Review pubs.acs.org/JAFC
Buckwheat as a Functional Food and Its Effects on Health Juan Antonio Giménez-Bastida and Henryk Zieliński*
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Division of Food Science, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, P.O. Box 55, 10-748 Olsztyn, Poland ABSTRACT: Buckwheat (BW) is a gluten-free pseudocereal that belongs to the Polygonaceae family. BW grain is a highly nutritional food component that has been shown to provide a wide range of beneficial effects. Health benefits attributed to BW include plasma cholesterol level reduction, neuroprotection, anticancer, anti-inflammatory, antidiabetic effects, and improvement of hypertension conditions. In addition, BW has been reported to possess prebiotic and antioxidant activities. In vitro and animal studies suggest that BW’s bioactive compounds, such as D-chiro-inositol (DCI), BW proteins (BWP), and BW flavonoids (mainly rutin and quercetin) may be partially responsible for the observed effects. The purpose of this paper is to review the recent research regarding the health benefits of BW, in vitro and in vivo, focusing on the specific role of its bioactive compounds and on the mechanisms by which these effects are exerted. KEYWORDS: common buckwheat, bioactive compounds, Fagopyrum, rutin, buckwheat protein
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INTRODUCTION The family Polygonaceae is a group of plants composed by approximately 1200 species.1 Buckwheat (BW), which belongs to this family, is found almost everywhere but grows mainly in the northern hemisphere. Russia and China are the main producers of BW in the world.2 Furthermore, the consumption of this product has become increasingly popular in the United States, Canada, and Europe.3 Among the main nine species with agricultural meaning, common BW (Fagopyrum esculentum Moench) and tartary BW (Fagopyrum tataricum Gaertn.) are the most widely grown species. Tartary BW is cultivated in some mountain regions, whereas common BW is grown from temperate Europe to Japan.4 BW seeds are the main form of consumption of this pseudocereal. Dehulled seeds (raw groats) are principally used for human consumption as breakfast cereals or as processed flour for making different bakery products (bread, cookies, snacks, and noodles) enriched with BW flour (0.3−60%) and BWenhanced nonbakery products (tea, honey, tarhana, and sprouts).5 Because BW is a gluten-free pseudoceral, these products may be included in gluten-free diets for patients suffering gluten intolerance.6 BW is recognized as a good source of nutritionally valuable protein, lipid, dietary fiber, and minerals, and in combination with other health-promoting components, such as phenolic compounds and sterols, it has received increasing attention as a potential functional food.7 Functional foods are those that exert a scientifically proven specific health benefit (health claim) beyond their nutritional properties, although the consumption of its specific formulation is not essential for human life.8 It has been described that the consumption of BW and BW-enriched products is related to a wide range of biological and healthy activities: hypocholesterolemic, hypoglucemic, anticancer, and anti-inflammatory (Figure 1). Buckwheat proteins (BWPs) and phenolic compounds are presumed to be responsible, at least in part, for these benefits.4 It has been recognized that some of these effects may be related to the antioxidant capacity of these © 2015 American Chemical Society
compounds, but newly discovered mechanisms of action may be also responsible for the observed healthy effects.9,10 The purpose of this paper is to review the recent literature addressing the health benefits of BW, its proteins, and phytochemicals and to describe the mechanisms underlying the beneficial effects attributed to these compounds.
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BIOACTIVE COMPOUNDS IN BUCKWHEAT BW is presently considered a food component of high nutritional value. BW seed is the main form consumed, although the consumption of BW sprouts is increasingly popular in North America and other parts of the world. The general composition of sprouts and dehulled, unroasted BW seeds or groats from common and tartary BW is described in Table 1.7,11−16 Fagopyritols are mono-, di-, and trigalactosyl derivatives of DCI termed fagopyritols B1, B2, and B3, respectively. Fagopyritols A1, A2, and A3 have also been identified as isomers of B1, B2, and B3, respectively.13,17,18 Fagopyritols are concentrated in aleurone and embryo cells of the seed, being the most abundant the fagopyritol B1 (0.392 mg g−1 dry matter (dm) of whole common BW groats).13 DCI, the free form, is present in lower concentration (0.21−0.42 mg g−1 dm).12 The role of DCI and fagopyritols as molecules exerting insulin-like activity has been previously reported.12,19,20 Chemically synthesized DCI has been shown to reduce elevated plasma glucose levels in an important number of studies.21,22 Although studies investigating the effect of DCI and fagopyritols in humans have not been conducted so far, these compounds may have positive effects in diabetes treatment. D-Fagomine is a minor component detected in common BW groats (1−25 mg kg−1 in common BW-based foodstuffs) that exhibits a glucose-lowering effect.23,24 The anthraquinone emodin is present in BW at concentrations between 1.72 and 2.71 mg kg−1 dm.25 Due to the Received: Revised: Accepted: Published: 7896
May 20, 2015 August 6, 2015 August 13, 2015 August 13, 2015 DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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Figure 1. Simplified scheme summarizing the health benefits associated with buckwheat consumption.
mainly due to its numerous beneficial effects observed in vitro and in vivo: anti-inflammatory, antidiabetic, hypocholesterolemic, antiatherosclerotic, and anticarcinogenic.34 Its activity has been associated with its antioxidant capacity, although the precise mechanism of protection is not known. Quercitrin (quercetin-3rhamnoside) is another glycoside present in BW at concentrations ranging from 0.01 to 0.05% dm in tartary BW and from 0.54 to 1.80% dm in common BW.31,35 Isoquercetin (quercetin3-glucoside) is present in BW hypocotyls (1.4 μM g−1 dm),36 and it has been shown to exert antidiabetic and anticancer activities.37−39 The aglycone quercetin is present in BWG (0.001 mg g−1 dm) and BW hull (0.009−0.029 mg g−1 dm) at lower concentration than rutin.12,32 The flavone C-glycosides present in BW seedlings (vitexin, isovitexin, orientin, and homoorientin), the content of anthocyanins and proanthocyanins,36 and the presence of squalene, epicatechin, and vitamin E (tocopherols)40 make BW a good antioxidant source in the human diet. Phenolic acids of BW also contribute to its antioxidant capacity. 4-Hydroxybenzoic (p-hydroxybenzoic), 3-(4-hydroxy3-methoxyphenyl)-2-propenoic acid (ferulic), and 3,4-dihydroxybenzoic (protocatechuic) acids are prominent in the seeds of different cultivars of tartary BW, and other phenolics, including 4-hydroxycinnamic (p-coumaric), 3,4,5-trihydroxybenzoic (gallic), 3,4-dihydroxycinnamic (caffeic), 4-hydroxy-3-methoxybenzoic (vanillic), and 3,5-dimethoxy-4-hydroxybenzoic (syringic) acids, have been detected.41 Several phenolic acids were described in the inflorescences of different varieties of BW: 3(3,4-dihydroxycinnamoyl)quinic (chlorogenic), 4-methoxybenzoic (p-anisic), 2-hydroxybenzoic (salicylic), and methoxycinnamic acid.42 The most abundant phytosterol in BW flour (BWF) is β-sitosterol (0.86 mg g−1 dm) followed by campesterol (0.11 mg g−1 dm) and stigmasterol (0.02 mg g−1 dm).43 BW is also an important source of vitamins. Total vitamin B content, including B1 (thiamin, 2.2−3.3 μg g−1 dm), B2 (riboflavin, 10.6 μg g−1 dm), B3 (niacin, 18 μg g−1), B5 (pantothenic acid, 11 μg g−1), and B6 (piridoxine, 1.5 μg g−1), is higher in tartary BW than in common BW, and the levels of vitamin C have been reported as 50 μg g−1 dm, reaching 250 μg g−1 dm in sprouts.5,44,45 Along with vitamins, other compounds such as glutathione (1.10 mmol g−1 dm in BWG), phytic acid (35− 38 mg g−1 dm in BW bran), carotenoids (2.10 mg g−1 dm in BW seeds), and melatonin (470 pg g−1 dm in BWG) have been detected and may contribute to the antioxidant activity of BW.4,32 Recently, γ-aminobutyric acid (GABA) and 2″-hydroxynicotianamine (2HN) have been found to serve as functional compounds in BW. Seeds and sprouts contain GABA, whereas
Table 1. General Composition of Common and Tartary Buckwheat (BW) (A) Groats and (B) Sprouts level (%) parameter
common BW
(A) Groats (Dry Matter) starch 54.50 soluble carbohydratesa 1.60 dietary fiber 7.0 protein 12.30 lipids 3.80 ash 2.0 other compoundsb 18.40 (B) Sprouts (Fresh Weight) water 92.80 dietary fiber 0.70 protein 0.17 lipids 0.38 ash 0.68
tartary BW 57.40 1.78 10.60 13.15 3.84 2.70 10.53 92.34 0.73 0.14 0.14 0.49
a
Including sucrose and fagopyritols. bOrganic acids, phenolic compounds, tannins, phosphorylated sugars, nucleotides and nucleic acids, and unknown compounds.
broad spectrum of biological activities exerted by emodin, it may be an important bioactive factor in BW.26 Buckwheat proteins (BWPs) have a high biological value due to a well-balanced amino acid composition. They are rich in lysine, which is generally the first limiting amino acid in other plant proteins, and arginine. However, the content in glutamine and proline is much lower than in wheat,27 and threonine and methionine are the first and second limiting amino acids, respectively. Thiamin-binding proteins isolated from BW may be used in the care of people who suffer from the lack of thiamin.7 Furthermore, many researchers have reported that the low digestibility of BWPs and lysine/arginine and methionine/ glycine rates are critical factors in determining the cholesterollowering effects of the plant proteins.7,28 The contents and composition of flavonoids are dissimilar in different BW species. Generally, the flavonoid content in F. tataricum (40 mg g−1) is higher than in F. esculentum (10 mg g−1), reaching concentrations of 100 mg g−1 in tartary BW flowers, leaves, and stems.2 BW seeds (groats and hull) and sprouts are important sources of rutin (quercetin-3-rutinoside), and its content depends on the variety and growth conditions.29,30 Tartary BW groats (BWG) contain more rutin (80.94 mg g−1 dm) than common BW (0.20 mg g−1 dm),31,32 whereas tartary BW sprouts (BWS) possess 2.2-fold more rutin than common BWS.33 Rutin has attracted increasing attention 7897
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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triglycerides (TG) (4.85%; p > 0.05), and LDL (9.05%; p < 0.01) and an increase of high-density lipoproteins (HDL) (6.9%; p < 0.01) in the participants who consumed BW (n = 1628) compared with the population who consumed corn (n = 1914). In addition to this, a decrease in blood glucose concentration (14.5%; p < 0.01) was also described in the group that consumed BW compared to the other group.69 In 2011, Wieslander et al. performed a double-blind randomized crossover study with 62 healthy volunteers who were divided in two groups consuming four cookies elaborated either with tartary or with common BW for 4 weeks. A decrease in serum TCh (13.56%; p < 0.001) and HDL (15.44%; p < 0.001) and myeloperoxidase (MPO) (enzyme involved in oxidative stress and inflammation) was documented.70 The hypocholesterolemic effect of BW has also been observed in an important number of in vivo and in vitro studies to a similar extent. Early work investigating the hypocholesterolemic effect of BW consumption on animals dates back to the 1990s. In 1995, Kayashita et al. reported that BWP consumption by Sprague−Dawley rats reduced body fat content, decreased TCh, and increased the level of HDL in plasma compared to those groups that consumed soy protein or casein.71 In a second study, lower Ch (14.4%; p < 0.05) and TG (38.1%; p < 0.01) levels in plasma and liver, respectively, were observed in rats fed a BWP-enriched diet compared with those fed a casein diet.72 This hypocholesterolemic effect exerted by BWP was more effective in rats consuming Ch-containing diets than in those consuming Ch-free diets.73 It has been suggested that the Ch-lowering activity of BWP is mediated by its influence on fecal excretion of bile acids and neutral sterols. In 2001, Tomotake et al. found that Sprague− Dawley rats consuming BWP-enhanced Ch-free diets showed lower plasma TCh levels (11−22%) and higher fecal excretion of bile acids and neutral and acidic steroids relative to animals consuming a casein- or soy protein-enriched diet.74 Studies investigating the effect of BWP in rats fed a high-Ch diet reported a Ch-lowering effect accompanied by higher fecal excretion of neutral sterols. Tomotake et al. also reported that a BWPcontaining diet markedly suppressed gallstone formation compared with casein- and soy protein-enriched diets, and this effect was related to the lower level of Ch in gallbladder, plasma, and liver and the higher fecal excretion of bile acids and steroids.75 This effect of BWP suppressing gallstone formation and enhancing excretion of bile acids and steroids was also observed in ddY mice and Sprague−Dawley rats fed a Ch-enhanced diet.76 It has been suggested that the Ch-lowering effect and enhanced level of sterol secretion may be associated with the low digestibility of BWP.77 BW extracts (BWext) have also been reported to exhibit a hypocholesterolemic effect, reducing intestinal absorption of dietary Ch. In vitro studies have reported a decrease in the uptake of Ch micelles in Caco-2 cells in the presence of common BWPext.78 This effect may be mediated by reducing the gut transit time after BW consumption.79 Another possible mechanism was recently proposed by Yang et al., which investigated the Ch-lowering effect of the diet supplemented with tartary BWF, wheat, or rice in hamsters. BW (but not wheat and rice) reduced plasma as well as hepatic Ch levels and led to a greater neutral sterol excretion along with a down-regulation of intestinal acyl-CoA:Ch acyltransferatse 2 (ACAT2) and Niemann−Pick C1-like 1 (NPC1L1),80 two intestinal transporters that have been suggested to play a critical role in cholesterol absorption.81
2HN has been recently identified in BWF. These compounds have been reported to reduce blood pressure in humans and to inhibit the angiotensin I converting enzyme (ACE) activity.46−48
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HEALTH BENEFITS AND BUCKWHEAT Antioxidant Activity. Increasing appreciation of the nutritional and functional properties of BW has also encouraged some investigations about its antioxidant properties. The antioxidant features of BW pseudocereals appear reflected in human intervention studies. There have been reported increases in the total antioxidant capacity of plasma samples from healthy donors after consuming 1.5 g of BW honey kg−1 (single dose, n = 37),49 or when BW honey was added to water or black tea (160 g honey L−1, n = 25)50 as well as after BW-enriched wheat bread consumption.51 The biological antioxidant capacity of BW is further supported by in vivo experimental models fed a BWH-containing diet (0.75% in diet, 14 days),52 a BW byproduct-enriched diet (15% for 4 weeks),53 and 100 and 200 mg of BW kg−1 day−1 for 20 days.54 The results showed increased activity of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and gluthatione peroxidase (GSH-Px), and reduced lipid peroxidation parameters such as thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), and fluorescent substance (FLS) in plasma samples, red blood cells, and several different organs (heart, kidney, liver, and brain). In contrast, total plasma antioxidant status and the activities of SOD and GSH-Px were unaltered in healthy rats fed a normal diet containing 30% expanded BW seeds or 5% of BWS for 4 weeks.55 In vitro antioxidant activity of BW has been assessed in relation to its phenolic content and composition41,42,56−59 and compared to that of other cereals and pseudocereals.60−63 In this sense, Zieliński and Kozłowska established the following hierarchy of antioxidant activity: BW > barley > oat > wheat ∼ rye.64 The high antioxidant capacity of BW is connected with its high polyphenol content, especially rutin.65,66 Liu et al. described the antioxidant effects of BWS in human hepatoma HepG2 cells, revealing that tartary and common BW had a positive effect on the production of intracellular peroxide and superoxide anions. Tartary BW was more effective than common BW, and this effect was associated with the higher concentration of rutin.16 Studies by Zhou et al. also reported that BW honey showed protective effects on hydroxyl radical-induced DNA damage through is antioxidant activity.67 These studies seem to indicate that BW may exert its beneficial effects through its antioxidant activity. Hypocholesterolemic Activity. Increased cholesterol intake can induce oxidative stress and cause an increase in blood cholesterol level, leading to the up-regulation of low-density lipoproteins (LDL) and oxidized LDL (oxLDL), contributing to the development of chronic diseases such as atheroclerosis.68 In vitro and in vivo studies have proposed that BW’s protective effect against cardiovascular diseases may come from its ability to modulate the cholesterol (Ch) level. The number of studies investigating the cholesterol-lowering activity of BW in humans is small (Table 2). The investigation carried out by Zhang et al. in 2007 is one of the biggest studies in relation to the consumption of BW and health: 3542 Mongolians in two adjacent counties of Inner Mongolia (China) were randomly sampled in a cross-sectional study to assess the association of hypertension, dyslipidemia, and hyperglycemia with lifetime consumption of BW seed as a staple food. The authors described a reduction of total cholesterol (TCh) (4%; p < 0.05), 7898
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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Table 2. Human, Animal, and in Vitro Studies Describing the Hypocholesterolemic Effect Related to Buckwheat Consumptiona Human Studies population of study
intake; duration
foodstuff
healthy (n = 62 ♀)
group 1: four common BW cookies (daily) group 2: four tartary BW cookies (daily) 4 weeks (after 2 weeks, the groups switched their type of cookie)
BW cookies
healthy (n = 12 ♂)
100 g of sieved BW preparation; 4 week dietary period
healthy (♂)
healthy (n = 857 ♂)
parameters
effect
ref
↓ ↓ ↓
70
sieved BWF enriched diet HDL HDL/Ch
↑ ↑
160
100 g of whole BW preparation; 4 and 12 weeks
whole BW flour
HDL HDL/Ch glucose tolerance
↑ ↑ ↑
161
group 1 (n = 319), 0 g/day group 2 (n = 207), 200 g/day.
BW
serum: TCh serum: LDL systolic and diastolic pressure HDL/TCh
↓ ↓ ↓ ↑
162
effect
ref
MPO serum: TCh serum: HDL
Animal Studies model
dose; duration
assayed product
parameters
♂ Sprague−Dawley rats
38.1%; 3 weeks
BWPext
TG FFA TCh phospholipid HDL body fat content
↓ ↓ ↓ ↓ ↑ ↓
71
♂ Sprague−Dawley rats
323.1 g kg−1 (high-Ch diet); 3 weeks
BWPext
hepatic: TCh hepatic: HDL hepatic: TG hepatic: weight plasma: TCh
↓ ↓ ↑ ↓ ↓
73
♂ Sprague−Dawley rats
381 g kg−1; 3 weeks
BWPext
hepatic: TG body fat content enz activity: G6PD enz activity: FA synthase fecal excretion: fat fecal excretion: N2
↓ ↓ ↓ ↓ ↑ ↑
72
♂ Sprague−Dawley rats
307 g kg−1 (normal diet); 8 weeks
BWPext
plasma: TCh plasma: HDL fecal excretion: neutral steroids fecal excretion: acidic steroids fecal excretion: bile acids
↓ ↓ ↑ ↑ ↑
74
♂ Golden Syrian hamster
381g kg−1 (high-Ch diet); 2 weeks
BWPext
plasma: TCh plasma: TG plasma: phospholipids plasma: HDL plasma: HDL/TCh hepatic: Ch plasma: TCh plasma: phospholidis plasma: lithogenic index gallstone formation fecal excretion: Ch fecal excretion: bile acids fecal excretion: fecal steroids
↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑
75
7899
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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Journal of Agricultural and Food Chemistry Table 2. continued Animal Studies model
dose; duration
assayed product
parameters
effect
ref
♂ Sprague−Dawley rats
381 g kg−1 (high-Ch diet); 2 or 3 weeks
BWPext
plasma: HDL/TCh plasma: phospholipids plasma: TCh plasma: TG liver: rel wt liver: Ch liver: phospholipids
↑ ↑ ↓ ↓ ↓ ↓ ↓
77
♂ stroke-prone SHR (SHRSP)
34.4% in diet; 14 days
BWPext
atherogenic lipoproteins antiatherogenic apoE-HDL
↓ ↑
163
♂ Syrian Golden hamster
24% in diet; 6 weeks
BWF (tartary BW)
plasma: TCh plasma: non-HDL gepatic: TCh fecal excretion: neutral sterol fecal excretion: acidic sterolb mRNA exp: NCPC1L1 mRNA exp: ACAT2
↓ ↓ ↓ ↑ ↑ ↓ ↓
80
♂ Sprague−Dawley rats and ♂ ddY mice
30.7% of BWP in the diet (rats fed a normal diet or high-Ch diet); 10 days 54.8% of protein BWF (mice fed a high-Ch diet); 27 days
BWPext and BWF protein (common BW)
serum: Ch serum: TG serum: phospholipids hepatic: rel wt hepatic: Ch enz activity: FA synthase fat pad wt feces dry wt fecal excretion: N2 fecal excretion: bile acids fecal excretion: acid steroids fecal excretion: neutral steroids bile: Ch bile: phospholipids Ch-induced gallstone incidence lithogenic index
↓
76
♂ Mongrel rabbits
0.25 g kg−1 day−1 (high-fat diet); 12 weeks
BWext (common BW)
hepatic: TG plasma: MDA ascorbate free radicals serum testosterone insulin
↓ ↓ ↑ ↑ ↓
164
C57BL/6 mice
100 and 200 mg kg−1 body wt (high-fat diet); 8 weeks
ethanol-germinated extBW
hepatic: Ch hepatic: TG hepatic: wt serum: HDL serum: HDL/TCh mRNA exp: PPAR-γ mRNA exp: C/EBPα
↓ ↓ ↓ ↑ ↑ ↓ ↓
82
KK-Ay mice
0.05 mg g−1 body weight; 6 weeks
bran powder (common BW)
blood glucose level mRNA exp: ACC2 mRNA exp: SCD1 mRNA exp: FA synthase mRNA exp: ACC1b mRNA exp: SREBP-1c mRNA exp: ChREBPb
↓ ↓ ↓ ↓ ↓ ↓ ↓
83
7900
↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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Journal of Agricultural and Food Chemistry Table 2. continued Animal Studies model
dose; duration
assayed product
parameters
effect
ref
♂ F344/DuCrj rats
50 g kg−1 diet (Ch-free diet); 4 weeks
BWS powder (common and tartary BW)
plasma: TCh hepatic: TChb fecal excretion: SCFA fecal excretion: bile acids fecal excretion: neutral steroidsb fecal excretion: matter excretion mRNA exp: Ch 7-α-hydroxylase mRNA exp: HMG-CoA reductase
↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑
84
Syrian hamster
2.5 and 25% in the diet (high-fat and high-Ch diet); 4 weeks
BWS and seeds (common BW)
liver/body wt liver wt serum: TCh serum: TG serum: LDL serum: LDL/HDL serum: TCh/HDL hepatic: TCh
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
165
♂ Sprague−Dawley rats and ♂ ddY mice
30.7% of common BWP and 43.7% of tartary BWP in the diet (high-Ch diet); 27 days
BWPext and BWF protein (common and tartary BW)
serum: Ch hepatic: Ch liver rel wt feces dry wt fecal excretion: N2 fecal excretion: neutral sterols fecal excretion: bile acids bile: Ch bile: phospholipids bile: lithogenic index gallstone incidence
↓ ↓ ↓ ↑ ↑ ↑ ↑ ↓ ↓ ↑ ↓
166
♂ Syrian hamster
1−5% in the diet (high-Ch diet); 4 weeks
sprouts (common BW)
antioxidant capacity serum: LDL serum: TG serum: LDL/HDL serum: TCh/HDL
↑ ↓ ↓ ↓ ↓
167
♂ pathogen-free Wistar rats
0.2−1 g kg−1 body weight (high-fat diet); 6 weeks
bran extract (tartary BW)
serum: TG serum: TCh serum: HDL serum: MDA ApoB/ApoA1b antioxidant enzymes HDL/TCh atherogenic index hepatic: TG hepatic: TCh hepatic: SOD hepatic: MDAb
↓ ↓ ↑ ↓ ↑ ↑ ↑ ↓ ↓ ↓ ↑ ↓
168
♂ Wistar rats
5% in the diet (high-fat diet); 13 weeks
BW leaf and flower mixture (common BW)
SFA PUFA body wt gain plasma TCh, TG, LDL atherogenic index DPPH MDA
↓ ↑ ↓ ↓ ↓ ↓ ↓
169
7901
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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dose; duration
assayed product
parameters
effect
ref
♂ diabetic db/db and ♂ nondiabetic db/+ mice
5% in diet and 10% in diet; 21 days
sprouts (common BW)
HbA1c liver: TCh liver: lipids liver: TG plasma: TCh plasma: HDL TBARS fecal bile acids atherogenic index
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓
170
♂ Sprague−Dawley rats
5% in the diet (high-fat diet); 6 weeks
BW leaf and flower mixture
body wt gain plasma: TG plasma: TCh plasma: HDL plasma: non-HLD HDL/TCh atherogenic index hepatic: TG hepatic: TCh hepatic: ACAT hepatic: HMG-CoA reductase fecal excretion: TG fecal excretion: acidic sterols epididymal adypocites size
↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↓
171
In Vitro Studies test model
dose; duration
assayed product
parameters
effect
ref
human colon cancer cells (Caco-2)
0.2% (w/v); 30 min
BWPext (common BW)
Ch micelle uptake
↓
78
Antiatheromatosus plaque formation index = HDL/TCh; arteriosclerotic index = ([TCh − HDL]/HDL); atherogenic index of plasma = log (TG/ HDL); lithogenic index = (molar % of Ch/molar % of Ch at saturation); ↑, increase; ↓, decrease. Abbreviations: ACAT2, acyl-CoA:Ch acyltransferatse 2; ACC1 and 2: acetyl-coenzyme A carboxylase 1 and 2; ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; ApoE, apolipoprotein E; BW, buckwheat; BWF, buckwheat flour; BWPext, buckwheat protein extract; C/EBPα, CCAAT/enhancer-binding protein-α; Ch, cholesterol; ChREBP, carbohydrate resopnsive element-binding protein; CPT, carnitine palmitoyltransferase; DPPH, 2,2-diphenyl-1-picrylhydrazyl; FA, fatty acid; FFA, free fatty acid; G6PDH, glucose-6-phosphate dehydrogenase; HbA1c, glycated hemoglobin A1c; HDL, high-density lipoprotein; HMGCoA, 3-hydroxy-3-methylglutaryl-coenzyme A; LDL, low-density lipoprotein; MDA, malondialdehyde; MPO, myeloperoxidase; N2, nitrogen; NPC1L1, Niemann−Pick C1-like 1; PPAR-γ, peroxisome proliferator-activated receptor-γ; PUFA, polyunsaturated fatty acids; SCD1, stearoylcoenzyme A oxidase; SCFA, short-chain fatty acids; SFA, saturated fatty acid; SOD, superoxide dismutase; SREBP-1c, sterol regulatory elementbinding protein 1c; TBARS, thiobarbituric acid reactive substances; TCh, total cholesterol; TG, triglycerides. bNot significant. a
years there has been a considerable interest in the possibility of improving diabetic control by altering the glycemic impact of the carbohydrates ingested. A low glycemic index (GI) diet has been related to advantages in the prevention and treatment of diabetes.87 BW for dietary use is one way to prevent diabetes in China.88 In the study of Skrabanja et al., 10 healthy volunteers consumed (single dose) boiled BW groats, bread enriched with 50% of BW groats, or white wheat bread. The postpandrial plasma glucose and insulin production were lower in volunteers who consumed BW products, especially BW groats, than those who consumed white wheat bread.89 Su-Que et al. randomly recruited 10 type 2 diabetic subjects. All patients showed a decrease of 51% (p < 0.05) in the postpandrial 2 h plasma glucose after consumption of BW compared with those who consumed white wheat bread.90 Reduction of energy consumption is an important consideration for those attempting to control glycemia. In the aforementioned study89 the volunteers consuming BW products, especially groats, showed high postprandial satiety. Berti et al.
BW consumption also seems to have an effect on the activity and mRNA expression of enzymes involved in lipid metabolism. The intake of BWP exerted a lipid-lowering effect accompanied by a decrease in hepatic activities of glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid (FA) synthase.72,76 Other BWext, such as an ethanol extract of germinated BW rich in rutin, and BW bran extracts down-regulated mRNA expression of the adipogenic transcription factors peroxisome proliferatoractivated receptor-γ (PPAR-γ), CCAAT/enhancer-binding protein-α (C/EBPα), sterol regulatory element-binding protein 1c (SREBP1c), and carbohydrate responsive element-binding protein (ChREBP) and of lipogenic genes acetyl-coenzyme a carboxylase 1 or 2 (ACC1 and 2), stearyl-coenzyme A oxidase (SCD1), and FA synthase.82,83 Meanwhile, BWS has been shown to up-regulate the expression of Ch-7-α-hydroxylase and 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA).84 Antidiabetic Activity. Diabetes is a chronic disease caused by deficient insulin secretion or ineffective insulin activity, which lead to an increase in plasma glucose levels.85,86 In the past few 7902
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
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Journal of Agricultural and Food Chemistry
PPAR-γ activity, a molecule involved in regulating insulin sensitivity and glucose homeostasis,104 was shown in COS-1 cells.105 Another study carried out by Curran et al. described that BW inhibited glucose uptake in rat H4IIE hepatoma cells. Furthermore, these authors reported that other compounds, such as DCI, rutin, or quercetin, were not the active components responsible for the observed effects.106 These contradictory results point out the need for future studies to clarify the cellular and molecular mechanisms underlying the beneficial effects attributed to BW and its individual compounds and the compound(s) responsible for the observed effects. Anticancer Activity. Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries.107 Functional food for the prevention of chronic diseases such as cancer is one of the century’s key global challenges. In the study carried out by Shen et al. (2008) in Xuanmei (China), the frequent consumption of different foods, including BW, was associated with a reduced risk of lung cancer.108 Because oxidative DNA damage is implied in cancer initiation and promotion,109 the anticancer activity of BW has been associated with its antioxidant properties. It has been reported that ethanol BWext from tartary and common BW protected DNA from being damage by hydroxyl radical.110 Methanolic extracts of common and tartary BWF, rutin, and quercetin showed high antioxidant capacity (DPPH scavenging activity) and reduced tert-butylhydroperoxide-induced DNA damage in the HepG2 cell line.111 In addition to the antioxidant capacity, mechanisms of action such as alteration of gene expression, inhibition of proliferation, cell cycle arrest, and/or the induction of apoptosis have been documented in vivo and in vitro. Sprague−Dawley rats fed a BWPext showed a decreased development in mammary tumor by lowering serum estradiol112 and a lower incidence of colon adenocarcinoma (Table 3).113 In the latter study a decrease in the colonic cell proliferation and a down-regulation in the expression of c-myc and c-fos, genes involved in colon cancer development, were also described.114 Different fractions of an ethanolic BWext decreased tumor formation in mice treated with sarcoma cells and inhibited the cell growth of different cancer cell lines.115 BWHext rich in polyphenols exhibited antioxidant activity and growth inhibitory activity in HeLa cancer cells (up to 50% at 100 μg mL−1, 72 h).116 Flavonoids,39,117,118 polysaccharides,119 lectins,120 and phenylpropanoids121,122 from BW have been shown to induce apoptotis, differentiation, and cytotoxicity against a wide range of cancer cell lines in vitro. In a recent study, Yuan et al. observed that a ribonuclease isolated from BW seeds inhibited the proliferative activity of HepG2 (IC50 = 79.2 μM) and MCF-7 (IC50 = 63.8 μM) cancer cells.123 BW proteins have also been revealed to exert anticancer activity. As reviewed by de Mejia and Dia, isolated BWPs such as BW protease inhibitors (BWI-1 and BWI-2a) and the recombinant form of BWI-1 (rBWI-1) have anticancer activity, evidenced mainly by induction of apoptosis and growth inhibition against a wide range of cancer cell models.124 Recent studies have reported new BWPs that show anticancer activity. Leung and Ng isolated a peptide from BW seeds that exhibited antiproliferative activity against HepG2 cells (IC50 = 33 μM), leukemia L1210 (IC50 = 4 μM), breast cancer MCF-7 (IC50 = 25 μM), and liver embryonic WRL68 (IC50 = 37 μM) cell lines.125 TBWSP31 protein, isolated from tartary BW, has been identified as novel antitumor protein showing antiproliferative activity, causing cell cycle arrest in G0/G1
also described a positive effect of BW lasagna consumption on energy intake and time satiety in healthy volunteers.91 In a singleblind, controlled, crossover study conducted by Stringer et al., the efficacy of BW crackers compared with rice crackers to modify glucose metabolism in both healthy and type 2 diabetic subjects was investigated. No changes were observed in glucose or insulin concentrations. However, a modulation of the gastrointestinal satiety hormones such as glucagon-like peptide-1 (potentiator of insulin secretion) and glucagon-dependent insulinotropic peptide (GIP) was documented after consumption (single dose) of BW cracker in healthy and type 2 diabetic volunteers.92 Therefore, BW consumption may modulate satiety by altering the postprandial levels of satiety hormones. Attempts to identify the bioactive compounds responsible for the observed effects and the mechanisms associated have led to several publications looking at the antidiabetic effects of different BWext or their individual compounds in vitro and in vivo. Previous studies by Larner et al. have highlighted the role of DCI mediating mechanisms associated with diabetes.93−97 Kawa et al. investigated the effects of a BW concentrate (common BW), containing 10 and 20 mg DCI kg−1 of body weight, on serum glucose concentrations of streptozotonic (STZ) rats in comparison with normal rats, demonstrating that a single oral dose of BW concentrate reduced the serum glucose level by 12−19% in STZ rats after 90−120 min of treatment.98 Using hyperinsulinemic KK-Ay mice, Yao et al. studied the effect of DCI-enriched tartary BW bran extract (equivalent to 40 mg kg−1 DCI) supplementation for 5 weeks on blood glucose, lipid profile, and other markers related to diabetes. The results showed that oral administration of 45−182 mg kg−1 of DCIenriched tartary BW bran extract lowered plasma glucose, Cpeptide level, glucagon, TG, and plasma urea and improved glucose tolerance and insulin immunoreactivity.99 Diabetic rats administered 100−400 mg kg−1 day−1 of the overall flavonoids from BW flowers and leaves showed lower blood glucose (20.8−27.7%) and improvement in renal damage.100 BW bran extract decreased the blood glucose level in nondiabetic Balb/c mice following sucrose administration, which was associated with the capacity of this extract to inhibit α-glucosidase activity, an enzyme that hydrolyzes carbohydrates in the gastrointestinal tract.101 Lee et al. investigated the antihyperglycemic and antiinsulin resistance of an ethanol BWext (tartary BW), rutin, and quercetin in vitro and in vivo. These authors demonstrated that ethanol BWext (50 mg kg−1 body weight (bw)), rutin (11.5 mg kg−1 bw), and quercetin (3 mg kg−1 bw) improved hyperglucemia and hyperinsulinemia in C57BL6 mice fed a high-fructose diet for 8 weeks, suggesting that rutin was the major active compound of the extract. The in vitro assay revealed that the hypoglycemic effect may be due to an increase in the glucose uptake mediated by increasing levels of glucose transporter 2 (GLUT2) in FL83B cells, the major glucose transporter in hepatocytes. These hypoglycemic effects were accompanied by a reduction of oxidative stress, induction of antioxidant enzymes, and improvement of plasma and hepatic lipids.102 Further evidence of the antidiabetic properties of BW has been reported recently by Lee et al., describing that ethanol BWext (200 mg mL−1) and rutin (40 mg mL−1) reduced oxidative stress, attenuated AGE formation, and inhibited α-amylase and α-glucosidase activity.103 Although the animal and in vitro studies support the antidiabetic effect of BW in humans after its consumption, some investigators have reported contradictory results. Schrader et al. described that BW (0.1 and 1 g kg−1 diet) had no blood glucose-lowering effect in db/db mice, but a dose-dependent 7903
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
Review
Journal of Agricultural and Food Chemistry Table 3. Animal and in Vitro Studies Describing the Anticancer Activity Related to Buckwheat Consumptiona Animal Studies model
dose; duration
effect
ref
♀ Sprague−Dawley rats
38.1% in diet; 61 days
BWPext
assayed product
incidence mammary tumors serum estradiol
parameters
↓ ↓
112
♂ Sprague−Dawley rats
277 g kg−1; 124 days
BWPext
incidence colon adenocarcinoma incidence bloody stool cell proliferation mRNA c-myc and c-fos
↓
113
↓ ↓ ↓
♂ BALB/C mice (n = 78) infected with sarcoma-180 tumor growth cells
20 or 50 mg kg−1 day−1; 20 days
ethanol BWHext
tumor growth
−
115
♀ BALB/C mice (n = 50) infected with H22 hepatic carcinoma cells
6.25−1 mg kg−1; 8 days
rBWI (common BW)
ascites formation
↓
172
In Vitro Studies test model
dose; duration
assayed product
effect
ref
lymphoblastic leukemia (JURKAT and CCRF-CEM)
up to 50 μg mL−1; 24−48 h
BWI-1 and BWI-2a (common BW)
cell growth apoptosis DNA fragmentation
↓ ↑ ↑
173
breast cancer (Bcap37)
5−200 μg mL−1; 48−72 h
TBWSP31 (tartary BW)
cell growth
↓
127
myeloid leukemia K562
12.5−200 μg mL−1; 24 h
rBWI
cell growth apoptosis DNA fragmentation
↓ ↑ ↑
174
hepatoma (Hep G2) leukemia (L1210) breast cancer (MCF-7) liver embryonic (WRL 68)
up to 50 μM; 48 h
isolated peptide (common BW)
cell growth
↓
125
human B lymphoblast IM-9
25−200 μg mL−1; 24 h
rBWI (common BW)
apoptosis cell growth
↑ ↓
175
lung cancer (A594) breast cancer (MCF-7) gastric cancer (AGS) cervix cancer (HeLa) liver cancer (Hep3B)
0.25−1 mg mL−1; 48 h
ethanol BWHext (common BW)
proliferation
−
115
esophageal carcinoma (EC9706) hepatoma (HepG2) cervix cancer (HeLa)
6.25−50 mg mL−1; 6−60 h
rBWI (common BW)
cell growth apoptosis DNA fragmentation expression: Bax expression: Bak expression: bcl-2 expression: Bcl-xl release of Cyt c caspase-3 and -9 disruption of MMP
↓ ↑ ↑ ↑ ↑ ↓ ↓ ↑ +
176
breast cancer (Bcap37)
5−200 mg mL−1; 24−96 h
TBWSP31 (tartary BW)
apoptosis cell growth expression: bcl-2 expression: FAS cell cycle arrest in G0/G1
↑ ↓ ↓ ↑
126
leukemic (THP-1) monocytes from peripheral blood
5−200 μg mL−1 1−5 days
BW polysaccharides (tartary BW)
cell viability cell differentiation TNF-α IL-1β
↓ ↑ ↑ ↑
119
7904
parameters
DOI: 10.1021/acs.jafc.5b02498 J. Agric. Food Chem. 2015, 63, 7896−7913
Review
Journal of Agricultural and Food Chemistry Table 3. continued In Vitro Studies test model
dose; duration
effect
ref
lung cancer (A594) colon cancer (HCT116) leukemia (HL-60) breast cancer (ZR-75−30)
0.001−100 μg mL−1; 72 h
phenylpropanoids (tartary BW)
assayed product
proliferation
parameters
−
121
cervix cancer (HeLa)
100 μg mL−1; 72 h
BWHext (common and tartary BW)
cell death
↑
116
hepatoma (HepG2)
0.04−1% v/v (extBW) 4−100 μM (rutin) 2−50 μM (quercetin)
BWext (common and tartary BW) rutin quercetin
antioxidant activity tert-butylhydroperoxide-induced DNA damage
↑ ↓
111
hepatoma cells H22; normal liver cells 7702
6.25−50 μg mL−1
rBWI (common BW)
apoptosis cell viability release of Cyt c caspase-3, -8, and -9 DNA fragmentation
↑ ↓ ↑ + ↑
172
a ↑, increase; ↓, decrease; +, activation; −, inhibition. Abbreviations: BW, buckwheat; BWext, buckwheat extract; BWHext, buckwheat hull extract; BWI, buckwheat protease inhibitor; BWPext, buckwheat protein extract; Cyt c, cytochrome c; MMP, mitochondrial membrane potential; rBWI, recombinant buckwheat protease inhibitor.
significantly reduced by ethanol BWext (50 mg kg−1 bw) in the liver of mice and rats treated with ethanol and CCl4. Rutin (11.5 mg kg−1 bw) and quercetin (3 mg kg−1 bw) could also reduce ethanol- and CCl4-induced expression of the cytokines.134 These studies indicate that BW, through its phenolic acids and flavonoids, has potential anti-inflamatory properties. Nevertheless, it is difficult to draw conclusions due to the low number of studies performed so far. Therefore, further studies investigating the anti-inflammatory effects of BW are required. Effects on the Vascular System. It was reported that >25% of the population worldwide (approximately 1 billion) were affected by hypertension in 2000, and this figure is predicted to increase to 1.56 billion by 2025.135 The renin−angiotensin system regulates blood pressure. Plasma renin is responsible for the conversion of angiotensinogen into angiotensin I, which in the presence of angiotensin I-converting enzyme (ACE) is transformed into angiotensin II, a vasoconstrictor that increases blood pressure.136 Therefore, the use of ACE inhibitors is believed to lower hypertension. Although there is increasing interest in the identification of antihypertensive foods, the number of studies investigating the hypotensive effect of BW consumption is scarce. Li et al. cited a study performed by Kawasaki et al. in which a clinical examination made in the Mustang District of Nepal, where the inhabitants rely on BW as their principal food, demonstrated that the pathogenesis of hypertension was quite low (
