In general, cereal-derived peptides have been shown to possess opiate, antithrombotic, anticancer, antihypertensive, immunomodulatory, mineral-binding, antimicrobial, and antioxidant properties (de Mejia et al., 2012). Various bioactive peptides have been found and reported in maize (Tnani et al., 2013; Li et al., 2014). Maize bioactive peptides are obtained by the hydrolysis of kernels and sub-products. Among the different techniques for peptide generation, enzymatic hydrolysis is the most widely used method for maize. The main enzymes used in the hydrolysis of maize protein are listed in Table 1. For bioactivity evaluations, peptides have been fractionated by ultra-filtration (Wang Y. et al., 2014; Jin et al., 2016), and separated using chromatographic techniques with multiple purification steps (Puchalska et al., 2013; Wang X.-J. et al., 2014; Jin et al., 2016; Wang et al., 2016) to obtain low molecular weight peptides that have shown promise in further characterization. Various bioactive properties of maize peptides have been reported, including anticancer activity and other activities that have beneficial effects on health, such as antioxidant, antihypertensive, hepatoprotective, and alcohol protective activities. The different studies reporting the bioactive properties of maize peptides are listed in Table 1.

In the past few years, an important advance in cereal peptides research has been the finding that novel cereal-derived proteins and peptides exert preventive effects in different stages of cancer, including initiation, promotion, and progression. Because of the urgent need for effective cancer prevention therapy, chemoprevention has emerged as a viable anti-cancer approach. Chemo-preventive agents are expected to be safe, inexpensive, and abundant. Peptides fulfill these criteria, and are considered to be safer than synthetic compounds as they are present in the regular human diet and have a wide range of availability and acceptability (Li et al., 2014). Several studies have shown the anti-cancer potential of dietary proteins, peptides, and amino acids in the regulation of apoptosis and angiogenesis, important steps in controlling tumor metastasis; these molecules are naturally occurring or generated by fermentation, enzymatic hydrolysis, or gastrointestinal digestion (de Mejia and Dia, 2010).

Bioactive peptides exert anti-tumor activity via several key mechanisms: (a) Apoptosis induction, which involves an energy-dependent cascade mediated via specific proteases or caspases; strategies to overcome tumor resistance to apoptotic pathways include activation of pro-apoptotic receptors, restoration of p53 activity, caspase modulation, and proteasome inhibition (Burz et al., 2009). (b) Blockade of intermediate tumor generation by regulating cellular mechanisms associated with cell proliferation and survival, or biosynthetic pathways that control cell growth (Kornienko et al., 2013). (c) Regulation of immune system function by increasing the expression of tumor-associated antigens (antigenicity) in cancer cells, by triggering tumor cells to release danger signals that stimulate immune responses (immunogenicity), or by increasing the predisposition of tumor cells to be recognized and killed by the immune system (susceptibility) (Zitvogel et al., 2013).

The anticancer activities of different peptides have been characterized, with most of them showing pro-apoptotic activity (Dia and Mejia, 2010; Gonzalez de Mejia et al., 2010; Dia and Gonzalez, 2011; McConnell et al., 2015). Some mechanisms proposed for the anticancer activity of peptides are autophagy and apoptosis (de Mejia and Dia, 2010; Hernandez-Ledesma et al., 2013), and maize peptides may promote these processes in different cancer cells.

A primary anticancer effect of maize peptides has been demonstrated using in vitro models. HepG2 cells showed an increase in apoptotic activity when they were exposed to maize peptides obtained by enzymatic hydrolysis of protein extracted from corn gluten meal (Li et al., 2013). In that study, maize peptides were also evaluated in H22-tumor bearing mice. Treatment of animals with these peptides at a dose of 400 mg/kg resulted in an inhibition of tumor growth. Moreover, the administration of maize peptides enhanced immune system activity compared with that in the control group.

More recently, a study by Ortiz-Martinez et al. (2017) revealed important anti-cancer effects of maize peptides in HepG2 cells. Peptide fractions isolated from albumin Alcalase hydrolysates from normal maize were stronger than the ones from quality protein maize. The treatment of HepG2 cells with this peptide fraction from the different maize varieties increased the apoptosis induction rates an average of 4-fold. These results suggested that the antiproliferative effect of peptide fractions isolated from both varieties was based on the induction of apoptosis due to the decrease in antiapoptotic factor expression.

Antioxidant capacity is the main reported biological activity of maize peptides. This activity is explained by the presence of specific amino acids with radical scavenging and reducing capacities, such as lysine, tyrosine, phenylalanine, proline, alanine, histidine, and leucine (Zhou et al., 2015). Several peptides with antioxidant activity have been identified; however, their antioxidant potential depends on the enzymatic process used to obtain them. Zheng et al. (2006) studied the antioxidant capacity of peptides obtained using an optimized enzymatic hydrolysis process. Peptides with low molecular weight (<5 kDa) exhibited higher antioxidant activity (Li et al., 2008; Zhou et al., 2012; Zhuang et al., 2013; Tang and Zhuang, 2014). The properties of these small peptides included hydroxyl radical and free radical scavenging activity, inhibition of lipid peroxidation, and ion chelating capacity. The antioxidant potential is not altered in peptides obtained from total protein or zein fraction (Li et al., 2010; Tang et al., 2010). Another factor affecting antioxidant activity is the pH: native α-zein has more antioxidant activity than α-zein extracted in less basic or acidic conditions (Zhang et al., 2011). Synthesized peptides also show similar antioxidant activities (Wang X.-J. et al., 2014; Jin et al., 2016).

Additionally, peptides smaller than 3 kDa have shown potent antioxidant activity in in vitro assays in HepG2 and Caco2 cells exposed to high oxidative stress (Wang et al., 2015). Maize peptides also enhance the activity of cellular enzymes, and therefore, may exert preventive effects against cell damage via their antioxidant activity (Wang et al., 2016). Furthermore, in studies conducted in macrophage models, maize peptides have shown anti-inflammatory effects (Hernández-Ledesma et al., 2009; Cam and Gonzalez, 2012), which could have been exerted via their antioxidant properties. Oxidative stress has been shown to induce lipid peroxidation, protein oxidation, and DNA damage, subsequently causing mutant cell proliferation and finally, carcinogenesis (Thanan et al., 2014). These properties are relevant because of the relationship between oxidative stress and degenerative processes like carcinogenesis. Therefore, the antioxidant activity of maize peptides could be beneficial for cancer treatment.

Maize peptides have shown antihypertensive effects. A single peptide with an Ala–Tyr sequence, obtained from corn gluten meal, which is a main by-product of maize wet milling, showed significant inhibitory activity against angiotensin I-converting enzyme (Yang et al., 2007; Lin et al., 2011). Moreover, the same peptide has shown antihypertensive activity in spontaneously hypertensive rats with a minimum effective oral dose of 50 mg/kg resulting in a diastolic blood pressure reduction of 9.5 mm Hg (Yang et al., 2007), and with an oral dose of 450 mg/kg resulting in a reduction of 40 mmHg (Lin et al., 2011). In another report, peptides smaller than 3 kDa showed greater blood pressure reductions (up to 34.45 mmHg) at a dose of 100 mg/kg in a spontaneously hypertensive rat model (Huang et al., 2011). These results show that molecular weight influences antihypertensive activity, with peptides smaller than 1 KDa being the most active. In addition, enzymes used for protein hydrolysis and peptide generation also influence the antioxidant activity of the resulting peptides, with peptides obtained using trypsin and thermolysin being the most potent (Parris et al., 2008). In addition, ultrasonic treatment applied to corn gluten meal proteins before hydrolysis appears to increase the antihypertensive activity of the resulting peptides (Zhou et al., 2013). Antihypertensive peptides have been isolated and identified as LRP (leucine–arginine–proline), LSP (leucine–serine–proline), and LQP (leucine–glutamine–proline) by using high-performance liquid chromatography (Puchalska et al., 2013). Hence, molecular interactions of peptides can affect enzymes responsible for vascular hemodynamics, suggesting further potential applications for these enzymes.

Recent studies have shown that maize peptides exert a protective effect by reducing damage to hepatic tissue. Using rats with liver damage induced by exposure to lipopolysaccharides from bacillus Calmette-Guérin, Guo et al. (2009) showed that administration of 600 mg/kg peptide significantly lowered the level of cell necrosis, hepatic lesions, and enzymes indicative of liver damage compared to that in control rats. In this study, the peptides protective effect on liver cells could be attributable to their antioxidant capacity. Maize peptides smaller than 5 kDa exerted a hepatoprotective effect in a mouse model of carbon tetrachloride-induced hepatic damage. At a dose of 200 mg/kg, these peptides altered hepatic enzyme levels, lowering aspartate transaminase and alanine transaminase, and elevating superoxide dismutase and glutathione (Yu et al., 2012). Maize peptides may also exert a hepatoprotective effect by facilitating alcohol metabolism. Peptides as small as five amino acids have been shown to display this activity in mice (Ma et al., 2012). This effect is explained by the presence of leucine, which maintains the tricarboxylic acid cycle by supplying NAD+ (antioxidant effect). The same small peptide shown anti-apoptotic activity in mouse liver cells treated with alcohol to induce damage (Ma et al., 2015). A similar study found a hepatoprotective effect in mice at a dose of 200 mg/kg with peptides smaller than 5 kDa, which resulted in lower blood alcohol concentrations (Yu et al., 2013). Maize peptides have also shown protective activity against hepatic fibrosis. In rats exposed to thioacetamide, which induces hepatic fibrosis, the minimum protective dose was 100 mg/kg (Lv et al., 2013). These studies demonstrate the hepatoprotective effect and mechanisms of action of maize peptides in response to different types of stress, suggesting another possible field of therapeutic application.

In addition to the effects discussed so far, a few more bioactive properties of maize peptides have been identified. Maize basic peptide 1 (BMP-1), which was obtained through protein hydrolysis, identified, and later synthetized, was shown to exert antimicrobial activity, inhibiting the growth of fungi and bacteria (Duvick et al. 1992). In an in vivo study in Caenorhabditis elegans, Zhang et al. (2016) demonstrated that a bioactive maize tetrapeptide possessed scavenging activity against intracellular reactive oxygen species. Additionally, this tetrapeptide inhibited the aggregation and oligomerization of β-amyloid peptide, which are involved in the development of Alzheimer's disease. These studies indicate the different bioactivities of maize peptides, which warrant further study and may be beneficial in the treatment of different diseases.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.