The Genus Capsicum: A Review of Bioactive Properties of Its Polyphenolic and Capsaicinoid Composition

Chili is one of the world’s most widely used horticultural products. Many dishes around the world are prepared using this fruit. The chili belongs to the genus Capsicum and is part of the Solanaceae family. This fruit has essential biomolecules such as carbohydrates, dietary fiber, proteins, and lipids. In addition, chili has other compounds that may exert some biological activity (bioactivities). Recently, many studies have demonstrated the biological activity of phenolic compounds, carotenoids, and capsaicinoids in different varieties of chili. Among all these bioactive compounds, polyphenols are one of the most studied. The main bioactivities attributed to polyphenols are antioxidant, antimicrobial, antihyperglycemic, anti-inflammatory, and antihypertensive. This review describes the data from in vivo and in vitro bioactivities attributed to polyphenols and capsaicinoids of the different chili products. Such data help formulate functional foods or food ingredients.

Chili belongs to the Solanaceae family [21][22][23][24][25], which includes eggplant, tomatoes, potato, and tobacco. It is an herbaceous plant or a small shrub with white or pink flowers pollinated by insects such as bees, bumblebees, and aphids. Plants of the genus Capsicum can grow worldwide, but their origin is in America. However, the tropical and subtropical environment is optimal for plant growth [22,24,26]. The pre-Columbian distribution of this genus probably extended from the southernmost edge of the United States to the warm temperate zone of southern South America [27]. The genus Capsicum contains more than Furthermore, to these compounds, chili contains various hydrocarbon chains derived from vanillin amides. These compounds are called capsaicinoids. Capsaicinoids have a linear or branched structure [55]. Other important compounds present in chili are carotenoids (some with provitamin A activity), phenolic compounds, ascorbic acid (vitamin C), and tocopherols (vitamin E) [21,22,56]. The composition and concentration of these metabolites are affected by the ripeness stage, cultivation systems, and fruit processing [22,[57][58][59][60][61][62][63].
Some chili metabolites act as defense mechanisms against several abiotic and biotic stresses [22]. It has also been suggested that capsaicin in chili plants forms part of one of the defense mechanisms against frugivorous animals and Fusarium [22,57]. These components are valuable not only to the plant but also to humans. On the other hand, phenolic compounds such as cinnamic acids, their derivatives, and flavonoids have in vitro antioxidant activity against free radicals and reactive oxygen species; in addition to potential antitumor activity. In recent years, several studies have been carried out on the bioactive potential of these compounds [22,58]. Moreover, chili has some volatile compounds such as phenols, aldehydes, ketones, ketone alcohols, ethers, nitrogen compounds, aromatic hydrocarbons, alkanes, esters, and lactones [55,59,60]. A brief description of some of the compounds of the Capsicum genus (polyphenols and capsaicinoids) that exert bioactivity is given below.

Bioactive Compounds Found in Chili Peppers
Since ancient times, it has been known that chili has a wide range of therapeutic properties. There are several applications for chili extracts in the formulation of various drugs. In the market, several ointments contain capsaicin, which is administered topically for pain relief, migraines, headaches, psoriasis, and herpes simplex virus infection [2,61]. Capsaicin also treats dyspepsia, lack of appetite, flatulence, atherosclerosis, heart disease, and muscle tension [55]. Other bioactive compounds attributed to various chili varieties are shown in Table 2.   In vitro potential against enzymes for hyperglycemia of several chili peppers (Capsicum). Four Capsicum annuum L. cultivars were studied at two stages of fruit ripening (immature and mature) Antiproliferative activity of L-asparaginase against three human cancerous cell lines [20] Capsaicinoids and carotenoids Algerian chili pepper (Capsicum annuum L.) The antitumor activity of capsaicinoids at a concentration of 200 µg·mL −1 was 52%, and carotenoids reached 90% activity at the same concentration Antitumor potential of capsaicinoids and carotenoids against cancerous (U937) and healthy (PBMC) cell lines

Phenolic Compounds
Phenolic compounds are secondary metabolites that plants synthesize during their growth or in response to stress conditions. These compounds are related to defense mechanisms against radiation and pathogenic microorganisms [58,[71][72][73]. Reactive oxygen species (ROS) are known to be responsible for oxidative stress. ROS are involved in developing chronic diseases such as atherosclerosis, cancer, obesity, diabetes, and coronary heart disease [43,74,75]. In the last decade, several studies highlighting phenolic compounds' protective effects on the progression of these chronic diseases have been carried out. This effect is thought to be due to the antioxidant activity of the phenolic compounds [76,77]. Most studies on the profile of phenolic compounds in species of the genus Capsicum are based on the content of capsaicinoids, which are distinctive compounds in pungent chili (Capsicum annuum and Capsicum chinense Jacq.). However, phenolic compounds have also been studied in low-pungency chili pepper species [78]. The predominant phenolic compounds in chili are catechin, quercetin, protocatechuic acid, and rutin [72,[79][80][81][82].

Flavonoids
Flavonoids are secondary metabolites of low molecular weight found in fruits, vegetables, herbs, spices, stems, and flowers. They occur in free form or are esterified as glucosides. Flavonoids can exert several crucial pharmacological functions in the body. Although very diverse, the flavonoids characteristically have a benzopyrone skeleton with varying degrees of saturation, and functional groups added to the rings. The most common flavonoids in nature are classified into one of six groups listed below: flavones, flavanones, chalcones, anthocyanins, condensed tannins, and flavonols [83][84][85]. In leguminous plants, other flavonoids known as isoflavones are also synthesized. In nature, there are about 6000 different flavonoids, which have various biological functions such as protection against UV radiation, protection against phytopathogens, signaling during the nodulation process, and coloring of the flowers as a visual signal that attracts pollinators, and protects the leaves by preventing photo-oxidative damage. Flavonols are the most relevant flavonoids and are involved in stress responses. They are also nature's oldest and most distributed flavonoids [83,86,87].
In general, flavonoids are synthesized through the phenylpropanoid route, which is responsible for transforming phenylalanine to 4-coumaroyl-CoA, which enters the synthesis pathway of flavonoids. This central route for flavonoid biosynthesis is prevalent in plants. However, depending on the species, other enzymes (isomerases, reductases, hydrolases) may act on them to modify their original skeleton and produce differences in the structures of flavonoids [83]. In the genus Capsicum, the glycosides of quercetin, luteolin, apigenin, and catechin form part of the composition of flavonoids. Quercetin glycosides are found only in the O-glycosylated form and are the most abundant forms (quercetin 3-O-rhamnoside and quercetin-7-O-rhamnoside). Apigenin glycosides are C-and O-glycosides, while luteolin is only found in its C-glycosylated structure [16]. Luteolin has been reported to have antioxidant, anticancer, anti-inflammatory, and neuroprotective effects [88,89]. The concentration of total flavonoids in chili pepper may vary depending on the cultivar. Some researchers have reported correlations between flavonoid composition and chili color. However, other studies have not reported this relationship [21]. In some varieties of purple or violet chilies, anthocyanins (delphinidin) have been reported as the compounds responsible for the color of such varieties [90].
Quercetin glycosides are found only in the O-glycosylated form and are the most abundant forms (quercetin 3-O-rhamnoside and quercetin-7-O-rhamnoside). Apigenin glycosides are C-and O-glycosides, while luteolin is only found in its C-glycosylated structure [16]. The concentration of total flavonoids in chili pepper may vary depending on the cultivar. Some researchers have reported correlations between flavonoid composition and chili color. However, other studies have not reported this relationship [21]. In some varieties of purple or violet chilies, anthocyanins (delphinidin) have been reported as compounds responsible for the color of such varieties [90].

Capsaicinoids and Capsinoids
Capsaicinoids are amides produced by species of the genus Capsicum. These substances are responsible for the spicy and pungent flavor of chili. Capsaicinoids are compounds that differ in structure from the residues of branched fatty acids attached to a benzene ring of vanillylamine. Any variation in the chemical structure of the capsaicinoids, including the acyl moieties, affects the degree and level of pungency [22,[91][92][93][94]. Capsaicinoids include capsaicin, dihydrocapsaicin, nordihydrocapsaicin, and homocapsaicin. The main capsaicinoids found in hot chilies are capsaicin and dihydrocapsaicin (they may represent 90% of total capsaicinoids), whereas norhydrocapsaicin, homodihydrocapsaicin, and homocapsaicin are found in low concentrations. The capsaicinoids are generally expressed in Scoville Heat Units (SHU). This scale is used to measure the degree of the pungency of chili. The number of Scoville Heat Units indicates how many times a chili extract must be diluted to make its pungency imperceptible. The scale of Scoville categorizes in four groups the pungency degree of chilies is non-pungent (0-700 SHU), mildly pungent (700-3000 SHU), pungent (3000-25,0000 SHU), highly pungent (25,0000-70,000 SHU), and extremely pungent (>80,000 SHU) [73,95]. The chili with the highest pungency is the Trinidad Moruga Scorpion, with up to 2,000,000 SHU [96][97][98].
Capsaicin is synthesized in the chili placenta by enzymatic condensation of vanillylamine with a medium chain branched fatty acid. The key enzyme involved in the formation of capsaicinoids is capsaicin synthetase (CS). This enzyme is an acyltransferase responsible for the condensation of vanillylamine with a fatty acid. The levels of capsaicinoid production and their relative abundance vary depending on the cultivar [99][100][101].
Capsinoids, analogous to capsaicin, have been found in bell pepper (Capsicum). The main capsinoids of bell pepper are capsiate, dihydrocapsiate, and nordihydrocapsiate [102][103][104]. These substances share a structure similar to capsaicinoids as they have an aliphatic hydroxyl group in a vanillin alcohol bound to a fatty acid [99,105]. The difference lies in the type of bonds because capsaicinoids have amide bonds, while capsinoids have ester bonds [103,[106][107][108][109].
Over the last fifteen years, capsaicinoids and capsinoids have gained much interest because they can exert physiological effects when administered at specific concentrations (bioactivity). These bioactivities are increasingly relevant in the pharmaceutical sector, as they are used in the formulation of ointments and medicines. The main bioactivities that have been attributed to capsaicinoids and capsinoids are the following: (i) analgesic activity, (ii) anticancer activity, (iii) anti-inflammatory activity, and (iv) anti-obesity activity [99,[110][111][112][113][114].

Bioactivities Associated with Polyphenols and Capsaicinoids of the Genus Capsicum
As mentioned above, chili not only has nutritional compounds but also contains bioactive compounds. To date, the most studied bioactivities in several types of chilies and peppers are antioxidant and antimicrobial activity [8,9,11,14,62,115]. More recently, studies with other bioactivities, such as antihyperglycemic and antihypertensive activity, have been given greater importance because natural alternatives are sought to help control two of the world's most severe public health problems: hypertension and diabetes [3,[116][117][118]. The bioactivities studied in chili extracts, mainly attributed to polyphenols and capsaicinoids, will be briefly described below.
Hervert-Hernández et al. [8] evaluated the antioxidant activity of the polyphenolic extracts of four varieties of hot chilies. The hot peppers analyzed were Arbol, Chipotle, Guajillo, and Morita. The antioxidant activity was quantified using two ABTS and FRAP methods. The authors found that the total antioxidant activity of the chilies quantified by the FRAP method was 63.9 and 82.3 µmol of Trolox equivalents/g of dry matter; the Guajillo chili was the only one that presented the lowest antioxidant activity. In the case of total antioxidant activity evaluated using the ABTS method, the highest activity was found in the Chipotle chili (44 ± 0.6 µmol Trolox equivalents/g of dry matter), and the lowest activity was observed in the Guajillo chili (26.6 ± 1.0 µmol Trolox).
Galvez-Ranilla et al. [65] quantified the antioxidant potential of extracts of medicinal plants, chilies, and some herbs widely used in Latin America. The analyzed extracts corresponding to the genus Capsicum were: Arbol, Ancho, Yellow, Japanese, Red, Paprika, and Rocoto. It was found that all extracts analyzed showed antioxidant activity, which was measured using the DPPH method (between 61 and 73%). Additionally, it was found that red chili had the highest antioxidant activity (73%). The antioxidant activity found in the extracts of the chilies evaluated in this study was due to the concentration of polyphenols and other compounds, such as carotenoids. Another work carried out by Ghasemnezhad et al. [66] determined the concentration of phenolic compounds, ascorbic acid, and the antioxidant capacity of extracts of various red chilies (Capsicum annuum) in two different maturity stages. The authors found that the higher antioxidant potential (measured by the DPPH method) depended on the type of variety and the maturity stage because chili peppers with higher maturity showed higher antioxidant activity.
Zhaung et al. [67] analyzed the bioactive compounds (vitamin C, carotenoids, phenolic compounds, and capsaicinoids) and the antioxidant activity of nine pepper cultivars from Yunnan Province in China. The antioxidant activity of pepper cultivars were evaluated using DPPH, reducing power, and lipid peroxidation inhibitory activity. The ethanolic extracts of chili cultivars showed significant antioxidant activity (quantified using three methods). However, the red Fructus Capsici variety extracts had a higher antioxidant potential and a higher concentration of phenolic compounds. It was also observed that the antioxidant activity of all extracts evaluated was directly related to phenolic compounds content.
In a study conducted by Segura-Campos et al. [11], the antioxidant activity of the Habanero chili was analyzed using the β-carotene decolorization method and the ABTS method. The authors used seven genotypes of Habanero pepper (Capsicum chinense Jacq.) from the state of Yucatan for the study. The antioxidant activity reported as Trolox equivalents (TEAC) ranged from 1.55 to 3.23 mM/mg sample. For antioxidant activity quantified as β-carotene bleaching, it was observed that the extracts could bleach the β-carotene between 36 and 57% during the first 30 min. The authors suggest that the antioxidant activity is related to the phenolic compounds, carotenoids, and ascorbic acid concentration.
Another work by Castro-Concha et al. [10] quantified the antioxidant potential and content of total polyphenols of red and orange Habanero peppers (Capsicum chinense Jacq.) at different stages of maturity. The extracts of the peppers were obtained from two different stages of maturity (immature and mature). The antioxidant activity was evaluated using the DPPH method and the cupric-reducing antioxidant capacity (CUPRAC). The immature placental tissue of the red habanero pepper was the one that presented the highest antioxidant activity quantified in both methods, and it also showed the highest number of phenolic compounds.
Carvalho et al. [7] quantified the concentration of bioactive compounds (polyphenols, anthocyanins, carotenoids, and vitamin C) and the antioxidant activity of various chili genotypes. The genotypes used in this study belong to the species Capsicum sp., Capsicum annuum L., Capsicum chinense Jacq., and Capsicum baccatum L. var. umblicatum. The antioxi-dant activity of the chili extracts (methanol and acetone) was measured using the ABTS and DPPH methods. It was found that genotype IAN186311 showed the highest antioxidant activity and the highest concentration of phenolic compounds.
In another work, Chavez-Mendoza et al. [68] studied the antioxidant potential by selecting different combinations of varieties and rootstock of various bell pepper cultivars (Capsicum annuum L.). The combinations used in this study were: Jeanette/Terrano (yellow), Sweet/Robusto (green), Fascinato/Robusto (red), Orangela/Terrano (orange), and Fascinato/Terrano (red). The antioxidant activity of the extracts was determined by the DPPH method. The extract of the combination Fascinato/Robusto was the extract that presented higher antioxidant activity (79.65%). The extract with the Jeanette/Terrano combination showed the lowest antioxidant potential (64.90%) of DPPH radical inhibition. This study demonstrated that antioxidant activity was significantly affected by the cultivar/rootstock combination and the color of the peppers used. The authors observed that the Fascinato/Robusto combination had the highest concentrations of lycopene and total phenols and the most increased antioxidant activity of all cultivar/rootstock combinations evaluated.
Loizzo et al. [69] evaluated the antioxidant potential of twenty chili cultivars belonging to Capsicum annuum, Capsicum baccatum, Capsicum chacoense, and Capsicum chinense. This study assessed the antioxidant activity of fresh and processed chili extracts. The antioxidant activity of the ethanolic extracts of chilies was evaluated using four methods: ABTS, DPPH, FRAP, and β-carotene bleaching. The cultivars of the species Capsicum annuum showed the highest antioxidant activity. Nevertheless, the researchers reported that the antioxidant activity of chili peppers does not directly correlate with the concentration of phytochemicals they contain, demonstrating that different classes of compounds are poorly associated with antioxidant parameters, even within assays in which they share the same mechanism of action.
Sora et al. [125] conducted a comparative study of the antioxidant activity, capsaicinoid content, and polyphenols found in six extracts of chili pepper extracts belonging to the genus Capsicum. The extracts analyzed were from Bell, Habanero orange, Cayenne, Habanero red, Malagueta, and Dedo de moça chili peppers. To quantify the antioxidant activity of the ethanolic extracts of seeds and pulps of chili used. Antioxidant activity was measured using ABTS, FRAP, and DPPH assays. The antioxidant activity was higher in the seeds than in the pulp. This bioactivity was directly related to the content of polyphenols and capsaicinoids. The ethanolic extract of red habanero seeds showed the highest antioxidant activity.
The antioxidant activity of the capsaicinoids and carotenoids extracted from Algerian chili was evaluated using the DPPH, ABTS, and FRAP methods. The carotenoid extracts showed higher antioxidant activity than capsaicinoids. The antioxidant activity of the carotenoid extract was: 2.8 ± 0.3 mmol Trolox equivalents/g determined using the DPPH method, 3.4 ± 0.003 mmol Trolox equivalents/g determined using the ABTS method, and 5.9 mmol Fe 2+ /g determined using the FRAP method [9].
Hamed et al. [73] studied the capsaicinoids and other bioactive compounds in chilies from different cultivars at two maturity stages (green and red) on antioxidant activity. The effect of roasting on their nutritional content was also investigated. They found that both raw and roasted chilies exhibited strong antioxidant activity as determined by DPPH (61-87%) and ABTS (73-159 µg/g). The results showed a relatively weak positive correlation of total phenolics and total flavonoid concentration with DPPH and ABTS antioxidant activities, with the highest correlation between total phenolics concentration (r = 0.55) and the DPPH antioxidant assay.

Antimicrobial Activity
The microbiological quality of food is one of the major concerns of the food sector. There are currently many strategies for controlling microbial growth in food; however, some issues still need to be resolved. Today, many chemical preservatives are approved for use in food, but the current trend is the use of naturally occurring antimicrobial substances, which are safe, effective, and sensorial accepted [126,127]. A study by Mokhtar et al. [9] evaluated the antimicrobial potential of an extract of capsaicinoids from Algerian chili (Capsicum annuum). It was found that this extract had activity against Listeria monocytogenes ATCC 1392 and Enterococcus hirae ATCC 10541. Additionally, this same study proved that this extract had no antimicrobial activity against the beneficial bacteria Lactobacillus rhamnosus LbRE-LSAS and Bifidobacterium longum ATCC15707.
Nascimento et al. [13] quantified and evaluated the antimicrobial potential of capsaicin, dihydrocapsaicin, and chrysoeriol extracted from different tissues (fruit, seeds, and shell) of various Malagueta chili varieties. The antimicrobial effect was evaluated against the growth of the pathogenic microorganisms: Enterococcus faecalis, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Candida albicans. The minimum inhibitory concentration of each extract was determined against each pathogenic microorganism, and the three compounds showed a significant antimicrobial effect against the microorganisms evaluated in this study (0.06 to 25 µg/mL). Capsaicin, dihydrocapsaicin, and chrysoeriol inhibit the growth of Gram-positive and harmful bacteria.
Gayathri et al. [62] determined the antimicrobial potential of capsaicin extracts (acetone and acetonitrile) obtained from various tissues (callus, leaves, shoots, fruits, and seeds) of Capsicum chinense Jacq. The obtained extracts have antimicrobial activity against Salmonella typhi, Aspergillus flavus, Bacillus cereus, Staphylococcus aureus, and Streptococcus pyogenes.

Anti-Inflammatory Activity
The inflammation process is a natural defense mechanism of the body's immune system in response to damage caused to cells and tissues by toxic agents such as microorganisms, chemicals, and necrosis. Mostly, it is a protective response that localizes and destroys the injurious agent and then prepares the damaged tissue for repair. However, inflammation and oxidative stress are involved in the development of various diseases such as cancer, rheumatoid arthritis, asthma, diabetes, and cardiovascular and degenerative illness [15,63].
In a study by Spiller et al. [63], the anti-inflammatory potential of red chili (Capsicum baccatum) has been quantified on an inflammation induced by carrageenan and on an immune inflammation induced with bovine serum albumin methylated in mice. It was observed that pretreatment with red chili juice at a concentration between 0.25 and 2 g/kg applied 30 min before carrageenan administration significantly reduces leukocyte and neutrophil migration, exudate volume, protein concentration, and the level of lactate dehydrogenase (LDH) in the exudates of the induced pleurisy model. Red chili juice also inhibits the migration of neutrophils and reduces vascular permeability in carrageenaninduced peritonitis in rats. On the other hand, this extract reduces the recruitment of neutrophils and levels of pro-inflammatory cytokines (TNF-α and IL-1β) in immuneinduced peritonitis in rats. The authors suggest these effects are due to the capsaicin in red chili juices.
Zimmer et al. [15] evaluated the antioxidant and anti-inflammatory potential of red chili (Capsicum baccatum) seeds and pulp extracts. The extracts were extracted with ethanol, butanol, and dichloromethane. Anti-inflammatory activity was quantified using carrageenan-induced pleurisy models in mice. This study observed an anti-inflammatory effect of ethanolic and butanolic extracts (200 mg/kg per os) compared to dexamethasone (0.5 mg/kg subcutaneously). It was also observed that the content of polyphenols might be related to the antioxidant and anti-inflammatory activity of the extracts evaluated.
Cho et al. [64] studied the in vitro anti-inflammatory effects and flavonoid content of pepper leaves (PL) and pepper fruit (FP). Pepper extracts ameliorated the lipopolysaccharide (LPS)-stimulated inflammatory response by decreasing nitric oxide production and the levels of interleukin-6 and tumor necrosis factor-alpha in RAW 264.7 cells, with greater efficacy of the activities of PL than FP.
Simpson et al. [128] studied the effect of a single application of a high-concentration capsaicin dermal patch (NGX-4010) in patients with HIV-associated distal sensory polyneuropathy. The patch application was safe and provided at least 12 weeks of pain reduction in patients. Thus, the authors suggest that these results could be used as a promising new treatment for painful HIV neuropathy.

Antihypertensive Activity
Angiotensin-converting enzyme (ACE) is a crucial enzyme in the control of blood pressure. This enzyme converts angiotensin I (inactive decapeptide) to angiotensin II (vasoconstrictor octapeptide) and hydrolyzes bradykinin, a potent vasodilator, forming inactive fragments. Inhibition of ACE activity is a therapeutic alternative for the control of hypertension [129]. Currently, food-derived ACE-inhibitory compounds are being sought to treat hypertension, as it is one of the most serious health problems worldwide. ACE-inhibition is one of the methods used to quantify antihypertensive activity in vitro.
Galvez-Ranilla et al. [65] studied the ACE-inhibitory activity of the extracts of medicinal plants, herbs, chilies, and species commonly used in Latin America. The inhibitory potential of the angiotensin-converting enzyme (ACE) from chili extracts was evaluated at three different concentrations (0.5, 1.25, and 2.5 mg dry weight). It was found that almost all extracts of the evaluated chilies showed ACE-inhibitory activity except the extracts at a concentration of 0.5 mg of Arbol, Ancho, and Rocoto chili peppers. The ACE-inhibitory activity of the analyzed extracts was between 20 and 90%. They found a correlation (r = 0.61) between ACE-inhibitory activity and polyphenol concentration.
In another work, Chen and Kang [3] evaluated the inhibitory potential of essential enzymes in controlling hypertension and hyperglycemia from extracts of various tissues of red chili (Capsicum annuum L.). The evaluated tissues were the pericarp, placenta, and stalk. The ACE-inhibitory potential of methanolic tissue extracts was tested at three different concentrations (1, 3, and 5 mg/mL). The extracts obtained from the pericarp showed the highest ACE-inhibitory activity. The degree of inhibition depended on the concentration of the extract. Regarding the ACE-inhibitory potential of the placenta extracts, they only inhibited the enzyme when the extract had a concentration of 3 and 5 mg/mL. The extracts obtained from the stalk of red chili only inhibited the enzyme's activity by 10% when they had a concentration of 5 mg/mL. On the other hand, in this work, the high total phenolic content did not correlate to the ACE-inhibitory activity of these extracts. However, this activity is unrelated to the concentration of polyphenols found in the evaluated extracts.

Antihyperglycemic Activity
Diabetes is one of the significant health problems worldwide. Type 2 diabetes is a metabolic disorder characterized by a high glucose concentration in the blood due to deficiency or null insulin production. In patients with diabetes, levels of α-amylase and α-glucosidase may be harmful. Inhibition of these enzymes may reduce the increase in blood glucose after food intake; and therefore, these can be a good alternative for the control of the level of blood glucose. The search for naturally occurring compounds that can control blood glucose levels for patients with type 2 diabetes is in process. Inhibition of α-amylase in the small intestine has been observed to be related to blood glucose levels after food intake; hence, the control of the activity of this enzyme is a crucial factor for the treatment of diabetes. Plant extracts are currently explored as natural alternatives to control hyperglycemia as an option to existing pharmacological treatments. The antihyperglycemic effect can be assessed in vitro by inhibition of α-amylase and α-glucosidase [3].
In a study conducted by Galvez-Ranilla et al. [65], the antihyperglycemic activities of extracts of spices, chilies, medicinal plants, and herbs were evaluated. The extracts from the chilies analyzed were: Arbol, Ancho, Yellow, Japanese, Red, Paprika, and Rocoto chili. The extracts were evaluated for three concentrations 0.5, 1.25, and 2.5 mg. The antihyperglycemic activity of the extracts was assessed by the inhibition of α-amylase and α-glucosidase. All the extracts analyzed had α-glucosidase inhibitory activity. However, only the extracts analyzed at a concentration of 1.25 mg had α-amylase inhibitory activity. The highest inhibitory activity of α-glucosidase was close to 50% in the Red, Rocoto, and Yellow chili extracts. Yellow, red, paprika, and Japanese chili pepper showed an α-amylase inhibitory activity close to 40%. However, this activity depends not only on the concentration of total phenols in chili but is due to a synergistic effect between these and other compounds in chili, such as capsaicinoids and carotenoids.
Tundis et al. [70] evaluated the antihyperglycemic activity and its relationship with phytochemicals in cultivars of Capsicum annuum during its development. The varieties of chili assessed in this study were: Fiesta, Acuminatum, Orange Thai, and Golden Cayenne. The antihyperglycemic activity was evaluated by the enzymatic inhibition of α-amylase and α-glucosidase. The ethanolic extracts of the immature Fiesta pepper, Orange Thai and Golden Cayenne were the ones that showed a more significant inhibitory effect of α-amylase. Regarding the α-glucosidase inhibitory activity, all ethanolic extracts of the mature and immature chilies evaluated were revealed to have a mean inhibitory activity (IC 50 ≤ 166.5 µg/mL), except the extracts of Fiesta and Acuminatum chili peppers in the mature state (IC 50 > 1000 µg/mL). The concentration of phenols and flavonoids was higher in the immature chilies, while the concentration of carotenoids and capsaicinoids was higher in the mature chilies. In contrast, the lipophilic fraction of the chili extracts at the two maturity stages evaluated showed a high inhibitory effect on the activity of the α-amylase enzyme (IC 50 ≤ 30 µg/mL) [69]. In addition, the authors found that both capsaicin and dihydrocapsaicin showed an inhibitory effect on α-amylase with IC 50 of 83.0 and 92.0 µg/mL, respectively.
Chen and Kang [3] quantified the inhibitory potential of essential enzymes involved in hyperglycemia from extracts of various tissues of red chili. The inhibitory activities of αamylase and α-glucosidase were evaluated using three different concentrations of extracts (1, 3, and 5 mg/mL). The methanolic extracts of the pericarp showed the highest degree of inhibition of α-amylase. It was also observed that the α-amylase inhibitory activity was unrelated to the polyphenol concentration. On the other hand, all the extracts evaluated at the three different concentrations showed α-glucosidase inhibitory activity. Methanolic red chili pericarp extracts showed higher inhibitory activity (≥30%). This study observed that the degree of inhibition of both enzymes depends on the dose of the extract used. The authors observed that high polyphenol contents correlated with higher alpha-glucosidase inhibitory activity for cultivar B.

Metal-Chelating Activity
Metal-chelating activity is intrinsically related to antioxidant activity. It is known that the binding of minerals such as iron and copper has an antioxidant effect because these metals can cause oxidative damage in cells at different levels. It has been observed that these oxidative reactions are involved in the pathogenesis of some neurodegenerative diseases [130].
Siddiqui et al. [19] studied the dynamics of changes in bioactive molecules and the antioxidant potential of the extracts of Habanero pepper during nine different states of maturity. The antioxidant activity was determined using the DPPH method and the metalchelating activity (chelating of ferrous ions). The authors concluded that the iron chelating activity of ethanolic extracts increases as a function of maturity until reaching a maximum.
The results indicated that at day 49 postharvest, extracts reached 75% iron-chelating activity. Furthermore, the authors observed that metal-chelating activity was strongly correlated with the concentration of total polyphenols (r = 0.972) and total flavonoids (r = 0.956).

Antitumoral Activity
A tumor can be defined as the uncontrolled multiplication of cells; the tumors can be benign or malignant. If a tumor is mildly benign, the cells only multiply uncontrollably but do not spread to another part of the body. Usually, this type of tumor does not endanger life. A malignant tumor or cancer can spread to other organs (metastasis). Cancer is one of the most significant health challenges worldwide. It is currently the second leading cause of death in the United States of America and is expected to become the leading cause of death in that country in the next few years [131,132].
Mokhtar et al. [9] evaluated the antitumoral potential of capsaicinoids and carotenoids extracted from Algerian chili (Capsicum annuum) against cancerous (U937) and healthy (PBMC) cell lines. Cell lines were exposed to various concentrations of extracts to observe their viability. The effect of the two extracts was higher in cancer cells than in healthy PBMC cells. The extracted capsaicinoids had a lower antitumoral effect than carotenoids. However, the antitumor activity of capsaicinoids at a concentration of 200 µg/mL was 52%, whereas, for carotenoids, antitumoral activity reached 90% activity at the same concentration.
Wang et al. [133] studied the effect of capsaicin on gastric cancer (GC) cell lines to understand the mechanism of cell growth inhibition. The researchers demonstrated that capsaicin could significantly suppress cell growth while altering histone acetylation in GC cell lines. In this study, reduced hMOF activity (histone H4 lysine K16-specific acetyltransferase) was detected in GC tissues, which capsaicin could restore in both in vivo and in vitro studies. These findings revealed an important role of hMOF-mediated histone acetylation in capsaicin-directed anticancer processes, and therefore, the authors suggested capsaicin as a potential drug for gastric cancer prevention and therapy.

Incorporation of Polyphenols and Capsacinoids from Capsicum on Food and Cosmetics Products
Chili paste is a fermented product typical of China. During fermentation, the burning sensation caused by eating unprocessed chili peppers is mitigated. In addition, it is a technique to preserve food and has unique sensory attributes [134]. Several studies have been conducted with chili paste fermented with different strains of lactic acid bacteria and yeasts [134][135][136][137][138][139]. However, most of these studies have studied the effect on the sensory attributes produced by fermentation [135][136][137][138] or monitoring of the microorganisms during autochthonous chili fermentation [139]. Consequently, further studies are needed to study the effect of fermentation on bioactive compounds (mainly phenolic compounds). In this regard, it is important to note that certain strains of LAB and yeast, during fermentation, can metabolize phenolic acids and thus increase their bioactivity or bioavailability [140][141][142][143][144][145][146][147]. This can lead to an increase in antioxidant, anti-inflammatory and antiglycemic activity, among others [146][147][148]. Therefore, studies on the effect of fermentation with LAB or yeast strains on the concentration of polyphenols, as well as on the bioactive effects due to the microbial transformation of these compounds, will be of great scientific importance.
Furthermore, in 2014, Song et al. [147] developed a vinegar with chili leaves (Capsicum annuum L.) that exhibited enhanced functional activity. The production of the vinegar supplemented with pepper leaves was carried out following a four-stage procedure: (i) preparation of the raw materials, (ii) a lactic fermentation (Fructilactobacillus fructivorans formerly known as Lactobacillus homohiochii), (iii) an alcoholic fermentation (Saccharomyces cerevisiae) and (iv) an acetic fermentation (Acetobacter aceti). The utilization of fermentation of chili leaves was very effective in producing a functional food by enhancing the content of bioactive components such as gamma-aminobutyric acid (GABA), citrulline, and polyphenols. In addition, the vinegar with chili leaves showed efficacy in the elimination of free radicals and the inhibition of α-glucosidase activity. These bioactivities were attributed to the increase in phenolic concentration during fermentation. Therefore, the authors conclude that the consumption of this vinegar supplemented with chili leaves could be used as a dietary strategy to prevent oxidative stress and alleviate postprandial hyperglycemia in diabetes.
Zellama et al. [149] evaluated the effect of supplementing extra virgin olive oil (EVOO) with chili. In this study, a higher concentration of polyphenols and ortho-diphenols was found. Four colorimetric methods were used to determine antioxidant activity (DPPH, ABTS, FRAP, and the β-carotene bleaching test). Compared to the non-supplemented control oil, a higher level of antioxidant activity was observed in the chili-enriched oil. In addition, a significant antimicrobial effect was obtained mainly against Gram-positive bacteria. These results provide a scientific basis for innovation in food technology for new food products. In addition, the incorporation of several Capsicum-derived ingredients has been documented in a wide variety of commercial products, as shown in Table 3. This shows the importance of the incorporation of these ingredients derived from the Capsicum genus in the cosmetic and food industries. On the other hand, it is worth mentioning that in traditional Asian and Mexican foods, many chili peppers are used as part of the recipes of a large number of dishes. However, there are no studies on the effect of chili as an ingredient. Table 3. Commercial products and cosmetics with ingredients derived from Capsicum.

Conclusions
The genus Capsicum is one of the most important horticultural products in the world. Horticultural products are an essential ingredient in all diets. They are a reliable source of carbohydrates, dietary fiber, proteins, lipids, and minerals. This fruit is traditionally used in many dishes and food products for its distinctive flavor, color, and aroma compounds. Additionally, it contains some compounds that may have beneficial effects when consumed on a regular intake, such as polyphenols, capsaicinoids, carotenoids, vitamin C, and tocopherols. Antioxidant, antimicrobial, anti-inflammatory, antihypertensive, antihyperglycemic, metal chelating, and antitumoral activity have been associated with polyphenol and capsaicinoid content. These bioactivities highlight the importance of chili peppers as part of the human diet and as a potential ingredient for the formulation and development of functional foods. Additionally, fermentation of chili pastes with various strains of LAB and yeasts can increase antioxidant, anti-inflammatory, and antiglycemic activities, among others, by the biotransformation of phenolic compounds with the microbial strains. Therefore, this increase in bioactivities can be very important for the formulation of new functional products.