Bidens pilosa : Nutritional value and benefits for metabolic syndrome

The genus Bidens (Asteraceae) encompasses over 240 different species. One of them is Bidens pilosa L. that is an easy-to-grow perennial, and broadly distributed in tropical and subtropical regions of the world. This plant has been regarded as an edible plant by the Food and Agriculture Organization of the United Nations since 1975, and has been traditionally used as a food and medicine in America, Africa, and Asia. B. pilosa has been claimed to possess active compounds with more than 40 distinct bioactivities. Although considerable progress has been made in studying the phytochemistry and biology of B. pilosa and its compounds over recent years, a critical review of its dietary functions for metabolic syndrome is unavailable. The present review summarizes the nutrition, benefits, phytochemistry, and safety of B. pilosa with respect to metabolic syndrome. As well as highlightingstudies oftheuse of B.pilosa formetabolicsyndrome, scientific evidence regarding the antimetabolic action, mechanism, and application of thisspeciesanditsactivephytochemicalsarediscussed.Thisreviewconsolidatesinfor-mation for further study into the medicinal benefits of the compounds in this plant.


NUTRITIONAL VALUE AND SAFETY
B. pilosa originated from South America and subsequently invaded other regions of the world (Ge, 1990). Taxonomically speaking, it is classified into the Bidens genus, which contains up to 240 species (Table 2) (Karis & Ryding, 1994;Pozharitskaya et al., 2010). B. pilosa is a shortlived perennial herb widespread worldwide. It has lobed, serrate, or separate green opposite leaves, barbed achenes, and white or yellow flowers ( Figure 1) (Bartolome, Villasenor, & Yang, 2013). The whole plant and, particularly, the leaves of B. pilosa are commonly used as ingredients in foods and drinks. The nutritional aspects of B. pilosa are indicated in Table 3 (Alikwe, Ohimain, & Omotosho, 2014). It is rich in phytochemicals, minerals, and essential amino acids (Alikwe et al., 2014). This plant prefers high temperature, full sun, and semidry soil for its propagation. However, it can also grow in arid and barren land at different altitudes (FAO, 1997). B. pilosa can be cultivated via plant cutting or seeds. B. pilosa achenes germinate in three to four days post soaking (Rokaya, Munzbergova, Timsina, & Bhattarai, 2012). Simple agricultural methods are sufficient for B. pilosa plantation because it is a notoriously fast-spreading weed found throughout the world (Young, Hsu, & Yang, 2010).

ANTIMETABOLIC PROPERTIES
B. pilosa has a variety of properties that are beneficial to humans. In terms of antimetabolic activity, B. pilosa and its antimetabolic polyynes have been proved to be prophylactically and therapeutically effective against diabetes and adipogenesis, both of which are etiologically different Chang et al., 2005;Chang et al., 2013;Chang et al., 2004;Chiang, Chang, Chang, Yang, & Shyur, 2007;Chien et al., 2009). However, hypotensive compounds of B. pilosa are still not clear.
In this section, we will focus on the antimetabolic functions and mechanism of B. pilosa extract and its active compounds.

Function and mechanism of B. pilosa for diabetes
Several lines of evidence from epidemiological investigations show that high-calorie foods and unhealthy lifestyles are the main causes of metabolic syndrome. Both factors contribute to hyperglycemia, hypertension, and obesity, leading to complications that can result in death.
Dietary intervention with antimetabolic phytochemicals is a feasible approach to preventing, treating, and reversing metabolic disorder (Clements & Bell, 1985). As shown in Table 3, B. pilosa is rich in phytochemicals for high blood sugar (Chien et al., 2009;Hsu et al., 2009), high blood pressure (Dimo et al., 2001;Dimo et al., 1999), and lipogenesis (Liang et al., 2016). In this section, we focus on the action and mechanism of B. pilosa against diabetes.
B. pilosa has traditionally been used as a folkloric herb for diabetes worldwide (Lin, Han, & Liao, 1994;Marles & Farnsworth, 1995;Ubillas et al., 2000). For the past 20 years, this plant has extensively been investigated for antidiabetic efficacy in mice of T2D. Ubillas and colleagues stated that the hydroethanolic extract of B. pilosa at a dose of 1 g/kg BW reduced FBG in db/db mice (Ubillas et al., 2000). The authors then took a bioactivity-directed identification strategy to isolate two polyynes, 1 and 2. Furthermore, the two compounds (1:2) mixed in a 3:2 ratio effectively decreased PBG level and food consumption on the next day in db/db mice fed with 0.25 g/kg, two times per day. Mice fed with 0.5 g/kg of the above mixture had a pronounced drop in PBG level and a stronger anorexic effect (food intake reduced by 57%) was observed (Ubillas et al., 2000). This work indicated that 1 and 2 were the active compounds in B. pilosa for diabetes (Ubillas et al., 2000). This activity of both polyynes against diabetes was partially attributed to reduced food intake. Nevertheless, this anorexic effect was not seen in the studies of Hsu et al. (2009)). Water extracts of B. pilosa (BPWE) were evaluated for diabetes in 6-and 8-week-old db/db mice. One oral dose of glimepiride, a commercial insulin releaser, could stimulate insulin release and lower blood sugar in db/db mice. Similarly, BPWE increased insulin production and decreased PBG from 374 to 144 mg/dL. Further, its hypoglycemic mechanism resulted from upregulation of insulin production. Interestingly, BPWE showed a faster kinetics for insulin secretion than glimepiride ). Nowadays, antidiabetics are notorious for their decreased efficacy over time.
Hsu et al. assessed the long-time effect of BPWE on diabetes in db/db mice. BPWE reduced PBG and Hb A1c but ameliorated the production of serum insulin and glucose tolerance. Both one-and multiple-dose studies report the superior action of BPWE on diabetes .
Moreover, they discovered that glimepiride could not preserve pancreatic islets. In contrast, BPWE strongly preserved islet architecture in mouse pancreases. The authors also checked the antidiabetic effect of three B. pilosa varieties at a single oral dose at 10, 50, and 250 mg/kg BW (Chien et al., 2009). As a result, the water extracts of three B.
pilosa varieties dose-dependently decreased PBG levels in db/db mice for 4 hr. Among the three varieties, the extract of B. pilsoa var. radiata (BPR) had a higher reduction in PBG levels than the other two varieties at the same dose. In addition, the BPR extract boosted serum insulin levels in db/db mice in comparison with the other varieties at 50 mg/kg. Three polyynes (1, 2, and 3 (cytopiloyne)) were present in all the Bidens strains, albeit with varied contents. Compound 3 exerted a better stimulation of insulin production in db/db mice than compounds 1 and 2 when administered at the same dose, 0.5 mg/kg. In contrast, oral intake of the Bidens extracts and 3 polyynes in diabetic mice for 4 weeks were then evaluated. Results showed that like glimepiride, the crude extracts of the three varieties at doses of 10-250 mg/kg BW diminished the PBG levels in db/db mice. Nevertheless, BPR extract reduced PBG levels and augmented blood insulin levels more than that of the other two varieties because of a higher content of cytopiloyne. Hb A1c was also monitored since it is a long-term indicator of blood homeostasis.
Twelve-week-old diabetic mice had an Hb A1c of 7.9%. However, mice that received a daily dose of BPR crude extract (50 mg/kg), glimepiride (1 mg/kg), and cytopiloyne (0.5 mg/kg) had an Hb A1c of 6.6%, 6.1%, and 6.2% in the blood of age-matched controls, respectively (Chien et al., 2009). Further, cytopiloyne was used to analyze the antidiabetic effect and mechanism (Chang et al., 2013). The data confirmed that cytopiloyne reduced the level of PBG and Hb A1c , augmented serum insulin, and ameliorated glucose tolerance and islet preservation in db/db mice. However, cytopiloyne did not decrease PBG in mice whose β-cells were already destroyed by streptozocin. Moreover, cytopiloyne boosted insulin secretion and expression, calcium influx, diacylglycerol (DAG), and protein kinase Cα (PKCα) activation in β-cells. Collectively, the data suggest that B. pilosa and its active compound, cytopiloyne, regulate T2D via improvement of β-cell functions (insulin production TA B L E 3 Nutrients found in B. pilosa leaf (modified from Alikwe et al., 2014)  and β-cell preservation) implicated in the calcium/DAG/PKCα pathway ( Figure 2). One seminal study showed that B. pilosa reduced the level of FBG and Hb A1c in diabetics by 30%. In contrast, it increased fasting serum insulin in healthy subjects (Lai et al., 2015). Furthermore, B.
pilosa antidiabetics in a combined formula had better clinical outcomes in diabetic patients (Lai et al., 2015). The underlying antidiabetic mechanism of B. pilosa is relevant to the improvement of β-cell function in patients as indicated by the homeostatic model assessment (HOMA) data (Lai et al., 2015).
The above studies conclude that cytopiloyne (3)  pilosa slightly reduced PBG in rats which drank 10% fructose (Dimo et al., 2001). Compounds 7 and 8 were proposed to be antidiabetic compounds (Dimo et al., 2001). Intriguingly, 36 polyynes have been found in B. pilosa so far. Whether all the polyynes present in this plant have antidiabetic activities remains to be elucidated.

Function and mechanism of B. pilosa for obesity
People with obesity are generally consuming more calories than they require. Obesity and its complications are major global health threats.
Liang and colleagues investigated the antiobesity effect and mode of action of B. pilosa, and its active constituents. They found that B. pilosa F I G U R E 2 The mechanism through which B. pilosa (BP) and its bioactive compound, cytopiloyne (CP) alleviate diabetes. B. pilosa and/or CP reduce diabetes development through enhanced function and survival in β-cells. BP and/or CP upmodulate insulin expression/secretion (①) and cell protection (②) in β-cells. Calcium and diacylglycerol as well as their downstream PKCα pathway control this upmodulation (modified from the previous publication; Lai et al., 2015) substantially diminished fat content and elevated protein content in ICR mice (Liang et al., 2016). Consistently, B. pilosa decreased fat content, adipocyte size, and/or BW in mice in a dose-dependent manner (Liang et al., 2016). Furthermore, mechanistic studies indicated that B. pilosa reduced peroxisome proliferator activated receptor γ (PPARγ) expression, CCAAT/enhancer binding proteins (C/EBPs), and Egr2 in adipose tissue. Cytopiloyne was identified as an adipolytic compound from B. pilosa based on bioactivity-guided fractionation and isolation (Liang et al., 2016). This plant also strongly suppressed the lipid formation and accumulation. This suppression was linked with the downregulation of expression of Egr2, C/EBPs, PPARγ, adiponectin, and adipocyte Protein 2 (aP2). This study illustrated that B. pilosa and its polyynes inhibited adipogenesis and lipid content in adipocytes and/or animals via downregulation of the C/EBPs/Egr2/PPARγ cascade and its responsive genes as described in Figure 3 (Liang et al., 2016).

Function and mechanism of B. pilosa for hypertension
Dimo and colleagues first showed that B. pilosa ameliorates hypertension in Wistar rats that took 10% fructose in drinking water (Dimo et al., 2001;Dimo et al., 1999;Dimo et al., 2002). They assessed the hypotensive effect of different extracts of B. pilosa whole plant on hypertension in rats induced by 6-week induction with 10% fructose. High fructose increased systolic blood pressure (SBP) from 100 to 140 mm Hg or more in 6 weeks. A calcium channel blocker, nifedipine, lowered SBP in hypertensive rats. The water extract and methylene chloride extract of B. pilosa could reduce SBP (Dimo et al., 2001). The reduction of SBP by B. pilosa at 350 mg/kg is comparable to that of SBP by nifedipine at F I G U R E 3 A schema illustrating the likely mechanism of B. pilosa (BP) crude extract and cytopiloyne (CP) in obesity. BP and/or CP can decrease the expression of Egr2, an upstream regulator of C/EBPs, C/EBPα, C/EBPβ, C/EBPγ, and PPARγ, and, in turn, downregulate adiponectin and aP2 gene expression during adipogenesis in adipocytes. Consequently, BP and/or CP diminish adipogenesis and lipid metabolism (adopted from the previous publication; Liang et al., 2016) 10 mg/kg (Dimo et al., 2001). In another study, the same group indicated that the methanol extract of B. pilosa leaves could prevent and treat hypertension in fructose-fed rats. Consistently, this extract also normalized plasma insulin levels in rats fed with a high fructose diet.
Both lines of evidence suggest that B. pilosa exerts its antihypertensive effect in part by improving insulin sensitivity (Dimo et al., 2002).
Besides, in normotensive rats, B. pilosa decreased heart rate by 24% and 61% at doses of 20 and 30 mg/kg, respectively. The data imply that it exerts hypotensive effects by acting on the cardiac pump efficiency and, subsequently, vasodilation (Dimo et al., 2003). Overall, the data suggest that B. pilosa possesses antihypertensive action although its mode of action is not clear. However, the antihypertensive phytochemicals need to be identified.
In summary, B. pilosa and/or cytopiloyne control metabolic syndrome via multiple mechanisms. Their mechanisms include inhibition of β-cell failure, suppression of adipogenesis, anorexic action, and reduction of blood pressure. As a consequence, B. pilosa and/or cytopiloyne improve metabolic syndrome.

PHYTOCHEMISTRY
B. pilosa is an extraordinary herb with 43 activities documented (Bartolome et al., 2013). So far, we and other groups have discovered 301 phytochemicals from B. pilosa (Bartolome et al., 2013;Xuan & Khanh, 2016 (Bartolome et al., 2013;Xuan & Khanh, 2016). B. pilosa has a rich complexity of chemicals, which may reflect its various biological functions. The structures and biological activities of these compounds have been previously reviewed (Bartolome et al., 2013); however, the information is outdated. Here, we summarized the chemical structures of 36 polyynes present in B.

IUPAC Names
Common Names

CONCLUSIONS
B. pilosa is a plant that can be found all over the world, and is widely used as a food and in folk remedies. It has been claimed to treat diabetes, obesity, and high blood pressure on several continents. Nevertheless, a comprehensive review of studies on B. pilosa for metabolic syndrome has not been made. In the present article, scientific reports on the use of B. pilosa as a functional food for metabolic syndrome have been summed up and critically discussed from nutritional, functional, phytochemical, and toxicological angles. Of note, 8 (Compounds 1 to 8) out of 36 polyynes of this plant have been shown to possess antimetabolic activities. The antimetabolic use of B. pilosa and its mechanisms of action with respect to its known polyynes were also discussed. Medical doctors must be consulted before applying B. pilosa as a functional food, health food, and remedy for metabolic syndrome.

ACKNOWLEDGMENTS
We thank our laboratory colleagues for their excellent technical assistance and the preparation of the figures. We also thank the authors of the publications we cited. This work was supported by