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Scientific Evidence of Rice By-Products for Cancer Prevention: Chemopreventive Properties of Waste Products from Rice Milling on Carcinogenesis In Vitro and In Vivo.

1. Introduction

Cancer is a significant health concern. One in eight deaths worldwide is due to cancer [1]. It represents the first or second cause of death in advanced countries. Therefore, urgent action is warranted to reduce the threats of this disease, particularly in developing countries in which the prevalence and incidence of this disease are expected to increase. Genetic defects only account for nearly 5-10% of all cancer cases, whereas 90-95% are due to the environment and lifestyle [2]. Therefore, most of the cancer cases and deaths worldwide are actually preventable [3]. It has also been reported that up to 30% of human cancers could be prevented via an appropriate dietary modification [4].

Carcinogenesis is a complex multistage process comprised Of initiation, promotion, and progression stage. Cancer chemoprevention involves the use of natural, synthetic, or biological agents to delay, inhibit, or prevent the initial phases of carcinogenesis, as well as the progression of premalignant cells to invasive disease [5]. In chemoprevention, a vital goal is to block tumor progression [6]. In developed countries, chemopreventive drugs, such as celecoxib and tamoxifen, are being used in high-risk populations; however, due to their adverse side effects, these drugs are not feasible in the developing countries [7-9].

Extensive studies in the past few decades have shown that there are varieties of dietary and botanical natural compounds with chemopreventive properties including garlic, green tea, soy, apple, olive oil, and grape [11-13]. Several recent studies also reported that natural products play a critical role against cancer [14-16]. Identification of bioactive compounds which have medicinal properties from natural products or by-products may promote the nutraceuticals as an inexpensive alternative to anticancer drug therapies which are toxic, immune-suppressive, mutagenic, and even carcinogenic [17, 18]; besides, major treatment modalities include surgery, immunotherapy, and radiotherapy [19-21]. Natural products and their compounds may act as a modulator of antitumorigenicity either as separate entities or by serving in synergism [22]. The combination of two or more components in drug design has also been proven to have clinically synergistic benefits against cancer treatment [23].

In this review, we present the findings from a preclinical study both in vitro and in vivo on the promising role of rice by-products with focus on cancer perspective.

2. Production of Rice By-Products

High demands of crop production in the world are primarily due to the three key forces which are increasing human population, meat and dairy consumption from growing affluence, and biofuel consumption [24-27]. Thus, global agricultural production is projected to increase by 60-110% by 2050 to meet the increasing demands [26, 28, 29] and provide food security to nearly 870 million chronically undernourished individuals [30].

Rice areas with doubling yield rates are only observed in several local areas within Afghanistan, India, Bangladesh, Laos, Vietnam, and Cambodia. In contrast, a significant reduction in the rates of rice yield is reported in some parts of India (particularly in Uttar Pradesh, Maharashtra, and Tamil Nadu) and in North Korea. Rice provides approximately 30% and 27% as a source of energy in India and China, respectively. The world's third largest rice producer, Indonesia, produces about 49% of energy, in which the yield improvement rates are slightly lower at 0.4% per year [32]. The production, area harvested, and yield of paddy in several countries are shown in Table 1.

Rice (Oryza sativa) is a staple food of dietary calories for half of the humanity and has been widely demonstrated as a chemopreventive component [33]. The rice milling process is comprised of two basic stages: first is to remove the husk to produce brown rice and the other is to remove the bran layer from brown rice to produce the polished (or white) rice. Additionally, the milling process also separates the germ and some of the endosperm as broken kernels and powdery materials [34]. Therefore, the output of a rice milling process consists of a main product, which is milled rice, and several rice by-products such as the husk, germ, bran layer, and broken kernels [35]. Traditionally, rice is consumed as polished white rice with the removal of husk, bran, and germ fractions [36], but currently the consumption of brown rice or germinated brown rice is getting popular due to more people becoming aware about their health. The production of rice by-product in rice processing was previously described by Esa et al. [37]. Structure of rice grain is shown in Figure 1.

3. Nutrient Composition and Phytonutrients Properties of Rice By-Products

High intake of whole grain food has been suggested as an indicator of the reduction of risk in several digestive tract neoplasms, such as stomach, colon, and gall bladder [59]. In an earlier study, Deng et al. [60] studied the health beneficial components in pigmented rice such as flavones, tannins, phenolics, sterols, tocols, [gamma]-oryzanols, amino acids, [gamma]-aminobutyric acid (GABA), and essential oils. These compounds have been shown to have a variety of bioactivities including antitumor, antioxidant, antiatherosclerosis, hypoglycemic, and antiallergic activities. The other components in whole grain such as indigestible fibers (Tables 2 and 3), as well as other phytochemicals as illustrated in Tables 4 and 5, have also been considered to contribute to the beneficial effects of whole grain [61].

Rice bran has been extensively studied among all rice by-products. Besides containing high amounts of vitamins, minerals, and fiber, rice bran also is rich in numerous bioactive components which draw a great deal of attention in the prevention and treatment of several types of human cancers. These bioactive components were reported to have antioxidant activities that can be directly associated with their anticancer effects [62] including leukemia, breast, lung, liver, cervical, stomach, and colorectal cancers [33, 63]. Studies by Moldenhauer et al. [64], Renuka Devi and Arumughan [65], and Canan et al. [66] further supported the role of a unique complex of naturally antioxidant compounds in rice bran to fight several diseases including cancer.

In addition to the rice bran, more than 1 million tons of rice husks is produced annually in rice processing in South Korea. Rice husk consists of 20% of the rice grain kernel and is nearly similar to other plant biomasses, containing a high proportion of organic substances [75]. Rice husk is inedible, which is utilized in many nonfood applications as low-value agricultural waste product. However, it was reported that rice husk is a valuable source of bioactive compounds that contained a high antioxidant property. Rice husk contained phenolic acids, which are a valuable source of natural antioxidants and prevent the rice seed from oxidative stress [70]. Thus, it has been recognized as a potential source of energy and organic chemicals [76, 77]. Hydrothermal treatments of rice husks also produce lignin-derived components such as caffeic acid and ferulic acid [78], which are crucial constituents for pharmaceutical application because they provide protection against photooxidative damage [79]. Rice husk has also been reported to have fatty acids, including linoleic, stearic, oleic, and palmitic acids [78]. Phenolic compounds in the methanolic extract of rice husk also displayed a high antioxidant activity against scavengers of singlet oxygen and suppressed high hydrogen peroxide-induced damage against cellular deoxynucleic acid (DNA) in human lymphocytes [80].

Rice germ is also a by-product from rice processing which is known as embryo or reproductive proportions which germinate and grow into a plant [57]. The amount of vitamin E in rice germ is 5 times higher compared with that of rice bran. Most of the vitamin E in rice germ is [alpha]-tocopherol, which is the major active form of vitamin E, while, for rice bran, most of the vitamin E is [gamma]-tocopherol. Additionally, rice germ also comprised a substantial amount of vitamins ([B.sub.1], [B.sub.2], and [B.sub.6]), dietary fiber, and neurotransmitter GABA, which is believed to contain numerous beneficial health effects like improving blood pressure, cognition, and blood glucose levels. The amount of y-oryzanol in rice germ, however, was 5 times lower than that of rice bran [81].

In addition to the rice bran, rice husk, rice straw, and rice germ, brewers' rice is another by-product in the rice industry that has a significant nutritional value. Brewers' rice consists of a mixture of broken kernels with rice bran and rice germ, which is usually removed during the rice milling process [82]. Brewers' rice is typically used as an animal feed and brewing material [83]. The size of brewers' rice is less than one quarter of the full kernel of milled rice. It is the last and the smallest milling portion that is separated during the milling of paddy rice and is usually removed from larger rice kernels [84]. Brewers' rice demonstrated high carbohydrate, protein, and fat contents [55]; minerals such as calcium, phosphorus, iron, sodium, and potassium; fatty acids such as linoleic acid, oleic acid, and palmitic acid. Brewers' rice also contained a variety of phytochemicals with chemopreventive properties including y-oryzanol, phytic acid, vitamin E, phenolic antioxidants [72], and dietary fiber [55]. Compared with other cereal brans, such as corn, wheat, and oat, the lipid proportion present in brewers' rice has a unique ratio of vitamin E isoforms ([alpha]-, [gamma]-, and [delta]-tocopherols and tocotrienols) and [gamma]-oryzanol [72].

Since phenolic compounds are demonstrated to confer beneficial health benefits, this may partially explain a better nutritional value of rice by-products. Biological activities in the cereal grains were strongly correlated to their polyphenols content [85], which is known to exhibit potent antioxidant activities [86-88]. Majority of the antioxidants commonly present in fruits, vegetables, and cereals (wheat, rice, and oat) are polyphenolic compounds [89-92]. Li et al. [89] reported that most of the phenolic acids present in the whole grains are ferulic acid, p-coumaric acid, vanillic acid, caffeic acid, and syringic acid. Others have also reached a similar finding, in which the rice grains were rich in ferulic acid and p-coumaric acid [93, 94]. In view of the total phenolic content in various genotypes of rice by-products, rice brans have 2-11-fold higher content than rice husk, 4-15-fold higher content than brown rice, and 7-59-fold greater content than polished rice [95].

4. Anticancer Activities of Rice By-Products

4.1. In Vitro Cancer Chemopreventive Study. Colorectal cancer chemoprevention activity highlighted the role of bioactive constituents like rice bran phytic acid [96], tricin, and flavonoids [97]. Relative proportions of bioactive components in rice bran have been shown to inhibit the growth of colorectal cancer cells; however, they are different among other rice varieties [71]. Kong et al. [98] reported that rice bran phenolic compound cycloartenyl ferulate inhibited the proliferation of human colorectal adenocarcinoma (SW480) cell line. Chen et al. [63] used different cancer cell lines to study the cell-inhibiting activity in response to red rice bran extract and demonstrated that red bran exhibited strong inhibitory effects against leukemia, cervical, and stomach cancers. Forster et al. [71] also reported that total phenolics and y-tocotrienol from rice bran exhibited significantly reduced colorectal cancer cell proliferation (p < 0.05). Another rice by-product, momilactone B, an allelochemical of rice hull, has antiproliferative activity against human leukemic T-cells via activation of caspase and mitochondria pathways [99]. In addition to the effects observed in leukemic cancer, methanol extract of rice husk also inhibited the growth of colon cancer cells with inhibition concentration ([IC.sub.50]) values of 0.5[micro]g/mL [100].

Study on the effect of brewers' rice on colorectal cancer (HT-29) cell line was conducted by Tan et al. [72, 74]. They reported that water extract of brewers' rice (WBR) inhibited the proliferation of HT-29 cell line and the effect was suggested to be linked to the bioactive compounds present in WBR. The extract, however, was not cytotoxic against normal cell lines [72]. This finding was consistent with the data obtained by Ryan et al. [101], Fan et al. [102], and Kong et al. [98], who reported that the rice bran components were not cytotoxic against normal cell lines. Summary of in vitro studies on antiproliferative effect of rice by-products is shown in Table 6.

4.2. In Vivo Cancer Chemopreventive Study. Rice germ or the constituents present in the rice bran or germ have been identified to have chemopreventive effects against carcinogenesis in the colon [125], liver [126], stomach [127], esophagus [128], and bladder [129] of rodents. Kong et al. [98] observed that rice bran cycloartenyl ferulate significantly induced suppression of human colorectal adenocarcinoma (SW480) of xenograft in nude mice after 21 days and triggered both death receptor and mitochondrial apoptosis pathways. Similarly, Kim et al. [122] used pathogen-free female BALB/c mice to evaluate the effect of rice bran [gamma]-oryzanol on colon tumor growth and found that rice bran [gamma]-oryzanol could inhibit colon tumor and reduce expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX). In another study, Choi et al. [123] further demonstrated that feeding a diet containing 10% (w/w) black and brown rice brans reduced VEGF, COX-2, and 5-LOX expression in mouse colon carcinoma cells- (CT-26-) treated mice. Increased COX-2 expression, an inflammatory gene, is positively associated with the inflammatory response strength [130]. Reduction of COX-2 suggests that black and brown rice brans could attenuate the inflammatory response in cancer through reduction of oxidative stress. Interestingly, feeding with rice bran not only reduced the number of aberrant crypt foci (ACF) [120] but also improved lipid profile as described by Ausman et al. [131] suggesting the numerous functional potentials of rice bran. Additionally, Kawabata et al. [113] reported that feeding azoxymethane (AOM) (15 mg/kg body weight once weekly for 3 weeks) with rice germ for 5 weeks significantly suppressed colon adenocarcinoma (p < 0.01) in rats. Mori et al. [114] also observed that the ACF/colon in the rats induced with AOM and fed with rice germ (2.5% in diet) were significantly reduced compared to those of the group with AOM only (p < 0.005). In addition to the effects observed on rice bran and rice germ, using male F344 rats model that received carcinogen 1,2-methylhydrazine (DMH) subcutaneously once weekly for 6 weeks at a dosage of 180 mg/kg body weight, Kim et al. demonstrated that the methanolic extract of rice husk could reduce colon preneoplastic ACF formation by 35% after 40 weeks (p < 0.01) [100]. In view of the apoptotic-inducing efficacy observed in HT-29 cell line on water extract of brewers' rice (WBR), findings from an animal study mirror some of those from preclinical data obtained from an in vitro study. Tan et al. [55] reported that feeding AOM-induced colon cancer rats (15 mg/kg body weight) with a diet containing 40% brewers' rice reduced significantly colon tumor multiplicity after 20 weeks of treatment (p < 0.05). The suppressive effects seen in the highest concentration of brewers' rice treatment could be explained by its higher concentrations of active compounds that may confer better functional properties. However, it is not yet clearly understood which bioactive constituents are responsible for the functional benefits of brewers' rice, but it is more likely that several of the phytonutrients contribute towards these observed effects. Among the studies described to date, the improvements in these indices could be attributed to higher levels of [gamma]-oryzanol, phytic acid, vitamin E, and antioxidants [72]. So, it is important to encourage long-term clinical studies to verify these findings by providing a better alternative to curb the rising incidence and prevalence of colon cancer.

Several studies as reported by Henderson et al. [33] also demonstrated that rice by-products have chemopreventive potential not only in the colon but also in the breast, lung, mouth, bladder, liver, esophagus, and melanoma/skin in vivo. Wang et al. [119] observed that defatted rice bran sulfated polysaccharide (SRBPS2a) suppressed the implanted EMT-6 breast tumor cells growth in BALB/c mice. In another study, Yasukawa et al. [112] demonstrated that feeding ICR mice with rice bran cycloartenol ferulate is possible to suppress tumor promotion in 2-stage skin carcinoma. Furthermore, defatted rice germ has also been reported to reduce the incidence of tongue carcinomas and preneoplastic lesions in Fisher 344 rats [114] (Table 7).

The beneficial effects of bioactive components observed in rice by-products, as reported above, have been postulated by the concept of food synergy [132]. If so, the synergistic/additive effects of bioactive compounds in rice byproducts could in the long term be beneficial in the management of cancer via multiple mechanisms perhaps even better than some drugs as suggested by Ricciardiello et al. [133] who suggested that whole food or whole food extract can have high importance in combating carcinogenesis. These observations also supported the finding by Tsuda et al. [134] who demonstrated a synergistic and/or additive protective effect of several bioactive compounds.

5. Mechanisms of Action of Rice By-Products as Anticancer Agent

5.1. Apoptosis Induction and Inhibition of Cancer Cellular Proliferation. Apoptosis or programmed cell death plays a crucial role in the tissues maintenance, organ homeostasis, and genetically controlled cell death to balance cell proliferation [135]. Apoptosis is a normal and continuous process in healthy subjects accompanied with complex physiological processes, which controls some of the vital cellular processes like cell turnover, maintaining homeostasis of cell population, development of the immune system, hormone-dependent atrophy, embryonic development, and chemical-induced cell death [136]. Inappropriate regulation of apoptotic cell death mechanism has been identified in numerous human diseases. Thus, aberrant apoptosis contributes to cancer progression. Apoptosis can be stimulated via internal and external stimuli. An internal stimulus can be a p53 tumor suppressor gene, while external stimulus is external plasma membrane associated receptors [137].

The ability to modulate cell death is identified as a potential therapeutic agent for cancer. Numerous bioactive compounds present in rice bran like ferulic acid [95], [gamma]-oryzanol, phytic acid [138], p-coumaric acid [139], pectin [140], tricin, and tocotrienol-tocopherols are believed to be responsible for inducing apoptosis [101]. As shown by Serafim et al. [141], caffeic and ferulic acid derivatives play a crucial role in the increase of tumor suppressor protein p53 expression and enhance the mitochondrial depolarization and chromatin condensation. In addition to the effects observed on caffeic and ferulic acid, vitamin E, particularly tocotrienols, has also been shown to induce cell cycle arrest [142], activate p53 and caspase activity [143, 144], inhibit adhesion molecules [145], suppress nuclear factor-kappa B (NF-[kappa]B) [146], and downregulate c-Myc and telomerase [147]. Kannappan et al. [148] further demonstrated that [gamma]-tocotrienol not only has the ability to downregulate the Bcl-2 and Bcl-xL antiapoptotic proteins expression but also induces SHP-1 expression, which directly suppresses the activation of STAT3, as STAT3 pathway correlated well with cancer progression. Furthermore, [gamma]-tocotrienol-induced apoptosis was also demonstrated in Hep3B cells via caspase-3, caspase-8, and caspase-9 activities with the participation of Bax and Bid [149]. Findings by Ahn et al. [146] further showed that [gamma]-tocotrienol suppressed the NF-[kappa]B activation pathway via inhibition of receptor-interacting protein (RIP) and TAK1 and thus suppressed the antiapoptotic gene and contributed to apoptosis. Another vitamin E isomer, [delta]-tocotrienol, also induced apoptosis in human breast cancer cells through involvement of transforming growth factor-[beta], Fas, and c-Jun N-terminal kinase (JNK) signaling pathways [150].

In addition to the bioactive compounds mentioned above, [beta]-sitosterol has also been reported to have a beneficial effect against colorectal, stomach, and breast cancers [151, 152]. The possible mechanism is by increasing the damage of the cancer cell membrane, activation of caspase-3 activity [152], and increasing the production of cellular ceramide, which is related to the cell cycle arrest [151]. Study on the effect of water extract of brewers' rice (WBR) treatment also resulted in the induction of apoptosis by significant activation of caspase-3 and caspase-8 activities [153]. Momilactone B, an allelochemical extracted from rice husks, was also shown to induce apoptosis in human lymphoma (Jurkat) cells through caspase and mitochondria pathways [99].

In addition to the prevention of the initiation stage of cancer via the induction of apoptosis, it is also vital for cancer chemopreventive agents to suppress the proliferation of malignant cells. Phytic acid is generally known as an antinutrient compound due to its propensity to form a complex with minerals and subsequently contributed to deficiencies in animal/human. It was also revealed from several in vitro and in vivo studies to have potential in suppressing abnormal cell proliferation [124, 154].

The efficacy of these bioactive compounds as anticancer agents, however, depends on the bioavailability and the dosage [155]. For example, gastrointestinal esterases in the large and small intestines of humans and rats can release diferulic acid from bran fiber, which may promote its bioavailability [156]. In addition, ferulic acid also remains in the bloodstream longer and hence may confer more protection than other known antioxidants. On the other hand, even though phytic acid has been shown to inhibit the proliferation of cancer cells, the absorption in the small intestines of humans is low and relies on plasma concentration [157, 158]. However, several studies suggested that the bioavailability of phytic acid depends on the source of food that it comes from.

5.2. Regulation of Wnt/[beta]-Catenin Signaling Pathway. Deregulation of Wnt/[beta]-catenin signaling has been demonstrated to be associated with cancer especially with colorectal cancer [159-164]. Cyclin D1 is a well-known cell cycle protein targeted by [beta]-catenin [165] that is frequently overexpressed in colon tumor tissues [166]. c-Myc is another vital protein in the regulation of cell growth by [beta]-catenin and the Wnt pathway [167]. Leardkamolkarn et al. [168] reported that methanol extract of Thai rice, Riceberry bran, diminished the amount of cyclin D1 in colonic carcinoma (Caco-2) cell line. In this study, reduction of cyclin D1 observed in colon carcinoma cells, however, was attributed to vitamin E or tocotrienol content [169]. Similarly, Sun et al. [170] and Gysin et al. [169] reported that vitamin E or tocotrienol reduced the expression of cyclin D1 in gastric adenocarcinoma and prostate carcinoma. In addition to vitamin E, rice bran phytic acid has also been reported to have a similar effect in diminishing the expression of [beta]-catenin, which could potentially reduce colon carcinogenesis [171]. Inhibition of colon carcinogenesis via modulation of Wnt/[beta]-catenin signaling pathway was also shown in brewers' rice and its water extract (WBR). As indicated in Figure 2, WBR upregulated mRNA levels of casein kinase 1 (CK1) and adenomatous polyposis coli (APC), a destruction complex involved in the degradation of [beta]-catenin, and inhibited the low-density lipoprotein receptor-related protein 6 (LRP6), which is a crucial coreceptor in Wnt signaling, and glycogen synthase kinase 3[beta] (GSK3[beta]) mRNA levels [153]. The fact that WBR downregulates GSK3[beta] and produces better colon tumor inhibition suggests that other mechanisms are involved in WBR's anti-colon cancer properties and are likely modulated by NF-[kappa]B [172, 173]. Additionally, brewers' rice also reduced [beta]-catenin, cyclin D1, and c-Myc expression, as illustrated in Figure 3 [153]. Preclinical findings from in vitro and in vivo studies on mechanisms involved in anti-colon cancer effects suggest that rice by-products could modulate Wnt pathway in colon cancer.

5.3. Modulation of Inflammation Pathway. Numerous bioactive components present in rice by-products have been demonstrated to facilitate cancer chemoprevention through the enhancement of immune response. These cancer chemopreventive immune responses serve either via blocking viral infections related to virus-induced tumors or by specific suppression of tumor cells [174]. The early stages of an inflammatory response are vital in the protection against infection and injury; however, an uncontrolled or chronic inflammatory environment is favorable towards cancer development [33]. Chronic infection and inflammation stimulate the inflammatory-associated genes such as NF-[kappa]B [175] and inducible nitric oxide synthase (iNOS) expression [176]. As reported by Henderson et al. [177], the whole dietary rice bran modulates the mucosal immune response by increasing the numbers of mesenteric lymph nodes and lamina propria dendritic cells [177]. They also revealed that ferulic acid from rice bran has potential to be a promising cancer chemopreventive agent to inhibit the lipopolysaccharide-(LPS-) induced iNOS and COX-2 protein expression as well as suppress the release of tumor necrosis factor-[alpha] (TNF-[alpha]). This phenomenon was associated with the inhibition of I-[kappa]B phosphorylation and subsequently suppression of NF-[kappa]B signaling [178].

An earlier study by Morel et al. [179] reported the ability of [alpha]-tocopherol to promote cytokine production and monocyte recruitment, which are required in the adaptive immunity development. Boxer [180] and Sakurai et al. [181] also showed that [alpha]-tocopherol and ferulic acid promote the respiratory burst and interferon-[gamma] production in macrophages, respectively. A previous study by Sierra et al. [182] also reported the ability of rice bran oil to regulate the immune response by promoting the proliferation of B-cell and inducing interleukin-2 (IL-2) and TNF-[alpha] production. In addition, rice bran extract MGN-3 has been demonstrated to promote dendritic cell maturation [183] and enhance cytokine production and natural killer (NK) cell activity [184].

Feeding mice with diet supplemented with black rice bran extract prior to 12-O-tetradecanoylphorbol-13-acetate (TPA) administration was also shown to inhibit inflammation (edema) caused by TPA by a marked reduction in proinflammatory cytokines TNF-[alpha], interleukin-1[beta] (IL-1[beta]), interleukin-6 (IL-6), and eicosanoids leukotriene B4 (LTB4) [185]. Gamma-oryzanol primarily consists of esters of transferulic acid (trans-hydroxycinnamic acid) and phytosterols (sterols and triterpenic alcohols). Cycloartenol, [beta]-sitosterol, 24-methylenecycloartenol, and campesterol are present predominantly in [gamma]-oryzanol [186, 187]. Anti-inflammatory effects of [gamma]-oryzanol and cycloartenyl trans-ferulate markedly suppressed the inflammatory response in mice-induced colitis [188]. Accordingly, Islam et al. [189] demonstrated that rice bran phytosteryl ferulates modulated anti-inflammatory reactions via downregulation of inflammatory transcription factor, NF-[kappa]B, which may lead to the reduction of inflammatory enzymes like COX-2 and iNOS and proinflammatory cytokines such as IL-1[beta], IL-6, and TNF-[alpha]. Rice bran phytosteryl ferulates further enhanced blood adiponectin levels through indirect stimulation of peroxisomal proliferator-activated receptor-[gamma] (PPAR[gamma]) via suppression of NF-[kappa]B. Collectively, rice bran [gamma]-oryzanol inhibited tumor growth via stimulation of cytolytic activity in splenic (NK) cells, partial restoration of nitric oxide production, and phagocytosis in peritoneal macrophages, subsequently resulting in the liberation of proinflammatory cytokines TNF-[alpha], IL-1[beta], and IL-6 from macrophages.

MGN-3/biobran, arabinoxylan rice bran, was shown to have antitumor activity, through modulation of immune systems such as NK cells [190-192], TNF-[alpha] [184, 193], and macrophages [194]. The investigators found that MGN-3 suppresses tumor in solid Ehrlich carcinoma- (SEC-) bearing mice via induction of apoptosis through its immunomodulatory effects [184]. Additionally, isovitexin from rice husk has also been demonstrated to inhibit release of COX-2 expression and reduced LPS-stimulated prostaglandin [E.sub.2] [195]. In addition to the effects observed in rice bran and rice husk in the inflammation pathway, brewers' rice has also been demonstrated to have a similar effect against COX-2 activity. It was shown to reduce COX-2 and NF-[kappa]B levels. Findings from animal study also revealed that brewers' rice upregulated iNOS [196]. This is in agreement with an earlier finding that overexpression of iNOS attenuates the proliferation and metastasis of human renal cell carcinomas and murine fibrosarcoma [197]. In this regard, natural components present in the brewers' rice such as polyphenolic compounds, including ferulic acid, gallic acid, p-coumaric acid, syringic acid, vanillic acid [74], and vitamin E isomers, [gamma]-oryzanol [72], and [gamma]-aminobutyric acid (GABA) [198] have the potential to inhibit the proinflammatory immune signaling and subsequently reduce the colon cancer development.

5.4. Protection against Free Radicals and Modulation of Antioxidant Pathway. One of the effective mechanisms for cancer prevention is to inhibit initiation stage through suppression of the DNA damage caused by reactive oxygen species (ROS) or other carcinogens [199]. Oxidative stress can cause significant cellular damage and irreversible mutations; thus, a substantial amount of antioxidant may protect cells from free radical damage.

Study by Tan et al. [196] showed that dietary administration of brewers' rice helped to protect against oxidative stress in AOM-induced rat colon carcinogenesis by improved antioxidant capacity like superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO). They also observed that brewers' rice upregulated NF-E2-related factor 2 (Nrf2) signaling pathway via modulation of Nrf2 and heme oxygenase-1 (HO-1) transcriptional activities (Figure 3). Earlier study by Tan et al. [55] also reported that brewers' rice consists of phenolic antioxidants, phytic acid, vitamin E, oryzanol, and [gamma]-aminobutyric acid (GABA) which were shown by many previous studies to have a good antioxidant capacity. Ferulic acid, for example, is a well-documented phenolic compound that can be found in high amount in rice by-products, demonstrated to be an effective superoxide anion radical scavenger and lipid peroxidation inhibitor [155]. In another study, ferulic acid has been reported to protect against hydrogen peroxide-induced cellular damage via elevation of cellular levels of HO-1 and heat shock protein-70 [200]. Overall, this suggests that the protective effect of rice by-product on oxidative stress may be mediated partly via the synergistic/additive effects of these bioactive constituents.

Besides bioactive compounds stated above, MGN-3, an arabinoxylan extracted from rice bran, has also been reported to induce oncostatic activity against murine solid Ehrlich carcinoma via modulation of lipid peroxidation and enhanced the endogenous antioxidant scavenging activity such as SOD, glutathione peroxidase (GPx), catalase (CAT), and glutathione-S-transferase (GST) [201].

6. Summary and Future Prospects

This review has provided substantial evidence both in vitro and in vivo that consumption of rice by-products may provide the optimal chemoprevention due to antioxidant phytonutrients. Further clinical studies of rice by-products and their unique bioactive compounds hold great promise in future use as a dietary cancer chemopreventive agent.

In conclusion, rice by-products as a cancer chemopreventive dietary agent represent a unique approach to evaluate effective whole food compared to the individual phytochemical. Our review showed a promising result from both in vitro and in vivo studies, which warrants clinical studies designed to gain a better understanding of the relationship between rice bran/rice husk/rice germ/brewers' rice and cancers. The global availability and affordability of rice by-products provide a better public health opportunity in both developed and developing countries. Taken together, this review could pave the way for the potential use of rice by-products as a functional food in the prevention and treatment of cancers. The potential implication of the dietary intake of rice byproducts in place of conventional treatment modalities could be significant and is warranted to be evaluated further in long-term clinical studies.

Competing Interests

The authors declare that there are no competing interests regarding the publication of this paper.


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Bee Ling Tan (1) and Mohd Esa Norhaizan (1, 2, 3)

(1) Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

(2) Research Centre of Excellent, Nutrition and Non-Communicable Diseases (NNCD), Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

(3) Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

Correspondence should be addressed to Mohd Esa Norhaizan;

Received 14 October 2016; Revised 1 December 2016; Accepted 4 December 2016; Published 22 January 2017

Academic Editor: Sung-Hoon Kim

Caption: Figure 1: Structure of rice grain [31].

Caption: Figure 2: Summary of mechanisms involved in colorectal cancer (HT-29) cells of water extract of brewers' rice (WBR). APC: adenomatous polyposis coli; CK1: casein kinase 1; GSK3[beta]: glycogen synthase kinase 3[beta]; NF-[kappa]B: nuclear factor-kappa B; LRP6: low-density lipoprotein receptor-related protein 6; WBR: water extract of brewers' rice.

Caption: Figure 3: Summary of mechanisms involved in colon tumorigenesis of brewers' rice. COX-2: cyclooxygenase-2; GSK3[beta]: glycogen synthase kinase 3[beta]; HO-1: heme oxygenase-1; iNOS: inducible nitric oxide synthase; NF-[kappa]B: nuclear factor-kappa B; Nrf2: NF-E2-related factor 2.
TABLE 1: Production, area harvested, and yield of paddy [10].

Regions     Area harvested     Production       Yield
                 (Ha)        quantity (tons)   (Hg/Ha)

China          30486000         205015000       67249
India          43500000         159200000       36598
Indonesia      13835252         71279709        51520
Thailand       12373163         38787697        31348
Vietnam        7902808          44039291        55726
Malaysia        688207           2626881        38170

Regions     Area harvested     Production       Yield
                 (Ha)        quantity (tons)   (Hg/Ha)

China          26780124         162304280       60606
India          42592500         132789000       31177
Indonesia      11477357         52137600        45426
Thailand       10163878         29473521        28998
Vietnam        7452200          34568800        46387
Malaysia        671800           2257000        33596

Ha: hectares; Hg/Ha: hectogram/hectare.

Table 2: Proximate composition and minerals contents (% of dry
matter) of rice by-products.

Nutrients      Broken (a)   Husk (b)    Bran (c)

Dry matter     87.0-89.0    87.0-92.5     89-94
Protein (g)     6.7-9.8      2.1-4.3    10.6-16.9
Crude fat       0.5-1.9     0.30-0.93   5.1-19.7
Crude fiber       0.6       30.0-53.4   7.0-18.9
Ash               5.0       13.2-24.4   8.8-28.8
Carbohydrate       --       22.4-35.3     90.0
Calcium        0.09-0.19    0.04-0.21   0.08-1.4
Phosphorus     0.03-0.04    0.07-0.08    1.3-2.9

Nutrients      Polishings (d)   Straw (e)     Brewers' rice (f)

Dry matter          90.0          90.9               --
Protein (g)      11.2-13.4       1.2-7.5     9.01 [+ or -] 0.27
Crude fat        10.1-13.9       0.8-2.1     1.95 [+ or -] 0.11
Crude fiber       2.3-3.6       33.5-68.9            --
Ash               5.2-8.3       12.2-21.4    1.56 [+ or -] 0.26
Carbohydrate     51.1-55.0      39.1-47.3   72.42 [+ or -] 1.25
Calcium             0.05        0.30-0.71   0.013 [+ or -] 0.0016
Phosphorus          1.48        0.06-0.16   0.316 [+ or -] 0.028

(a) [38-42].

(b) [38, 39, 43-48].

(c) [38-40, 42-50].

(d) [41, 42, 48].

(e) [44, 45, 51-54].

(f) [55].

(g) Animal scientists commonly use a conversion factor of N x 6.25
for crude protein [56].

Table 3: Dietary fiber in rice husk, rice bran fiber, and rice straw.

                    Rice husk (a)   Rice bran   Rice straw (b)
                                    fiber (a)

Cellulose (%)           38.0          30.0           32.0
Hemicellulose (%)       20.0          20.0           35.7
Lignin (%)              22.0          20.0           22.3

(a) [57].

(b) [58].

Table 4: Phytochemicals and antioxidant properties of rice

Phytochemicals                          Rice bran
or antioxidant

Gamma-oryzanol       Methanol extract of defatted rice bran (India) =
(mg/g)                                   7.82 (a)

                      Methanol extract of rice bran from Thailand =
                                     0.56 - 1.08 (b)

                      Ethanol extract of rice bran from Suphan Buri
                                  (Thailand) = 9.81 (c)

                      Methanol extract of Japonica rice bran = 9.8
                                     [+ or -] 0.4 (d)

                    Ethyl acetate extract of Japonica rice bran = 13.8
                                     [+ or -] 0.9 (d)

                       Hexane extract of Japonica rice bran = 13.1
                                     [+ or -] 0.5 (d)

                   Acetone extract of Thai rice bran variety (Khao Dawk
                                Mali 105) = 3.43-5.38 (e)

                   80% methanol extract of whole rice bran = 0.93-5.13

Tocopherols        Methanol extract of defatted rice bran (India) = 138
[micro]g/g)                                (a)

                    Methanol extract of rice bran from Thailand = 350-
                                         670 (b)

                       Hexane extract of rice bran from Suphan Buri
                                   (Thailand) = 172 (c)

                   Methanol extract of Japonica rice bran = 573 [+ or -
                                         ] 13 (d)

                   Ethyl acetate extract of Japonica rice bran = 770 [+
                                       or -] 24 (d)

                   Hexane extract of Japonica rice bran = 196 [+ or -]
                                          24 (d)

                   Acetone extract of Thai rice bran variety (Khao Dawk
                               Mali 105) = 70.67-87.54 (e)

                     80% methanol extract of whole rice bran = 27.4 -
                                        129.6 (g)

Tocotrienols       Methanol extract of rice bran from Thailand = 220 -
[micro]g/g)                              460 (b)

                      Methanol extract of Japonica rice bran = 202
                                      [+ or -] 5 (d)

                    Ethyl acetate extract of Japonica rice bran = 237
                                      [+ or -] 6 (d)

                   Hexane extract of Japonica rice bran = 17 [+ or -] 1

                     80% methanol extract of whole rice bran = 20.8 -
                                        301.7 (g)

Total phenolic        Methanol extract of Japonica rice bran = 15.7
content                              [+ or -] 0.6 (d)
(g GAE/kg)

                   Ethyl acetate extract of Japonica rice bran = 19.7
                                     [+ or -] 0.8 (d)

                       Hexane extract of Japonica rice bran = 14.7
                                     [+ or -] 1.2 (d)

Total                70% ethanol extract of purple rice bran = 55.7
anthocyanins                         [+ or -] 2.1 (f)
(mg/g extract)

Total proantho-        70% ethanol extract of red rice bran = 66.88
cyanidins (mg                       [+ or -] 6.23 (f)
pro. B2 equiv./g

Phytic                                      --
acid (mg/g)

Phytochemicals             Rice husk              Brewers' rice
or antioxidant

Gamma-oryzanol      Acetone extract of Thai          14.20h
(mg/g)              rice husk variety (Khao
                       Dawk Mali 105) =
                         0.06-0.16 (e)

Tocopherols         Acetone extract of Thai           3.4h
[micro]g/g)        rice husk variety (Khao
                     Dawk Mali 105) = not
                         detected (e)

Tocotrienols                  --                      3.25h

Total phenolic                --                       --
(g GAE/kg)

Total                         --                       --
(mg/g extract)

Total proantho-               --                       --
cyanidins (mg
pro. B2 equiv./g

Phytic                        --               0.38 [+ or -] 0.01h
acid (mg/g)

GAE: gallic acid equivalents.

(a) [65].

(b) [67].

(c) [68].

(d) [69].

(e) [70].

(f) [63].

(g) [71].

(h) [72].

Table 5: Polyphenolic compounds present in the rice by-products.

Polyphenolic               Rice bran                  Rice husk

Gallic acid                    --               80% methanol extract =
([micro]g/g)                                         5.4-9.9 (a)

Protocatechuic       70% ethanol extract of     80% methanol extract =
acid ([micro]g/g)   light brown rice bran =          6.7-24.0 (a)
                        not detected (c)

                     70% ethanol extract of
                    purple rice bran = 5777
                        [+ or -] 98 (c)

                     70% ethanol extract of
                      red rice bran = 168
                         [+ or -] 4 (c)

p-Hydroxybenzoic               --               80% methanol extract =
acid ([micro]g/g)                                   10.8-110.4 (a)

Chlorogenic acid               --               80% methanol extract =
([micro]g/g)                                         4.8-11.3 (a)

Vanillic acid        70% ethanol extract of     80% methanol extract =
([micro]g/g)        light brown rice bran =     7.8-14.1a 80% aqueous
                       34 [+ or -] 2 (c)       methanol = 14.4-26.7 (b)

                     70% ethanol extract of
                    purple rice bran = 1568
                        [+ or -] 36 (c)

                     70% ethanol extract of
                      red rice bran = 72
                         [+ or -] 3 (c)

Syringic acid                  --               80% methanol extract =
([micro]g/g)                                         2.6-12.1 (a)

p-Coumaric acid      70% ethanol extract of     80% methanol extract =
([micro]g/g)        light brown rice bran =     14.8-32.5a 80% aqueous
                       424 [+ or -] 1 (c)       methanol = 4.84-28.90

                     70% ethanol extract of
                     purple rice bran = 517
                        [+ or -] 49 (c)

                     70% ethanol extract of
                      red rice bran = 511
                         [+ or -] 2 (c)

Ferulic acid         80% aqueous methanol =     80% methanol extract =
([micro]g/g)            20.70-33.45 (b)             18.1-64.2 (a)

                     70% ethanol extract of
                    light brown rice bran =
                      1995 [+ or -] 4 (c)

                     70% ethanol extract of
                    purple rice bran = 1593
                        [+ or -] 67 (c)

                     70% ethanol extract of
                     red rice bran = 1055
                        [+ or -] 11 (c)

4-Hydroxybenzoic     70% ethanol extract of               --
acid ([micro]g/g)   light brown rice bran =
                      673 [+ or -] 10 (c)

                     70% ethanol extract of
                     purple rice bran = not
                          detected (c)

                     70% ethanol extract of
                      red rice bran = 427
                        [+ or -] 15 (c)

Caffeic acid         70% ethanol extract of               --
([micro]g/g)        light brown rice bran =
                      157 [+ or -] 14 (c)

                     70% ethanol extract of
                     purple rice bran = Not
                          detected (c)

                     70% ethanol extract of
                      red rice bran = 111
                         [+ or -] 3 (c)

Sinapic acid         70% ethanol extract of               --
([micro]g/g)        light brown rice bran =
                      2544 [+ or -] 17 (c)

                     70% ethanol extract of
                    purple rice bran = 2039
                        [+ or -] 82 (c)

                     70% ethanol extract of
                     red rice bran = 2266
                        [+ or -] 16 (c)

Polyphenolic                     Brewers' rice

Gallic acid         Water extract = 26.09 [+ or -] 2.01 (d)

Protocatechuic                         --
acid ([micro]g/g)

p-Hydroxybenzoic                       --
acid ([micro]g/g)

Chlorogenic acid                       --

Vanillic acid        Water extract = 2.87 [+ or -] 0.15 (d)

Syringic acid        Water extract = 5.87 [+ or -] 1.71 (d)

p-Coumaric acid      Water extract = 7.13 [+ or -] 0.36 (d)

Ferulic acid        Water extract = 36.42 [+ or -] 2.97 (d)

4-Hydroxybenzoic                       --
acid ([micro]g/g)

Caffeic acid         Water extract = 5.32 [+ or -] 2.48 (d)

Sinapic acid                           --

(a) [73].

(b) [70].

(c) [63].

(d) [74].

Table 6: Anticancer effect of rice by-products in vitro.

Author(s)      Year         Components                 Findings

Hudson et      2000     Rice bran phenolic       Reduced the number of
al. [62]                 extracts (tricin,      viable SW480 cells and
                       ferulic acid, caffeic     inhibited the colony-
                             acid, and             forming ability.
                       methoxycinnamic acid)

Luo et al.     2005       Gamma-oryzanol         Moderate cytotoxicity
[103]                  (cycloartenyl trans-      effect against MCF-7
                         ferulate and 24-               cells.
                       trans-ferulate) from
                             rice bran

Kim et al.     2007     Methanol extract of        Highly cytotoxic
[100]                        rice husk           against colon cancer
                                                cells, with [IC.sub.50]
                                                     value of 0.5

Gollapudi      2008   MGN-3/biobran, modified    Treatment with MGN-3
and                   arabinoxylan from rice           increased
Ghoneum                        bran             susceptibility of human
[104]                                           breast cancer cells to
                                                daunorubicin (5.5-fold
                                                for MCF-7 and 2.5-fold
                                                   for HCC70 cells)
                                                 compared with that of
                                                  human breast cancer
                                                  cells treated with
                                                  daunorubicin alone.

Joung et       2008      Momilactone B, an        Suppressed hypoxia-
al. [105]             allelochemical of rice     induced increases of
                               husk               cyclin D1 in human
                                                 breast cancer cells.

Kannan et      2008    Peptide hydrolysates         Suppressed the
al. [106]               derived from heat-      proliferation of Caco-
                        stabilized defatted       2 and HepG2 cancer
                             rice bran                  cells.

Lee et al.     2008      Momilactone B, an           Inhibited the
[99]                  allelochemical of rice    proliferation of human
                               husks               leukemic T-cells

Punyatong      2008    PA and C3G in purple         Dose-dependent
et al. [107]            glutinous rice bran       cytotoxic effect on
                                                  X63, a mouse-plasma
                                                  cancer cell line of
                                                    myeloma cells.

Kannan et      2009    Peptide hydrolysates     Cytotoxicity effect of
al. [108]             derived from rice bran    <5 kDa peptide fraction
                                                  separated from rice
                                                     bran protein
                                                  hydrolysate against

Kong et al.    2009   Rice bran cycloartenyl     Induced apoptosis in
[98]                         ferulate            SW480 and SW620 cells
                                                  through activation
                                                    of caspase-3 and

Kannan et      2010    Peptides derived from     Inhibited Caco-2 and
al. [109]               defatted rice bran       HCT-116 cells growth.

Nurul-Husna    2010    Rice bran phytic acid        Suppressed the
et al. [110]                                    proliferation of HT-29

Chen et al.    2012        Red rice bran           Exhibited strong
[63]                                            inhibition on leukemia,
                                                 cervical, and stomach
                                                     cancer cells.

Forster et     2013     Rice bran (variety        Exhibited a strong
al. [71]                    Jasmine 85)            inhibitory effect
                                                against Caco-2 and HT-
                                                       29 cells.

Takashima et   2013      Water and ethanol      Markedly inhibited the
al. [111]              extracts of rice bran    growth of LS174T cells.

Tan et al.     2013      WBR and methanol            Inhibited the
[72]                    extract of brewers'     proliferation of HT-29
                               rice                   cell line.

C3G: cyanidin 3-glucoside; Caco-2: colon cancer cells; HCC70: human
breast cancer cells; HCT-116: human colon cancer; HepG2: liver cancer;
HT-29: human colorectal cancer; [IC.sub.50]: inhibition concentration
for 50%; LS174T: human colon cancer; MCF-7: human breast
adenocarcinoma; PA: proanthocyanidin; SW480: human colon cancer;
SW620: human colon cancer; WBR: water extract of brewers' rice.

Table 7: Anticancer effect of rice by-products in vivo.

Author(s)      Year         Components                 Findings

Yasukawa et    1998   Rice bran cycloartenol       Suppressed tumor
al. [112]                    ferulate            promotion in 2-stage
                                                 skin carcinoma in ICR

Kawabata et    1999          Rice germ              Suppressed ACF
al. [113]                                        formation and reduced
                                                 incidence of colonic

Mori et al.    1999          Rice germ          Reduced the numbers of
[114]                                               ACF-colon, ACF-
                                                    [cm.sup.2], and
                                                 aberrant crypts-colon
                                                 in the group treated
                                                   with AOM + GABA-
                                                enriched defatted rice
                                                germ (2.5% in diet) and
                                                the group treated with
                                                 AOM + rice germ (2.5%
                                                in diet) compared with
                                                   that of the group
                                                treated with AOM alone.
                                                 Inhibited AOM-induced
                                                 large bowel neoplasms
                                                 incidences in Fisher
                                                       344 rats.

                         Ferulic acid and        Reduced the incidence
                        defatted rice germ       of tongue carcinomas
                                                   and preneoplastic
                                                 lesions in Fisher 344

Mori et al.    2000     Rice germ and GABA-     Suppressed AOM-induced
[115]                 enriched defatted rice         ACF and colon
                               germ             carcinogenesis in rats.

Cai et al.     2005    Tricin from rice bran     Reduced the number of
[97]                                            intestinal adenomas via
                                                the suppression of COX
                                                activity and inhibited
                                                [PGE.sub.2] production.

Kim et al.     2007     Methanol extract of        Decreased colonic
[100]                        rice husk             preneoplastic ACF
                                                   formation by 35%.

Verschoyle     2007        30% rice bran          Reduced numbers of
et al. [8]                                      intestinal adenomas in
                                                  [APC.sup.Min] mice.

Kawasaki et    2008   Rice bran hemicellulose     Inhibited the total
al. [116]                                       number of colon tumors
                                                and tumor incidence in
                                                   Fisher 344 rats.

Boateng et     2009          Rice bran          Dietary administration
al. [117]                                        of 5% and 10% of rice
                                                 bran significantly (p
                                                  < 0.05) reduced the
                                                   AOM-induced colon
                                                  tumors incidence in
                                                 male Fisher 344 rats
                                                   after 44 weeks of

Panala et      2009        Rice bran oil        Inhibited incidence of
al. [118]                                       ACF in Fisher 344 rats.

Wang et al.    2009     Defatted rice bran       Suppressed implanted
[119]                 sulfated polysaccharide     EMT/6 breast tumor
                             (SRBPS2a)          cells growth in BALB/c

Norazalina     2010    Rice bran phytic acid     Reduced the number of
et al. [96]                                       ACF in the distal,
                                                 middle, and proximal

Li et al.      2011          Rice bran           Suppressed the number
[120]                                            of ACF and expression
                                                of COX-2 in the middle

Shih et al.    2011        Rice bran oil        Suppressed colon tumor
[121]                                              formation, mucin-
                                                depleted foci, and ACF
                                                especially sialomucin-
                                                   producing ACF in
                                                dextran sodium sulphate
                                                   induced colitis-
                                                associated colon cancer
                                                   after 13 weeks of

Kim et al.     2012    Rice bran y-oryzanol      Inhibited colon tumor
[122]                                               growth in mice.

Choi et al.    2013     10% (w/w) black and       Inhibited the colon
[123]                    brown rice brans       transplanted tumors in

Shafie et      2013    Rice bran phytic acid       Markedly reduced
al. [124]                                       [beta]-catenin and COX-
                                                 2 expression in colon

Tan et al.     2014        Brewers' rice        Markedly reduced colon
[55]                                                tumor in rats.

ACF: aberrant crypt foci; AOM: azoxymethane; APC: adenomatous
polyposis coli; COX: cyclooxygenase; COX-2: cyclooxygenase-2; GABA:
gamma-aminobutyric acid; PG[E.sub.2]: prostaglandin [E.sub.2].
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Author:Tan, Bee Ling; Norhaizan, Mohd Esa
Publication:BioMed Research International
Article Type:Report
Date:Jan 1, 2017
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