Polyphenol components in black chokeberry (Aronia melanocarpa)as clinically proven diseases control factors—an overview

Ningxun Go, Chi Shu, Yuehu Wng, Jinlong Tin, Yuxi Lng, Chenyu Jin,Xingyue Cui, Hnqin Jing, Shi’n Liu, Zhiying Li, Wei Chen, Ho Xu, Bin Li,

a Department of Food Science, College of Food, Shenyang Agricultural University, Shenyang 110161, China

b Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China

c Chaoyang Beihe Food Co., Ltd., Chaoyang 122100, China

Keywords: Black chokeberry Hyperlipidemia Hypertension Diabetes Inf lammation

ABSTRACT The black chokeberry is rich in polyphenols, including flavonoids with anthocyanins, flavanols and f lavonols as the main components and a variety of phenolic acids represented by chlorogenic acid. Because of these polyphenols, black chokeberry has the effect of preventing and adjuvant therapy diseases. This study summarized the current research results on the types and contents of functional components in black chokeberry, and analyzed their digestion, absorption and metabolism in human body. On this basis, the disease control functions that have been proved effective in clinical research were reviewed and analyzed. These studies showed that black chokeberry have good prevention and adjuvant therapy effects on hyperlipidemia,hypertension, diabetes and inflammation. Because there are different functional components in black chokeberry, its prevention and treatment of the same disease can come from multiple pathways, which provides a more reliable effectiveness for the disease control of different populations.

1. Introduction

Black chokeberry, also known asAronia melanocarpa, belongs to Rosaceae. As a type of berry, it is native to North America and naturally distributed from the northeast of the North American Great Lakes to the mountain swamps in the upper Appalachian Mountains Europe and has a history of more than 400 years of introduction and cultivation. There are large-scale cultivation and processing industries in Canada, Russia, Bulgaria, Hungary, Poland and the Czech Republic. The black chokeberry fruit presents dark purple color,which is rich in polyphenols. More and more studies have shown that these polyphenols make black chokeberry have obvious functional activity and adjuvant therapeutic effect on some diseases[1-3].

Traditional medicine in North America takes it as a herbs for treating colds[3-4]. With the deepening of research, researchers found that the role of these functional components was far more than this, which includes metabolic diseases such as hyperlipidemia and hyperglycemia[5-6], as well as cardiovascular and cerebrovascular diseases[7-8]. In addition, some studies have showed that black chokeberry also has a positive effect on the regulation of the immune system such as anti-inflammatory and anti-cancer[9]. However, it is worth noting that some studies on the functional activities of the extracted components of black chokeberry were only proved to be effectivein vitroexperiments, but not in human clinical trials,which led to the exaggeration of some functional activities of black chokeberry. Therefore, in order to obtain more reliable disease prevention and treatment functions and its mechanism, in this review,we summarized the current research results on the types and contents of functional components in black chokeberry, and analyzed their digestion, absorption and metabolism in human body. On this basis,we discussed the screening of functional activities confirmed by clinical trials, and made a more detailed analysis combined with the results of cell and animal experiments, so as to provide a more reliable overview for the research in this field.

2. Polyphenol components

Black chokeberry contains a large amount of polyphenols, whose content is up to 2 994 mg/100 g FW[10]. These polyphenols endow black chokeberry with a variety of functional activities and have potential disease prevention and treatment effects[2]. It is considered that these functional activities mainly come from the strong antioxidant activity of polyphenols, which can effectively remove human free radicals, and play an effective role in the prevention and treatment of some chronic diseases[11-12]. However, with the deepening of research, it is found that some polyphenols can directly act on some human tissues or organs, so as to improve the development direction of the disease. As shown in Fig. 1, these polyphenols can be divided into two parts: flavonoids and phenolic acids. The flavonoids are composed of flavanols, anthocyanins and flavonols, while the phenolic acids are mainly composed of chlorogenic acid and its isomers neochlorogenic acid. The contents of these components are shown in Table 1, which can be seen that flavanols are the highest proportion of polyphenols in black chokeberry. Proanthocyanidins dominates their polyphenols, and the total content can reach 4 790 mg/100 g FW[10].As for the anthocyanins in the black chokeberry, they are mainly composed of cyanidins, which combines different glycosides.Through the analysis of the content of these anthocyanins, it was found that the main anthocyanins were cyanidin-3-O-galactoside and cyanidin-3-O-arabinoside, which reached 989.7 and 399.3 mg/100 g FW respectively[13], which makes the anthocyanins as the second largest component in black chokeberry. The flavonol component is mainly quercetin which binds different glycosides, but the content of these substances is less (1.5−71.0 mg/100 g FW). In addition, some studies have also found some aglycone such as isorhamnetin, eriodictyol and kaempferol with glycosides, but these substances are less than quercetin[14], which makes flavonols is the component with complex species but the least content in black chokeberry polyphenols. In terms of phenolic acids, the types of phenolic acids are simpler than those of flavonoids. Chlorogenic acid and neochlorogenic acid are the main components. Both are formed by the combination of caffeic acid and quinic acid. In fact, these phenolic acids have high contents,which can reach 164 and 123 mg/100 g FW[14-15]. In addition, some studies also confirmed the existence of protocatechuic acid in black chokeberry[16]. As a result, phenolic acids also account for a large proportion of total polyphenols.

Fig. 1 Classification of polyphenols in black chokeberry fruit.

Table 1 Content and distribution of polyphenols compounds in black chokeberry.

2.1 Flavonoids

2.1.1 Flavanols

The highest content of flavonoids in black chokeberry is flavanols, which includes both (+)catechins and (−)epicatechins with small molecular weight and proanthocyanidins condensed from them. As showed in Table 1, these proanthocyanidins are the main body of polyphenols in black chokeberry. From the distribution point of view, the proanthocyanidins of black chokeberry mainly exists in pomace[17], and the content of proanthocyanidins in fruit juice is relatively low. From the perspective of monomer types, due to the different degree of polymerization, the composition of this component is complex and has a wide variety. Therefore, it is difficult to detect the monomer with the high degree of polymerization. According to the characteristic that its self-oxidation product is cyanidin, it can be determined that these proanthocyanidins should be procyanidins[18].Except that less content of procyanidin B2belongs to oligomeric proanthocyanidins (the degree of polymerization ≤ 4), others are polymeric proanthocyanidins (the degree of polymerization > 4)[19].The content of these polymeric proanthocyanidins in fresh fruit can reach 4 790 mg/100 g[10]. The study found that the content of proanthocyanidins in black chokeberry with degree of polymerization less than 4 was 27.94 mg/100 g FW, the content of degree of polymerization 4−6 was 40.32 mg/100 g FW, the content of degree of polymerization 7−10 was 52.87 mg/100 g FW, and the content of degree of polymerization greater than 10 was 542.60 mg/100 g FW,which made the polymeric proanthocyanidins in black chokeberry can account for more than 89% of the total proanthocyanidins[13]. On this basis, we have to pay attention to the effect of this component on the body after human intake. According to the existing research,we can know that proanthocyanidins will decrease their antioxidant and other functional activities with the increase of their degree of polymerization[20]. In addition, these polymeric proanthocyanidins are difficult to be absorbed by the human body due to the large molecular size of polymeric proanthocyanidins and gut barrier. Therefore, its main functional activities should be reflected in the digestive system,such as the interaction with digestive enzymes[21]. A large number of proanthocyanidins form non-covalent bonds with amylase and lipase in the digestive tract, which inhibits the activity of these digestive enzymes. It is possible for black chokeberry to inhibit the increase of blood glucose and fat digestion and absorption. In addition, except that a small part of these polymeric proanthocyanidins is metabolized in the intestine, the rest will enter the colon and act on the intestinal flora. Then they are degraded into phenylvalerolactones and phenolic acids by intestinal flora[19]. However, whether the effect on intestinal flora is positive is what remain to be studied.

2.1.2 Anthocyanins

Anthocyanins are another flavonoid components in black chokeberry, which are also the main source of fruit color. From the distribution in the fruit, the content of anthocyanins in pomace was higher than that in juice[22-23]. Different from blueberry and other berries, the inner pulp and juice of black chokeberry are also red,which indicates that anthocyanins not only exist in its purple peel,but also in its interior. According to the paraffin section of black chokeberry fruit (Fig. 2), anthocyanins were distributed in all parts of the fruit (except the core), and the anthocyanin content gradually increased with the fruit from the inside to the outside. The content of total anthocyanins in different varieties of black chokeberry was also significantly different. At present, it was found that the variety with the highest total anthocyanin content was “Viking” in black chokeberry. In addition, purple chokeberry also possesses high anthocyanin content[10].

Fig. 2 Paraffin section of black chokeberry fruit.

The anthocyanidin in black chokeberry is single, which is cyanidin. These cyanidins combine with four different sugars through glycosidic bonds to form anthocyanins. They are cyanidin-3-Ogalactoside, cyanidin-3-O-arabinoside, cyanidin-3-O-glucoside and cyanidin-3-O-xyloside, respectively. Among them, cyanidin-3-Ogalactoside and cyanidin-3-O-arabinoside are the main glycosides,while the other two glycosides are low in content[10,24-25]. Brand et al.[26]detected the anthocyanins in black chokeberry produced in same region for two consecutive years and found that the proportion of cyanidin-3-O-galactoside in the total anthocyanins was 65.4% and 71.7% respectively. Veberic et al.[27]also showed that the content of cyanidin-3-O-galactoside could account for 62.6% of total cyanidin content. The content of cyanidin-3-O-galactoside in such a high proportion was significantly different from other anthocyanin rich berries. Some studies have found that it contains few pelargonidin-3-O-arabinoside[13,27]. Yang et al.[16]found delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside in black chokeberry, which has not been reported in other studies. In addition, few studies have also detected some uncommon anthocyanin-(epi)catechin complexes in black chokeberry, but the content of these compounds is very low and difficult to detect[28]. Some studies on the hypoglycemic effect found that the cyanidin-3,5-diglucoside in black chokeberry juice had an obvious effect on lowering blood glucose[29]. However, it is worth noting that so far, cyanidin-3,5-diglucoside has not been detected in the analysis of polyphenols in black chokeberry. This kind of product was found in the processed juice of black chokeberry[29-30].Therefore, the formation of cyanidin-3,5-diglucoside should be caused by the further glycosylation of cyanidin glycosides during thermal processing.

The effects of anthocyanins in black chokeberry on the human body are mainly in two aspects. On the one hand, anthocyanins and their metabolites effectively absorbed would act on different organs of the human body with the flow of blood. On the other hand, the unabsorbed part would act on enzymes, intestinal flora and intestinal epidermal cells in the digestive tract. After black chokeberry is ingested, a small part of these anthocyanins will be hydrolyzed into aglycones which are further degraded into phenolic acids and aglycones under the action of pH and enzymes in the mouth[31]. Then it enters the stomach. Due to the low pH, these anthocyanins are relatively stable and partially absorbed in the stomach. However,after entering the small intestine, anthocyanins will be largely decomposed into phenolic acids and aldehydes[32]. Some studies have found that the degradation products of cyanidin glycoside derivatives are mainly protocatechuic acid and 2,4,6-trihydroxybe nzaldehyde[33]. These degradation products and some anthocyanins are absorbed by intestinal epithelial cells through passive diffusion and active transport. The unabsorbed part will enter the colon and regulate the intestinal flora. In fact, due to the low absorption rate of cyanidin glycosides in human body, the regulation of black chokeberry anthocyanins on intestinal microflora is one of its main functional activities[34-35].

2.1.3 Flavonols

Flavonols are one kind of flavonoids with the lowest content in black chokeberry. However, it has been widely studied by scholars in recent years because of its great biological activity[36]. The content of flavonols in black chokeberry was much lower than that of flavanols or anthocyanins. Quercetin is the main flavonols in black chokeberry. These quercetins have good water solubility because they combine with sugar molecules to form quercetin glycosides.At present, it is widely confirmed that quercetin glycosides in black chokeberry mainly include quercetin-3-O-rutinoside,quercetin-3-O-galactoside and quercetin-3-O-glucoside[37]. For the binding of quercetin glycosides, the conclusions are slightly different in different studies. On the basis of the binding types of the above three glycosides, Slimestad et al.[15]found a small amount of quercetin-3-O-vicianoside, quercetin-3-O-robinobioside and eriodictyol-glucuronide in the black chokeberry. This conclusion was later confirmed by Teleszko et al.[38]. With the deepening of research,researchers have found more flavonols such as glycoside derivatives of kaempferol and isorhamnetin in black chokeberry[14,28]. However,the content of these substances is low and uncommon, so whether they have special functional activities remained to be studied.

After ingestion, most of these quercetin glycosides are metabolized in the digestive tract, and a small amount will enter the blood. After entering the stomach, it can be partially degraded into protocatechuic acid and other phenolic acids under the action of gastric acid[39], and these phenolic acids can be partially absorbed in the stomach[40]. After entering the small intestine, the undegraded quercetin glycoside can be glucuronized andO-methylated under the action of uridine diphosphate glucuronosyltransferases and catechol-O-methyltransferase. Under the action ofβ-glucosidase, part of quercetin glycosides will be deglycosylated to quercetin[41]. It is found that these quercetin glycosides and their metabolites will enter human organs and be further metabolized after being absorbed[42].

2.2 Phenolic acid

In terms of phenolic acids, chlorogenic acid and neochlorogenic acid are the main components in black chokeberry[37,43-44],accompanied by a small amount of cryptochlorogenic acid and caffeic acid[28,45]. These phenolic acids usually present in the fruit in free form. From the distribution point of view, they mostly exist in juice,which benefits from their good water solubility. With the deepening of research, researchers have also foundp-hydroxycinnamic acid,protocatechuic acid and 3-O-p-coumaroylquinic acid in fruit, but they have not been widely studied because of their low content[16,28].

Although the absorption rate of chlorogenic acid and its isomer neochlorogenic acid after entering the human body is much lower than that of phenolic acids with simpler molecular structure such as caffeic acid[46]. However, the study showed that the total content of chlorogenic acid and neochlorogenic acid in black chokeberry could reach 1 498.06 mg/100 g DW[28]. Considering that it’s content in black chokeberry is much higher than that of caffeic acid, protocatechuic acid and other phenolic acids. This makes us still focus on chlorogenic acid and neochlorogenic acid when we study their biological activities.Some studies have found that phenolic acids such as chlorogenic acid have obvious antioxidant activity and can improve the microbiota-gut-brain axis related diseases by regulating intestinal flora. This provides a lot of potential value for the further study of the regulatory effect of black chokeberry on human health[47-48].These phenolic acids can be absorbed in small amounts in the gastrointestinal tract and enter the blood[49]. Due to the poor excretion of absorbed phenolic acids in bile or intestinal cavity,their bioavailability depends more on the content of phenolic acids absorbed into intestinal mucosa[46]. These chlorogenic acids and their isomers are formed by combining caffeic acid esters with quinic acid. Since there is no esterase that can release caffeic acid from chlorogenic acid in human tissues, chlorogenic acid is relatively stable in the gastrointestinal tract[50], and only a small amount of metabolite quinic acid is produced[51]. After entering the colon, chlorogenic acid will be degraded to quinic acid and caffeic acid under the action of intestinal microorganisms. Quinic acid will be further converted to hippuric acid, and caffeic acid will be converted to hydrocaffeic acid and hydroferulic acid under the action of hydrogenases and dehydroxylases[51]. These chlorogenic acids and neochlorogenic acids generate a large number of new phenolic acids through degradation,such as caffeic acid, which not only has better bioavailability, but also still has a large number of functional activities. The unabsorbed part will act on the regulation of intestinal flora. In addition, because these phenolic acids and their metabolites have good water solubility,some of them will be discharged with urine after entering the human body[52]. This has a good effect on the human urinary system, such as preventing urinary tract infection[53].

3. Pharmacological activity

3.1 Hyperlipidaemia and obesity

Hyperlipidemia and obesity can be caused by many factors,such as metabolic syndrome, genetics, bad living habits and other factors[54-55]. Black chokeberry polyphenols can reduce blood lipid and inhibit obesity. At all stages much fat intake, it will be inhibited by black chokeberry polyphenols. As showed in Fig. 3, this includes the inhibition of pancreatic lipase activity in the digestion stage, the inhibition of cholesterol absorption by small intestinal epithelial cells in the absorption stage and the inhibition of adipogenesisin vivo. It is precisely because of its role in different stages that black chokeberry polyphenols have excellent weight loss and lipid-lowering effect. Reducing blood lipid of black chokeberry polyphenols is of great significance for the development of cardiovascular and cerebrovascular diseases[56]. Kim et al.[57]investigated the effect of black chokeberry polyphenols on blood lipid regulation in patients with cardiovascular and cerebrovascular diseases by knocking out mice with the apolipoprotein E gene. They found that plasma cholesterol in mice decreased significantly after continuous intake of black chokeberry extract for 4 weeks.

Fig. 3 Polyphenols of black chokeberry inhibit the digestion, absorption and production of fat in human body.

In the stage of fat digestion, black chokeberry polyphenols can effectively inhibit the digestion of fat in the intestine. Takahashi et al.[58]found that a large number of polyphenols in black chokeberry can effectively inhibit pancreatic lipase activity, so as to reduce fat absorption and visceral fat accumulation by using the mouse model of high-fat diet. On this basis, Worsztynowicz et al.[59]found that methanol and acetic acid extracts rich in anthocyanins components of black chokeberry had a significant inhibitory effect on lipase activity.It was found that cyanidin-3-O-glucoside had the most obvious inhibitory effect on lipase activity. Sosnowska et al.[21]fractionated the polyphenol extract of black chokeberry and investigated the inhibitory effects of different fractions on pancreatic lipase activity. It was found that the aqueous fraction rich in anthocyanins and polymeric proanthocyanidins had higher inhibitory ability on pancreatic lipase than the ethyl acetate fraction mainly composed of flavonol, phenolic acid and oligomeric proanthocyanidins.

Kim et al.[60]used Caco-2 cells to simulate the inhibition of black chokeberry polyphenol extracts on cholesterol absorption in the small intestine, and found that black chokeberry polyphenol could effectively reduce the gene expression of cholesterol uptake at the top and cholesterol outflow at the bottom of cells, which shows that the polyphenols of black chokeberry could effectively reduce the absorption of cholesterol in the small intestine. In addition,these polyphenols also significantly induced the mRNA and protein expression levels of ABCG5 and ABCG8, and mediated the outflow of cell top cholesterol to the intestinal cavity.

In recent years, researchers have paid more and more attention to the effect of gut microbiota on obesity. Some studies have found that the gut microbiota interferes with body weight by affecting the efficiency of the calories obtained from the diet, and how this harvested energy is used and stored[61]. Further studies showed that there was a significant negative correlation between reducing the Firmicutes/Bacteroidetes ratio (F/B ratio) and obesity[62]. Because a large amount of polyphenols in black chokeberry can reach the colon after ingestion, it has a strong regulatory effect on gut microbiota.The most obvious is that it can significantly increase the diversity of gut microbiota and reduce the F/B ratio[63]. Gao et al.[64]found throughin vitrodigestion and fermentation experiments that the anthocyanins of black chokeberry after digestion could significantly reduce the F/B ratio. In anin vivoexperiment to investigate the effect of black chokeberry polyphenols extracts on rats fed a high-fat diet,Zhu et al.[65]found that the intake of black chokeberry polyphenols could regulate the composition of gut microbiota. Including reduced the F/B ratio, and increased the relative abundance ofBacteroides,Prevotella,Akkermansiaand other bacteria related to anti-obesity properties. At the same time, black chokeberry polyphenols could significantly reduce obesity, liver steatosis and improve dyslipidemia in rats fed with high-fat diet.

On the one hand, the increase of body fat is due to the intake of fat. On the other hand, the intake of high sugar can also be transformed into fat in the body, and intake of black chokeberry polyphenol extracts can effectively inhibit the production of fat in the body.Qin et al.[66]induced weight gain in rats through a high fructose diet and intervened with black chokeberry polyphenol extracts. It was found that the intake of black chokeberry polyphenols could significantly reduce the contents of triglyceride, cholesterol and low-density lipoprotein. Kim et al.[6]fractionated the polyphenol components of black chokeberry and prepared 7 polyphenol component monomers. Through the treatment of mouse 3T3-L1 adipocyte,it was found that amygdalin, prunasin, cyanidin and caffeic acid derivatives could inhibit PPARγ (peroxisome proliferator-activated receptor γ) and C/EBPα (CCAAT enhancer binding protein α),SREBP1c (sterol regulatory element binding protein 1c), FAS (fatty acid synthase) and aP2 (adipocyte fatty-acid-binding protein). In addition, they intervened the obesity induced by high-fat diet in mice by using the black chokeberry extracts, and found that the body weight, serum triglyceride and low-density lipoprotein cholesterol levels of mice were significantly reduced.

Nonalcoholic fatty liver disease (NAFLD) is a disease related to lipid metabolism. After intake of high-fat and high sugar diet,mice with NAFLD were treated with black chokeberry freeze-dried powder. The fat production in mice was limited by the polyphenols of black chokeberry, and the total cholesterol decreased significantly.The decrease of total cholesterol was accompanied by the changes of mRNA expression related to hepatocyte adipogenesis and TG level: SREBP1, acetyl CoA carboxylase (ACC) and FAS[67]. Black chokeberry powder with a dose of 50 mg/(kg∙day) could effectively improve the liver lipid metabolism of C57BL/6N mice fed a high-fat diet (60% energy comes from lard). The improvement of lipid metabolism is manifested in preventing lipid accumulation and reducing the increase of liver weight. Intake of black chokeberry juice could reduce the expression of genes related to liver lipid metabolism and PPARγ2 protein level. PPARγ2 is a factor that regulates the transcription of adipocyte protein 2 (aP2) binding free fatty acids and lipoprotein lipase (LPL) target genes. The expression levels of aP2 and LPL decreased significantly, indicating that black chokeberry fruit powder passed through PPARγ2 dependent pathway affects liver lipid metabolism. In addition, under the influence of free fatty acids,mouse hepatocytes increased the expression of genes related to lipid metabolism and lipid accumulation. The inhibition rates of lipid by the intake of 40 and 80 μg/mL extracts were 7% and 33.4%, respectively.They also limit the mRNA expression ofPPARγ2,aP2andLPLin hepatocytes[58,68]. The researchers found that black chokeberry polyphenols could enhance the utilization of glucose, promote the synthesis of liver glycogen, inhibit liver gluconeogenesis and reduce blood glucose. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was activated by black chokeberry extracts through the elevation of insulin receptor substrate-2, PI3K, Akt, and glycogen synthase kinase-3β (Gsk3β) phosphorylation and glucose transporter 2. These might contribute to the promotion of glycogen synthesis and improvement of hepatic insulin resistance[69]. As the main component of anthocyanins in black chokeberry, cyanidin-3-O-galactoside can inhibit obesity through another mechanism. As an important regulator of energy balance, adenosine 5’-monophosphate(AMP)-activated protein kinase (AMPK) is a molecular target for the treatment of obesity and other metabolic diseases[70]. By intervening in the rat obesity model induced by high-fat diet, the researchers found that the intake of cyanidin-3-O-galactoside could reduce the obesity of rats by promoting the AMPK.

In clinical studies, it was found that the long-term intake of black chokeberry as a nutritional supplement could significantly maintain the healthy level of blood lipid. Kardum et al.[71]conducted a clinical intervention experiment on 20 menopausal women with abdominal obesity, aged between 45 and 65. The experiment lasted for 4 weeks.During this period, each person drank 100 mL of black chokeberry juice containing 2 g glucomannan fiber every day. After 4 weeks, the plasma high-density lipoprotein content of these people was lower than that in the initial stage, which shows that black chokeberry juice could effectively reduce the function of female blood lipid.

It should be noted that for healthy people, black chokeberry did not show the ability to reduce blood lipid and body fat. Kardum[72]in the intervention experiment of black chokeberry in healthy population,29 healthy women aged between 25 and 49 were selected. Each person takes 100 mL of unprocessed black chokeberry juice every day as a nutritional supplement. After 12 weeks, the physical examination of these 29 people found that their body mass index, weight and waist circumference had not changed. Their blood samples showed that there was no change in blood lipid parameters such as triacylglycerol,total cholesterol, low-density lipoprotein and high-density lipoprotein,which illustrated that the intake of black chokeberry had no effect on body fat and blood lipid in healthy people. However, different experimental results also appear in healthy smokers. In the clinical observation of 49 healthy volunteers who smoked, Xie et al.[73]found that the levels of total cholesterol and low density lipoprotein in volunteers’ serum decreased significantly after ingesting 500 mg of black chokeberry extracts every day for 12 weeks. Through the detection of polyphenol components in urine, it was found that the metabolites peonidin-3-O-galactoside, 3-(4-hydroxyphenyl) propionic acid, and unmetabolized cyanidin-3-O-galactoside were most related to the decline of these two indexes.

Hypertension is usually accompanied by hyperlipidemia and other symptoms. Kardum et al.[74]selected 23 volunteers with normal blood pressure and mild hypertension with an average age of 47.5 years,including 12 males and 11 females. A 4-week intervention experiment was carried out. During the experiment, each person consumed 200 mL of black chokeberry juice every day. Through the collection and analysis of volunteers’ plasma after 4 weeks, it was found that the content of triacylglycerol in their plasma decreased significantly,which demonstrates that black chokeberry juice had an obvious antihyperlipidemic effect on people with normal blood pressure and mild hypertension.

Sikora et al.[75]used black chokeberry extract as a nutritional supplement for patients with metabolic syndrome. In this experiment,70 people were volunteers. One group was consisted of 25 patients with metabolic syndrome aged between 50 and 69 who had not been treated with drugs. The control group was consisted of 45 volunteers aged between 55 and 71, including 20 healthy volunteers and 25 patients with metabolic syndrome who had received drug treatment.These volunteers received a 2-month clinical intervention experiment of black chokeberry extract, and each person ingested 100 mg of black chokeberry extract three times a day. The results showed that the contents of total cholesterol and low density lipoprotein decreased significantly in these patients with metabolic syndrome.Sikora et al.[76]conducted a 40 days clinical intervention on 38 patients with metabolic syndrome and 14 healthy volunteers with 10% ethanol extract of black chokeberry, during which each person ingested 30 mL every day. The ages of these people are between 42 and 65. The results showed that long-term intake of black chokeberry extract could reduce the levels of triglyceride, total cholesterol and LDL. However, same as the test results of Sikora et al.[75-76], the extract of black chokeberry failed to affect the body mass index and waist circumference of patients with metabolic syndrome, which illustrates that black chokeberry has a good effect on reducing blood lipid in patients with metabolic syndrome, but it does not show the effect of weight loss.

Hypercholesterolemia is not only a familial genetic disease, but also a lipid metabolism disease, which can lead to the abnormal increase of low-density lipoprotein cholesterol (LDL-C) in patients’ plasma. Clinical studies have found that black chokeberry had an obvious regulatory effect on blood lipid in patients with hypercholesterolemia. Duchnowicz et al.[77]conducted a human trial on 25 patients with hypercholesterolemia and 20 healthy volunteers.The trial lasted for two months. Each person ingested 100 mg black chokeberry extract three times a day. The results showed that the total cholesterol content of red blood cells decreased significantly.Similarly, Lancrajan et al.[78]found that the contents of triacylglycerol,total cholesterol and LDL in the plasma of patients with hypercholesterolemia, arterial hypertension and protein metabolism disorder decreased significantly after 40 days of intervention with black chokeberry extracts.

In fact, black chokeberry can interfere with human blood lipids and body weight in multiple dimensions, which includes digestion,absorption and synthesis of fat and metabolism of energy. The completion of this series of complex biochemical reactions depends not only on its high content of polyphenols, but also on its diversity of polyphenols.

3.2 Hypertension

Hypertension is a complex cardiovascular disease characterized by elevated arterial blood pressure. Its formation is affected by many factors, including renin angiotensin aldosterone system, sympathetic nerve, vascular dysfunction, inflammation, oxidative stress and so on. Long-term hypertension will cause damage to target organs such as blood vessels, heart and kidney. The injury of target organs will further promote the increase of blood pressure. For a long time, it has been found that black chokeberry and its products have the effect of reducing blood pressure. With the deepening of the research on black chokeberry, researchers found that a large number of polyphenols and non-polyphenols in black chokeberry could effectively reduce human arterial blood pressure and have obvious curative effect on alleviating the symptoms of patients with hypertension. Previous studies have shown that cyanidins could effectively reduce blood pressure. Most of the anthocyanins in black chokeberry are cyanidins, which exist in the form of binding different sugar molecules (including galactose,arabinose, glucose and xylose). In addition, chlorogenic acid, as the main component of phenolic acid in black chokeberry, also possess anthypertension function. As showed in Fig. 4, different from traditional antihypertensive drugs, the functional components of black chokeberry can produce the effect of reducing blood pressure from multiple pathways.

Fig. 4 Mechanism of black chokeberry polyphenols inhibiting the increase of blood pressure. Black is the inhibitory effects; blue is the promoting effect.

Ćujić et al.[8]evaluated the effect of long-term consumption of black chokeberry extracts on anthypertension by using the spontaneously hypertensive rat model. It was found that the systolic and diastolic blood pressure of spontaneously hypertensive rats decreased significantly after intake of black chokeberry extracts for 4 weeks. Through the detection of daily urine volume, it was found that the daily urine volume of rats fed with black chokeberry extracts for a long time was significantly higher than that of the control group,which showed that the black chokeberry extracts could play the role of diuretics, and the use of diuretics to increase micturition was also one of the common methods to reduce blood pressure in the clinic. In addition, a large number of polyphenols in the extracts have strong antioxidant activity and could effectively remove free radicals in the body. It was found that thiobarbituric acid reactive substances(TBARS) decreased significantly and FRAP value increased significantly after intake of black chokeberry extracts. At the same time, detection found that the superoxide dismutase (SOD) activity in the rat model decreased. The researchers believed that this was because the reactive oxygen species (ROS) in the body was largely cleared by the polyphenols in the black chokeberry extracts, resulting in the body reducing the enzyme activity in order to save energy when it is not needed. These results showed that black chokeberry polyphenols could effectively reduce lipid peroxidation in blood, so as to effectively reduce blood pressure of spontaneously hypertensive rats by inhibiting oxidative stress. For the mechanism of oxidative stress leading to hypertension, some studies have showed that the increase of ROS levelin vivowill inhibit dihydrofolate reductase(DHFR) activity and improve the level of mitochondria-derived reactive oxygen species (mito-ROS). This will lead to vascular dysfunction and hypertension[79-81].

Vascular dysfunction is an important factor in the increase of blood pressure, and endothelial progenitor cells have the function of repairing damaged blood vessels. A large amount of angiotensin II in patients with hypertension will accelerate oxidative stress, induce endothelial progenitor cell aging and inhibit its growth, so as to damage the repair of endothelial progenitor cells and damaged vascular function. Parzonko et al.[82]found that the black chokeberry extracts could inhibit the oxidative stress caused by angiotensin II, so as to protect endothelial progenitor cells. In the experiment, compared with vascular endothelial progenitor cells treated with angiotensin II only,the growth rate and telomerase activity of cells exposed to non black chokeberry extracts before angiotensin II treatment were significantly increased, while the content of ROS in cells was significantly reduced.In addition, chokeberry extracts also improved the migration ability and angiogenesis potential of endothelial progenitor cells. By inducing the expression of nuclear factor erythroid 2-like 2 (Nrf2) transcription factor in endothelial progenitor cells, black chokeberry extracts could improve the level of heme oxygenase 1 (HO-1) in endothelial progenitor cells, which could not only protect endothelial progenitor cells from oxidative stress, but also enhance the regeneration ability of endothelial progenitor cells to damaged blood vessels. Ciocoiu et al.[83]also found that black chokeberry extracts, as an antioxidant, could effectively protect the integrity of vascular endothelium, which also verified the research results of Parzonko et al.[82]to a certain extent.

As a vasodilator in the vascular system, nitric oxide (NO) can reduce the contraction of vascular smooth muscle cells, so as to expand blood vessels and reduce blood pressure. Some studies have found that the antihypertensive effect of black chokeberry comes from promoting the production of NO.N’-nitro-L-argininemethylesterhydrochloride (L-NAME), as an inhibitor of NO synthase,could inhibit the production of endogenous NO and cause endothelial dysfunction. Therefore, researchers often useL-NAME to induce the increase of blood pressure in mice to build the animal model of hypertension. Cebova et al.[84]used theL-NAME mice model to explore the antihypertensive effect of black chokeberry extracts. After 3 weeks, the blood pressure of hypertensive mice was significantly lower than that of the control group not treated withL-NAME. This showed that black chokeberry could alleviate the inhibitory effect ofL-NAME on NO production, effectively improve the activity of NO synthase, and thus inhibit the increase of blood pressure[85].The same phenomenon is also reflected in endothelial cells of other animals. Kim et al.[86]simulated endothelial dysfunction by inducing contraction of porcine coronary endothelial cells withL-NAME.Black chokeberry juice caused the potent endothelium-dependent relaxations in porcine coronary artery rings, which is mainly owing to that cyanidins and chlorogenic acid in black chokeberry juice can phosphorylate endothelial nitric oxide synthase (eNOS) by redox-sensitive activation of the Src/PI3-kinase/Akt pathway.By treating bovine coronary artery endothelial cells with black chokeberry extracts, the researchers found that low-dose black chokeberry extracts (0.1 μg/mL) for 10 min could significantly improve the synthesis of NO and the phosphorylation of eNOS. When the treatment time reached 48 h, black chokeberry extracts could significantly increase the sensitivity of eNOS[87].

The activation of the renin angiotensin system (RAS) is also an important cause of hypertension, and inhibition of this system pathway can effectively reduce blood pressure. As one of the widely used antihypertensive drugs, angiotensin converting enzyme (ACE)inhibitor uses this mechanism to inhibit the increase of blood pressure.Yamane et al.[88]found throughin vitroexperiments that water extracts of black chokeberry had the strong inhibitory effect on the activity of ACE, so as to reduce the production of angiotensin II. Angiotensin II could promote vasoconstriction and increase blood pressure. On this basis, Yamane et al.[88]investigated the antihypertensive function of spontaneously hypertensive rats by intake of black chokeberry freeze-dried powder. Compared with the control group, the blood pressure of rats fed with 10% black chokeberry freeze-dried powder was significantly lower than that of the control group after 28 days of continuous intake. Through the determination of serum, lung and kidney of rats, it was found that the activity of ACE in kidney of rats was significantly lower than that in the control group after 28 days of intake of black chokeberry freeze-dried powder, while the activity of ACE in plasma and lung did not decrease. This showed that after ingesting the black chokeberry freeze-dried powder, the functional components in black chokeberry could effectively inhibit the activity of ACE in the kidney of spontaneously hypertensive rats,so as to reduce the production of angiotensin II in the kidney, inhibit the activation of RAS, and inhibit the occurrence of hypertension.The significance of inhibition of ACE activity is far more than reducing the contraction of vascular smooth muscle cells. A large number of cardiovascular and cerebrovascular studies have showed that angiotensin II produced by ACE could promote NADPH oxidase X1/2/4 to produce a large amount of ROS, which further aggravates oxidative stress[79,89-92]. In addition, angiotensin II will also promote the secretion of aldosterone in the body, so as to increase the reabsorption of water by renal tubules, and further increase blood pressure. However, Hellström et al.[93]treated ACE with black chokeberry juice and extracts of viking varietyin vitro, and the results showed weak ACE-inhibitory activity. However, in the followupin vivoexperiments, it was also found that this variety of black chokeberry had a significant antihypertensive effect on spontaneously hypertensive rats. In RAS system, the inhibition of renin can also inhibit the increase of blood pressure. Ciocoiu et al.[94]found that the intake of black chokeberry extracts could effectively reduce the blood pressure of hypertensive rats, and the effect of reducing blood pressure is more obvious when these extracts are combined with renin inhibitors. Although this does not indicate that black chokeberry polyphenols have an inhibitory effect on renin, these polyphenols can be used as a combination of renin inhibitors to reduce blood pressure.

A large number of clinical studies also showed that black chokeberry had a significant effect in reducing blood pressure, and could be used as a nutritional supplement to assist in reducing blood pressure[95]. However, clinical data show that due to different users,there will be some differences in the antihypertensive effect of black chokeberry. In general, black chokeberry polyphenols have a certain effect on reducing blood pressure in patients with hypertension,metabolic syndrome and obesity, but it can not cause significant change of blood pressure in healthy people[96].

Kardum et al.[74]observed 23 healthy volunteers and patients with one grade hypertension for 4 weeks, including 12 males and 11 females, with an average age of 47.5 years. During the observation period, each person consumed 200 mL of black chokeberry juice every day. Through the detection of systolic and diastolic blood pressure, it was found that black chokeberry juice could effectively reduce the diastolic and systolic blood pressure of patients for 24 h.However, Loo et al.[97]did not found a significant decrease in blood pressure through 16 weeks of black chokeberry juice intake in the clinical observation of patients with mild hypertension of higher age.

Metabolic syndrome is often accompanied by an abnormal increase of blood pressure, and black chokeberry had obvious antihypertensive effect on this disease[98]. Kardum et al.[71]used 100 mL black chokeberry juice containing glucomannan fiber as a nutritional supplement to 25 postmenopausal women with abdominal obesity every day. After 4 weeks, they found that their systolic blood pressure decreased significantly, but their diastolic blood pressure did not change significantly. The same phenomenon also occurs in the clinical observation of patients with metabolic syndrome.Sikora et al.[75]used the black chokeberry extract to intervene in 25 patients with metabolic syndrome. After ingesting 100 mg three times a day for two consecutive months, the patient’s systolic blood pressure decreased significantly, but the diastolic blood pressure did not change significantly. In addition, it was found that the activity of ACE decreased significantly, which showed that the black chokeberry extract could reduce the contractile effect of angiotensin on arterial vessels and then reduce arterial blood pressure by reducing the activity of ACE in the blood of patients with metabolic syndrome.Another clinical observation for 25 patients with metabolic syndrome and 22 healthy volunteers found that 100 mL of black chokeberry juice was taken 3 times a day. After 2 months, the patient’s systolic blood pressure decreased significantly, while the diastolic blood pressure decreased slightly but not significantly. In this study,the researchers analyzed the patient’s plasma and found that after intervention with the black chokeberry juice, the level of endothelin-1(ET-1) in the plasma decreased significantly. As a factor that acts on vasoconstriction, the decrease of ET-1 content could effectively lower blood pressure, which proves that black chokeberry polyphenols reduces blood pressure in patients with metabolic syndrome not only by regulating RAS, but also by regulating the content of ET-1 to reduce blood pressure[99].

Through clinical experiments on healthy people, it is found that the intake of black chokeberry will not affect the normal blood pressure. Kardum et al.[72]conducted human experiments on 29 healthy women aged 25−49 years old and found that they consumed 100 mL of black chokeberry juice every day for 12 weeks. After the volunteers’ systolic and diastolic blood pressure did not change significantly. This showed that healthy people would not have an adverse effect on human blood pressure after ingesting an appropriate amount of black chokeberry and related products.

Hypertension, as a common disease in middle aged and older people, can be caused by many factors. At present, the drugs for the treatment of hypertension mainly include calcium antagonists(CCB), diuretics, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARB), β receptor blockers (BB), α receptor blocker (AB).Regulating sodium metabolism and vasodilation is the most effective way to reduce blood pressure, and it is also the main mechanism of antihypertensive drugs. Due to the single effect of these drugs,several drugs are often used together in clinical application. In addition, long-term drug intake also brings more and more negative effects to the human body. Due to the rich variety of antihypertensive functional components, black chokeberry can regulate human blood pressure from various channels, so it can more effectively deal with the abnormal increase of blood pressure caused by different factors.This provides more possibilities for it as a functional food to assist in lowering blood pressure.

3.3 Hyperglycaemia

In the aspect of inhibiting the increase of blood glucose, the black chokeberry polyphenols also showed obvious effect[100]. This inhibition is mainly manifested in two aspects. On the one hand,black chokeberry polyphenols can effectively inhibit the hydrolysis of starch in the digestive tract, so as to reduce and slow down the level of glucose entering the human body. Worsztynowicz et al.[59]extracted polyphenols from black chokeberry with different solvents,and evaluated the effects of different extracts on polyphenolsin vitroinhibition ofα-amylase activity. The results showed that the methanol extracts rich in chlorogenic acid and cyanidins had the strongest inhibitory effect on amylase activity. The main contribution comes from chlorogenic acid. Momoko et al.[101]further found that chlorogenic acid and cryptochlorogenic acid in black chokeberry juice could be inhibited byα-glucosidase reduces the absorption of glucose in the intestine. These inhibitory effects onα-glucosidase were mainly concentrated in the upper region of the small intestine[102].

On the other hand, the hypoglycemic effect of black chokeberry is to inhibit the expression of related genes such as insulin resistance and metabolic syndrome. Through cell experiment, it was found that the anthocyanin extracts of black chokeberry could improve insulin sensitivity and glycogen synthesis by downregulatingSOCS3gene[103].Hypoglycemic mechanism of black chokeberry was mainly found through a large number of animal experimentsin vivo. In an animal experiment, the blood glucose level of insulin resistant rats decreased significantly after receiving the black chokeberry extracts at the dosage of 100 and 200 mg/kg for 8 weeks[104].

In another experiment of rats receiving a high fructose diet,the researchers significantly reduced the blood glucose level and improved the lipid distribution of rats at the dosage of 100 and 200 mg/kg black chokeberry extracts[66]. The simultaneous reduction of blood glucose levels and insulin levels may be due to the elimination of insulin resistance. This effect was confirmed by mRNA level in adipose tissue of rats receiving black chokeberry extracts.Inhibition ofGsk3βmRNA expression induces insulin resistance in adipose tissue. Increased adiponectin mRNA levels could effectively increase insulin sensitivity. Insulin dependent metabolic pathways,glucose uptake and carbohydrate metabolism in adipose tissue also lead to increasing gene expression. Adipose tissue proliferation and dysfunction are caused by fatty diseases. Peroxidation is the main regulator of adipogenesis enzyme body PPARγ. The reduced expression of is involved in glucose metabolism and energy balance,which could lead to insulin resistance. Black chokeberry extracts increases mRNA expression ofPPARγand inhibit the expression of genes related to metabolic syndrome, insulin resistance,hyperglycemia and dyslipidemia. Because of its inhibitory effect on insulin resistance, black chokeberry can be used as an adjunctive food for type 2 diabetes. A large number of researchers have also found that cyanidin-3,5-diglucoside, cyanidin-3-O-glucoside,quercetin, chlorogenic acid and cryptochlorogenic acid in black chokeberry juice could be used as an effective dipeptidyl peptidase IV(DPP IV) inhibitor[101]. These inhibitors could inhibit the activity of DPP IV, thereby delaying the degradation of intestinal peptide glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP)by DPP IV[29,101,105-107]. These peptides could stimulate more secretion of pancreatic insulin after eating, so as to maintain the normal level of blood glucose.

The regulation of blood glucose by black chokeberry can be used as an effective auxiliary hypoglycemic food. In clinical research,black chokeberry showed different hypoglycemic effects for different types of patients. Long-term intake of black chokeberry can effectively reduce the blood glucose level of patients with metabolic syndrome, but it has no effect on healthy people and patients with other diseases but normal blood glucose level. This targeted hypoglycemic ability makes black chokeberry better as a health food that assists in hypoglycemic.

Lancrajan et al.[78]found through clinical observation of 67 years old patients with hypercholesterolemia, arterial hypertension and protein metabolism disorder that 30 mL of crude extract of black chokeberry per person per day could effectively reduce their blood glucose content after 40 days of continuous intake. However,for the clinical observation of other diseases, it was not found that long-term intervention of black chokeberry could reduce the level of blood glucose. Loo et al.[97]found through the clinical observation of patients with mild hypertension that there was no significant change in blood glucose level of patients with 300 mL black chokeberry juice every day for 8 weeks. Kardum et al.[74]also confirmed that black chokeberry juice failed to reduce the blood glucose level in the 4-week clinical experimental observation of patients with one grade hypertension.

For healthy people, long-term intake of black chokeberry and its products would not reduce people’s blood glucose level. This makes it unnecessary for people to worry about hypoglycemia caused by the intake of black chokeberry. In the clinical observation of 25 healthy female volunteers for three consecutive months, it was found that black chokeberry did not change the blood glucose level of volunteers[108]. And Kardum et al.[71]observed the intake of black chokeberry juice for 4 weeks in women with abdominal obesity. The results showed that there was no change in blood glucose level compared with that 4 weeks ago. But interestingly,in a short-term experiment, the researchers found that ingesting 100 mL black chokeberry juice before meal would effectively reduce the postprandial blood glucose level. This should be due to the inhibition of digestive enzyme activities in the digestive tract by a large number of polyphenols, such as amylase[109].

The effect of black chokeberry on regulating blood glucose has been confirmed by a large number of clinical trials, especially in patients with metabolic syndrome. Through the summary of existing studies, it can be found that the main functional components of its hypoglycemic effect are cyanidin glycoside derivatives and phenolic acids. The hypoglycemic effect of cyanidin has been confirmed by a large number of studies[110]. At present, the research on lowering blood glucose of black chokeberry has not focused on the gut microbiota.However, according to the current research results on the regulation of black chokeberry on gut microbiota, it has the potential to indirectly control the blood glucose level by regulating the gut microbiota to improve the body’s energy storage and utilization[64-65].

3.4 Inflammation

Black chokeberry juice and extracts have obvious immunomodulatory function because they contain a large number of polyphenols such as anthocyanins, proanthocyanidins and phenolic acid and other polyphenols[9,111]. The enhanced immunity are mainly manifested in the inhibition of hepatitis enteritis, and vascular inflammation (Fig. 5). In particular, its high content of anthocyanins can effectively inhibit the occurrence of hepatitis.Yang et al.[112]found on the mouse model of liver injury induced by CCl4that the anthocyanins of black chokeberry could reduce the expression of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1),interleukin-6 (IL-6) and other inflammatory factors. At the same time,anthocyanins of black chokeberry could significantly reduce the liver injury index of mice with hepatic fibrosis, and restore it to the state close to normal mice. Wang et al.[113]investigated the effect of black chokeberry fruit on chronic alcoholic liver injury by ingesting 0.5 and 2.0 g/kg of black chokeberry fruit on mice ingested alcohol. The results showed that the intake of 2.0 g/kg of black chokeberry could effectively reduce levels of interleukin-2 (IL-2), interleukin-4 (IL-4),IL-6, thioesterase 4, fibrinogen-like protein 1 and fibrinogen γ and other inflammatory factors in the liver. In addition, black chokeberry could also prevent alcohol induced chronic liver injury by regulating Nrf2 signaling pathway. In other animal experiment, cyanidin-3-O-galactoside monomer from black chokeberry was used to interfere with high-fat diet rats. The researchers found that compared with the high-fat diet model group, the intake of cyanidin-3-Ogalactoside also could significantly inhibit nuclear factor kappa-B p65(NF-κB p65) in the nucleus, thereby reducing levels of TNF-α, IL-6 and IL-1β of other inflammatory factors[114]. With the deepening of research, researchers used lipopolysaccharide to induce hepatitis in rats. The intake of black chokeberry polyphenols could promote the intestinal barrier function by regulating the intestinal flora of rats,such as increasing the abundance ofLactobacillusand increasing the expression of tight junction protein in intestinal epithelial cells,so as to reduce the absorption of lipopolysaccharide. Due to the decrease of lipopolysaccharide in serum, the expression level of inflammatory factors, such as IL-6, IL-1β, TNF-α, and related mRNA were decreased[115].

Fig. 5 Inhibition of black chokeberry polyphenols on hepatitis, enteritis and vascular inflammation.

In terms of vascular inflammation, black chokeberry polyphenols have anti-inflammatory and vascular protective effects on a variety of vascular inflammation. Intake of peroxynitrite could nitrify fibrinogen in the blood, resulting in vascular inflammation and thrombosis.Bijak et al.[116]found that the polyphenol extract of black chokeberry could effectively inhibit the peroxynitrite-induced nitrative damage of plasma fibrinogenin vitroexperiments. In order to investigate the anti-inflammatory effect of black chokeberry on patients with hypertension, Loo et al.[97]conducted an 8-week intervention experiment with black chokeberry juice in 38 patients with mild hypertension. During the experiment, each person ingested 300 mL black chokeberry juice and 2 g black chokeberry fruit powders every day. It was found that the intake of black chokeberry could reduce blood pressure and alleviate mild inflammation effectively. Through the examination of the patient’s plasma, it is found that intake of black chokeberry could significantly reduce the content of inflammatory factors such as interleukin-10 (IL-10) and TNF-α, and had a tendency to reduce the IL-4 and interleukin-5 (IL-5). In addition, black chokeberry extracts could inhibit the transcription of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) genes stimulated by TNF-α and reduce the expression of adhesion molecules in human aortic endothelial cells(HAECs). The results showed that the adhesion between peripheral blood mononuclear leukocytes and aortic endothelium decreased. In addition, the black chokeberry extract decreased the activity of nuclear transcription factors and the production of ROS in erythrocytes under the influence of TNF-α[117].

In terms of enteritis, Valcheva-Kuzmanova et al.[118]found that black chokeberry extracts could effectively inhibit trinitrobenzene sulfonic acid (TNBS) induced enteritis in mice. Martin et al.[119]found that black chokeberry extracts could inhibit the inflammatory response of mouse splenocytes induced by lipopolysaccharide, mainly through the inhibition of IL-6 by cyanidin-3-O-arabinoside and quercetin in black chokeberry extracts. Kang et al.[120]induced ulcerative colitis in mice by dextran sodium sulfate. Through the therapeutic intervention of black chokeberry polyphenols on mice with ulcerative colitis, it was found that black chokeberry polyphenols could effectively reduce the length of colon, inhibit the production of prostaglandin E2in mice with colitis, and reduce the levels of inflammatory factors such as, such NO, IL-6 and TNF-α in macrophages. The results showed that black chokeberry polyphenols could efficiently ameliorate clinical signs of ulcerative colitis and act as a natural drug for the treatment of ulcerative colitis. In addition, the researchers found that intake of black chokeberry could effectively improve the level of IL-10.In vitro, the researchers found in the follow-up study that the polyphenol catabolites 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylpropionic acid in black chokeberry extract inhibited generation of TNF-α in Jurkat T cells. Therefore, T cell and microbial catabolism mediate the anti-inflammatory effect of black chokeberry in colon to a certain extent[121].

In enhancing immunity, black chokeberry also showed certain activity, which was mainly due to its rich phenolic acids and flavonoids. Handeland[53]hope to use black chokeberry juice to inhibit the incidence rate of urinary tract infection in elderly people.Each 100 mL of black chokeberry juice contains 715 mg of gallic acid equivalent, including polyphenols such as proanthocyanidins,anthocyanins and chlorogenic acid. Statistics on the incidence of urinary tract infections in 236 elderly people in 6 nursing homes in Norway found that the incidence of patients who consumed 89 or 156 mL of black chokeberry juice daily for three months decreased by 38% and 55% respectively.

4. Concluding remarks

Black chokeberry, as a type of berry rich in polyphenols, has many functional activities, which mainly focus on regulating human energy metabolism, stabilizing human blood pressure and improving immune activity. This endows black chokeberry with the function of preventing and treating related diseases. Usually, the factors that cause the same disease come from different aspects. As a food source with multiple functional ingredients, black chokeberry can prevent and cure diseases by acting on different stages or multiple pathways,which could effectively promote the possibility and effect of its treatment for these diseases. However, due to the high content of tannin in black chokeberry, excessive intake will bring diarrhea and other symptoms. Therefore, as an auxiliary therapeutic food, attention should be paid to the control of the daily intake. With the deepening of research, polyphenol monomers and components with high functional activity and disease control in black chokeberry will be gradually screened. This will further clarify the important source of its functional activity. This review will also provide some guiding suggestions for the production of related products of black chokeberry, about which components need to be protected during processing and storage to prevent their oxidative degradation.

In addition, due to the low absorption rate of polyphenols in black chokeberry, a large number of unabsorbed polyphenols and their degradation products enter the colon. These substances will have a certain regulatory effect on gut microbiota, which makes it possible that part of the disease control effect of black chokeberry is caused by its regulation of gut microbiota. According to some current research results, it can be inferred that it can not only achieve the effect of anti-obesity, but also achieve the effect of lowering blood pressure,blood glucose and anti-inflammatory through the regulation of gut microbiota. These regulatory mechanisms include the balance of energy obtained by the body, the regulation of blood pressure by the change of gut microbiota metabolites (short-chain fatty acid), and the regulation of intestinal inflammatory cells and factors by the increase of the proportion of probiotics. At present, there is a serious lack of research in this area. In the future, this aspect can be taken as the research focus of its functional activity mechanism.

Conflicts of interest

Bin Li is an editorial board member forFood Science and Human Wellnessand was not involved in the editorial review or the decision to publish this article. The authors declare no conflict of interest.

Acknowledgment

This work was supported by National Science Foundation of China (31972090).