literature has demonstrated that the dietary

agents exert diverse modes of action via multiple biological targets, especially

differential modulations of ROS-associated ferroptosis, suggesting that ferroptosis is a

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attractive mechanism for treatment of neurological diseases and cancers. This notion

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has been confirmed in a large body of preliminary clinical data (Dixon et al., 2012;

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Liu, 2015; Xie et al., 2016; Eling, 2015). Further large-scale and multi-center clinical

trials are essential to provide more compelling evidence confirming the

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appropriateness of nutraceuticals in clinical oncology, as well as curing neurological
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diseases. Besides, great efforts can be made to improve the clinical trials via

standardizing the compound extraction method and the dosage. Better clinical designs
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can avoid the controversial treatment outcome of the dietary compounds.

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Conflict of interest statement

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The authors declare that they have no potential conflict of interest.

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Acknowledgements

We apologize to those colleagues whose important work could not be cited due

to space constraints. This work is partially financially supported by the National

Natural Science Foundation of China (Nos. 81671293, 81572928 and 81772978), the

National Key Research and Development Program of China (No. 2017FYA0205300),

and the National 973 Basic Research Program of China (No. 2013CB911300).

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Figure Legends

Figure 1. Classification, function, and regulation of ROS.

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(A) There are three sorts of ROS, i.e., superoxide radical (O2-), hydroxyl radical (HO),

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and non-radical molecule H2O2.

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(B) Under physical conditions, redox homeostasis is strictly maintained by ROS

scavengers (such as dietary antioxidants, tumor suppressors, glutathione, NADPH,

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and NRF2) and ROS inducers (such as Aβ, hypoxia, ER stress, oncogenes, and
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metabolic defects).

(C) The effects of different ROS levels on the biological functions of cells. Lowering
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ROS content by stress stimulators makes cells cytostatic, while elevated ROS level
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exacerbates cell death (for example, apoptosis, ferroptosis, and necrosis).

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(D) ROS is involved in multiple functional regulations, including inflammation,

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apoptosis, DNA damage, niche maintenance, mitochondrial regulation, cell

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reprogramming, antioxidant response, cell proliferation and survival, iron homeostasis,

and metabolic remodeling.

Figure 2. Maintenance of redox homeostasis in neurons and neuroprotection of

nutraceutical antioxidants by suppressing ROS level.

In neurons, ROS homeostasis is maintained by ROS production (such as

hypoglycemia, enhanced metabolism, and Aβ aggregation) and ROS elimination

(including dietary antioxidants, antioxidant enzymes, and NRF2 activation) systems.

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Under the stimulations of external stressors, for example, glutamate, H2O2 and

hypoglycemia, excessive production of ROS level is triggered via either resisting

GSH-related anti-oxidative function or activating NADPH oxidase-mediated

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oxidation. In addition, ROS accumulation contributes to preventing the activation of

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PI3K/Akt and ERK1/2 pathways, ultimately exacerbating cell death. Dietary

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compounds, such as EGCG, Baicalein and Curcumin, are proposed to exert

neuroprotective effects via manipulating the corresponding cellular signals,

suppressing ROS levels.

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Figure 3. Orchestra of redox homeostasis in cancer cells and anti-cancer effect of

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nutraceutical antioxidants by disrupting ROS addiction.

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In cancer cells, the intrinsic ROS level is higher than in normal cells. In addition, the
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ROS content is tightly maintained by more potent oxidant systems (such as hypoxia,
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oncogenes, enhanced metabolism, and UV radiation) and anti-oxidative systems

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(antioxidants, tumor suppressors, antioxidant enzymes, and activations of NRF2 and

HIF-1). Persistent ROS stress induces redox adaptation (ROS addiction) in some

cancer cells. ROS addiction is involved in multiple cell processes, including cell

survival, cell proliferation, cell apoptosis, angiogenesis, cancer cell immunity, stem

cell maintenance, and cellular senescence. Moreover, curcumin, vitamin C, apigenin,

and resveratrol can exert anti-cancer effects via modulating these processes.

Figure 4. Proposed nutraceutical antioxidants in neuroprotection and anti-cancer

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therapy by targeting ferroptosis, a lipid ROS-dependent regulated necrosis.

Ferroptotic cell death can be triggered by the activation of tranferrin protein, fat acid

metabolism and inactivation of system Xc- in the plasma membrane, as well as

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oncoRas induction. Specifically, transferrin-mediated iron uptake (via transferrin

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receptor 1) and ferritinophagic release of iron increase free iron concentration, which

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causes elevated lipid peroxidation, resulting in the occurrence of ferroptosis while

ferritin-mediated iron storage inhibits this type of cell death. The dietary compounds

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Artesuate, Baicalein and Vitamin E can modulate iron metabolism and lipid
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peroxidation, finally resisting ferroptosis. Activated fat acid metabolism also increases

lipid oxidation and induces ferroptosis. In particular, ACSL4 activation augments the
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generation of oxidized AA/AdA, and subsequently exacerbates cellular ferroptosis.

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Additionally, under external stimulation by glutamate, erastin or sulfasalazine, system

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Xc- function is impaired and GSH depletion occurs, finally triggering lipid
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peroxidation and ferroptosis. Baicalein can restore GPX activity and prevent lipid
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peroxidation and ferroptosis. AA, acyls-arachidonoyl; AdA, adrenoyl; FAT, fatty

acid translocase; FATP, fatty acid transport protein; ACSL4, acyl-CoA synthase 4;

GPX4, glutathione peroxidase 4.

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Figure 2
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Figure 3
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Table 1
Representative nutraceutcial antioxidants which are evaluated in clinic
Compound Medical use NCT number Status

Lung neoplasms NCT02577393 Phase 2

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(-)-Epigalloca Traumatic brain injury NCT02731495 Phase 3

-techin-3-gallate Breast neoplasms NCT02580279 Phase 2

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Curcumin Neoplasms NCT02944578 Phase 2

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Alzheimer’s disease NCT00099710 Phase 2

Resveratrol Aging NCT02523274 Phase 2

Chlorogenic acid Glioblastoma

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Advanced cancer NCT02245204 Phase 1

Vitamin C Pancreatic neoplasms NCT02905578 Phase 2

Non-small cell lung cancer NCT02905591 Phase 2

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Glioblastoma multiforme NCT02344355 Phase 2

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Table 2
Nutracutical antioxidants with neuroprotective and anti-cancer effects
Compound Chemical structure Formula Classification

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(-)-Epigallocatec C22H18O11 Flavonoid polyphenols
hin-3-gallate

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Quercetin C15H10O7 Flavonoid polyphenols

Apigenin NU
C15H10O5 Flavonoid polyphenols
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Genistein C15H10O5 Flavonoid polyphenols

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Baicalein C15H10O5 Flavonoid polyphenols

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Chrysin C15H10O4 Flavonoid polyphenols

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Kaempferol C15H10O6 Flavonoid polyphenols

Wogonin C16H12O5 Flavonoid polyphenols

Curcumin C21H20O6 Non-flavonoid

polyphenols in foods

Resveratrol C14H12O3 Non-flavonoid

polyphenols in foods

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Rosmarinic acid C18H16O8 Phenolic acids

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Carnosic acid C20H28O4 Phenolic diterpenes

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L-sulforaphane C6H11NOS2 Organosulfur compounds

Allicin
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C6H10OS2 Organosulfur compounds
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Table 4
Comparison of toxicity or drug efficacy in relationship to dose and disease type
of nutraceutical antioxidants
Compound Dose Role in the disease Refs

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Vitamin E 1000 IU/kg in the diet Blocking ferroptosis Chen et al., 2015

in neuron degeneration

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Vitamin E No accurate dose Reducing liver Zhang et al., 2012

cancer incidence

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Vitamin C 2 mM Inducing apoptosis in non Schoenfeld et al., 2017

small-cell lung cancer

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Vitamin C 5 mM Inducing apoptosis apoptosis in Schoenfeld et al., 2017

glioblastoma
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Vitamin C 3.96 mM Enhancing oxidative injury in Wei et al., 2017

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prostate cancer
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Vitamin A 25000 IU Increasing the risk of lung cancer Omenn et al., 1996
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Baicalein 25 μM Inducing apoptosis in Li et al., 2017

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oral squamous cell carcinoma

Baicalein 10 μM Suppressing ferroptosis Xie et al., 2016

in pancreatic cancer

Baicalein 40 mg/kg Attenuating epileptic seizures Mao et al., 2014

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Table 3
Summary of the efficacy of some nutraceutical antioxidants on neurological
diseases and cancers
Compound Disease type Effect Possible mechanism Reference

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(Chen & Zhang,

Neuroprotection 2007; Fang et al.,

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TBI, AD, PD APP Inflammation ROS NADPH oxidase 2003;Gutierrez-Or

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EGCG AGC gastric cancer, Neuronal injury TFR Iron chelation ozco et al., 2010;

HT-29 colon cancer, Proliferation Anti-cancer therapy Li, Huang, Fang,

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KYSE 150 esophageal Cancer apoptosis ROS NF-κB NOS & Le, 2004;

cancer, PC3 prostate TNF-α DNMT AMPK Reznichenko et al.,

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cancer 2006; Zhang,

Wang, Cao, &

D

Wang, 2015)
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AD, Ischemia APP Astrogliosis Neuroprotection (Costa et al., 2016;

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U138MG glioma, Hela Proliferation ROS NRF2 PON2 Dajas, 2012)

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cervical cancer, MDA- Melanoma invasion Autophagy SIRT1 (Caltagirone et al.,

Quercetin MB-453 breast cancer, Metastasis NOS Iron chelation 2000; Gibellini et
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HT-29 colon cancer, Cancer apoptosis Anti-cancer therapy al., 2011; Maurya

B16-BL6 melanoma, Inflammation ROS PI3K-Akt & Vinayak, 2017;

T-cell lymphoma Angiogenesis ERK1/2 COX-2 Williams, Spencer,

iNOS VEGF-A & Rice-Evans,

2004)

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DACD, AD, PD Cognitive deficits in Neuroprotection (Banerjee &

B16-BL6 melanoma, diabetes ROS NOS BACE1 Mandal, 2015;

HT-29 and HCT-15 colon APP Inflammation ERK-CREB BDNF Bridgeman et al.,

Apigenin cancer, UV-induced skin Invasion metastasis Anti-cancer therapy 2016; Mao et al.,

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cancer in keratinocytes, Cell proliferation ROS P21 Cyclin D1 2015; Patil et al.,

MDA-MB231 breast Cancer apoptosis mTOR signaling IP10 2014; Perrott,

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cancer Senescence Wiley, Desprez, &

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Campisi, 2017;

Zhao et al., 2013)

Ischemia,
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Ischemic damage Neuroprotection (Li et al., 2017; Li
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Hypoxic-induced Cell proliferation NRF2 Bcl-2/Bax ratio & Sarkar, 2002; Li

Genistein ischemia in PC12 Cell apoptosis K+ efflux GluR2 et al., 2011; Liu et

BGC-823 gastric cancer, G2/M arrest Anti-cancer therapy al., 2013; Wang et
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PC3 prostate cancer Angiogenesis NF-κB PTEN al., 2013; Wang et

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Cancer metastasis COX-2 Akt TGF al., 2017)

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Epilepsy, AD, PD, Epilepsy-induced Neuroprotection (Bie et al., 2017;

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Ischemia cognitive deficits ROS CHOP Cathcart et al.,

H460 non-small lung ER-induced apoptosis 12/15-lipoxygenase 2016; Chen, Chow,

cancer, Bel-7402 in HT22 neurons α-synuclein aggregation Lin, Wu, & Shen,

hepatocellular carcinoma H2O2-induced HO-1 ERK1/2 2006; Choi et al.,

Baicalein apoptosis in C6 Anti-cancer therapy 2010; Hu et al.,

glioma cell 12-lipoxygenase VEGF 2016; Leung,

Cancer cell apoptosis PI3K/Akt P21 p27 Yang, Lai, Lin, &

Angiogenesis miR- 3127-5p Lee, 2007; Mao et

Proliferation al., 2014; van

Cell cycle arrest Leyen et al., 2006)

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(Guo et al., 2016;

He, Wang, Bi, &

Du, 2012; Jiang,

Neuroprotection Gong, Zhao, & Li,

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ROS GSK3β

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PD, Ischemia, DACD Neuronal damage iNOS 2014; Kandhare,

Cognitive deficits in Neurological deficits NF-κB COX-2 Shivakumar,

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Chrysin cerebral hypoperfusion Inflammation Anti-cancer therapy Rajmane, Ghosh,

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PC-3 prostate cancer, Cancer cell apoptosis ROS PI3K Akt & Bodhankar,

MCF-7 breast cancer EZH2 DNMT activity 2014; Kanwal et

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al., 2016; Li et al.,

2014; Ryu, Lim,

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Bazer, & Song,

2017; Yao et al.,

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2014; Zhang et al.,

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2015)
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PD, AD Motor coordination Neuroprotection (Ebrahimi &

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Kaempferol Caco-2 colon cancer, Cognitive deficits ROS Aβ NRF2 Schluesener, 2012;

SK-HEP-1 hepatic cancer Cancer cell apoptosis Anti-cancer therapy Huang et al., 2013;
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Metallothionein Akt Kuo, Leavitt, &

G2/M arrest Cyclin B Lin, 1998; Li &

Pu, 2011; Saw et

al., 2014)

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Ischemia, AD, PD Neuroprotection (Chen et al., 2011;

U251 and U87 glioma, Neuronal damage ROS NF-κB Cho & Lee, 2004;

MDA-MB-231 breast Inflammation iNOS ERK1/2 Lee et al., 2003; S.

Wogonin cancer, Cancer cell apoptosis Anti-cancer therapy Li, Sun, Gao, &

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Panc-1 and Colo-357 Cancer invasion ROS GRP-78 GRP-94 Sun, 2016; Piao,

pancreatic cancer MMP-9 Beclin-1 Jin, Chun, Lee, &

R
Autophagy Kim, 2004; Tsai et

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al., 2012; Yeh et

al., 2014)

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Epilepsy, PD, Ischemia Seizures Neuroprotection (de Alcantara et al.,

Spinal cord injury neuronal damage ROS BDNF/TrkB 2017; Gersey et al.,

U251 glioma, 253J-Bv Inflammation PI3K/Akt signaling 2017; Kiasalari et

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Curcumin and T54 bladder cancer, Functional recovery COX-2 TNF-α al., 2013; Lim et
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LNCaP prostate cancer, Stem cell proliferation Anti-cancer therapy al., 2016; Park et

SGC-7901 and BGC-823 Cancer cell apoptosis ROS STAT3 ERK1/2 al., 2016;
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gastric cancer, 4T1 breast Proliferation Demethylation of Neurog1 Requejo-Aguilar et

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cancer Cancer cell immunity DNA polymerase γ CSN5 al., 2017; Shu et

al., 2011; Wang et

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al., 2017; Yang,

Song, Li, & Liang,

2014)

Resveratrol TBI, Ischemia, Epilepsy Neuronal damage Neuroprotection (Chang et al.,

CAR oral cancer, A549 Epileptic seizures Astrogliosis ROS 2017; Li, Hou et

lung cancer Inflammation Caspase-3 activity al., 2017; Pan et

Cancer apoptosis Anti-cancer therapy al., 2016; Saha &

Cancer senescence Beclin-1 P53 Chakrabarti, 2014;

Wang et al., 2002)

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Abbreviations: EGCG, (-)-Epigallocatechin-3-gallate; TBI, traumatic brain injury; APP, amyloid

precursor protein; PD, Parkinson’s disease; AD, Alzheimer’s disease; ROS, reactive oxygen

species; TFR, transferrin receptor; iNOS, inducible NO synthase; NRF2, NF-E2-related factor 2;

PON2, paraoxonase 2; SIRT1, sirtuin; PI3K, phosphoinositide3-kinase; Akt, protein kinase B;

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COX-2, cycloxygenase-2;DACD, diatebes-associated cognitive decline; VEGF-A, vascular

endothelial growth factor A; BACE1, β-site APP-cleaving enzyme 1; CREB, cAMP response

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element-binding protein; BDNF, brain-derived neurotrophic factor; UV, ultraviolet; mTOR,

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mammalian target of rapamycin; IP 10, interferon-γ-inducible protein 10; GluR2, glutamate

receptor subunit 2; NF-κB, nuclear factor kappaB; PTEN, Phosphatase and tensin homolog; TGF,

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tissue growth factor; ER, endoplasmic reticulum; CHOP, C/EBP homologous protein; HO-1, heme

oxygenase 1; GSK3β, Glycogen synthase kinase-3β; EZH2, enhancer of zeste 2 polycomb

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repressive complex 2 subunit; DNMT, DNA methyltranferase; GRP-78, glucose-regulated

protein-78; MMP-9, matrix metalloproteinase-9; STAT3, signal transducer and activator of

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transcription 3; CSN5, COP9 signalosome 5.

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