Horticultural products are an essential ingredient of all diets worldwide, as they are a reliable source of carbohydrates, dietary fiber, protein, lipids, and minerals. Additionally, these products contain compounds in a lower concentration that can have some physiological activity or bioactivity in the body when they are regularly consumed [1]. Chili (genus Capsicum) is one of the most important horticultural products. In the last two decades, many studies have shown this fruit’s possible biological activities ^{[2][3][4][5][6]}[2,3,4,5,6]. Some of the biological activities that have been evaluated in distinct species of the genus Capsicum are the following: (i) antioxidant ^{[7][8][9][10][11][12]}[7,8,9,10,11,12], (ii) antimicrobial ^[9][13][14][9,13,14], (iii) anti-inflammatory [15], (iv) antihypertensive ^[3][16][3,16], (v) antihyperglycemic ^[3][17][3,17], (vi) metal-chelating ^[18][19][18,19], and (vii) antitumoral [20].

Chili belongs to the Solanaceae family ^{[21][22][23][24][25]}[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][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 30 species of chili ^[28][29][28,29]. Still, the five most cultivated and representative species are Capsicum annuum L., Capsicum chinense Jacq, Capsicum frutescens L., Capsicum baccatum L., and Capsicum pubescens (Ruiz and Pav). The first four are in Mexico; C. frutescens and C. annuum have been domesticated there. C. annuum is the most cultivated and economically important species in the world. Mexico is its center of diversification, with more than 100 morphotypes present ^{[30][31][32][33]}[30,31,32,33]. There is evidence of its cultivation for approximately 6000 years. Its uses date back to pre-Columbian times, where its primary use was as a condiment, but the different types of chili peppers also played an essential role as a source of vitamin C in the various American cultures [34].

According to Market Report World data, the global Capsicum market size was valued at USD 4471.04 million by 2022, and the market is expected to reach USD 7325.67 million by 2028, at a CAGR of 8.58% [35]. The world’s leading chili pepper-producing countries in 2021 were China (16,725,716 tons), Turkey (2,864,100 tons), Indonesia (2,759,805 tons), and Mexico (2,701,293 Tons) [36]. Based on data from the Servicio de Información Agroalimentaria y Pesquera (SIAP) reported in 2021, Mexico’s production of chili was 3 million tons, representing 20.2% of the country’s total vegetable production [37]. The most cultivated chilies in Mexico are habanero, jalapeño, serrano, piquin, manzano, and serrano ^[38][39][38,39].

The fruits of the genus Capsicum contain nutritionally relevant metabolites such as carotenoids (provitamin A), ascorbic acid (vitamin C), tocopherols (vitamin E), phenolic compounds, and capsaicinoids ^[40][41][42][40,41,42]. These metabolites might have beneficial health effects, and some may exert antioxidant activity because they may have free radical scavenging and oxygen scavenging capabilities ^[43][44][43,44]. A significant percentage of the antioxidant activity that chili has, is due to the number of phenolic compounds and not only to the content of vitamins and carotenoids; therefore, the study of the phenolic fraction is very important ^[18][45][46][18,45,46].

Traditionally, chili is usually consumed fresh and processed in different forms, such as spice, powder, paste, etc. ^[8][47][8,47]. In addition, there are other uses that our ancestors developed, such as in medicine, punishment, currency, and tribute material, among others. It is used in traditional medicine to remedy the effect of asthma, cough, throat irritation, and other respiratory disorders ^[25][48][49][25,48,49].

2. Composition of the Genus Capsicum

2.1. Nutritional Composition

The genus Capsicum’s nutritional composition has been observed to depend on the fruit’s ripeness. Capsicum fruit is of ethnopharmacological importance and has been traditionally used in most cuisines and food products due to its distinctive flavor, color, and aroma ^[2][50][51][2,50,51]. The composition of nutrients and minerals in chili belonging to the genus Capsicum annuum L. is shown in Table 1. 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 ^[52][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][53][21,22,56]. The composition and concentration of these metabolites are affected by the ripeness stage, cultivation systems, and fruit processing ^{[22][54][55][56][57][58][59][60]}[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][54][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][55][22,58]. Moreover, chili has some volatile compounds such as phenols, aldehydes, ketones, ketone alcohols, ethers, nitrogen compounds, aromatic hydrocarbons, alkanes, esters, and lactones ^[52][56][57][55,59,60]. A brief description of some of the compounds of the Capsicum genus (polyphenols and capsaicinoids) that exert bioactivity is given below.

2.2. 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][58][2,61]. Capsaicin also treats dyspepsia, lack of appetite, flatulence, atherosclerosis, heart disease, and muscle tension ^[52][55].

2.2.1. 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 ^{[55][61][62][63]}[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][64][65][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 ^[66][67][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 ^[68][78]. The predominant phenolic compounds in chili are catechin, quercetin, protocatechuic acid, and rutin ^{[62][69][70][71][72]}[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 ^[73][74][75][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 ^[73][76][77][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 ^[73][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 ^[78][79][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 ^[80][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 ^[80][90].

2.2.2. 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][81][82][83][84]}[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) ^[63][85][73,95]. The chili with the highest pungency is the Trinidad Moruga Scorpion, with up to 2,000,000 SHU ^[86][87][88][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 ^[89][90][91][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 ^[92][93][94][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 ^[89][95][99,105]. The difference lies in the type of bonds because capsaicinoids have amide bonds, while capsinoids have ester bonds ^{[93][96][97][98][99]}[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 ^{[89][100][101][102][103][104]}[99,110,111,112,113,114].

3. Bioactivities Associated with Polyphenols and Capsaicinoids of the Genus Capsicum

3.1. Antioxidant Activity

The most studied biological activity in fruits of the genus Capsicum is antioxidant activity. This activity can be quantified in vitro by several methodologies, among which the following are highlighted: antioxidant activity by uptake of the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH), antioxidant activity by uptake of the 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS); oxygen radical absorption capacity (ORAC); ferric reducing-antioxidant power (FRAP); cupric reducing antioxidant capacity (CUPRAC); β-carotene bleaching assay; superoxide radical scavenging activity (SOD); thiobarbituric acid method (TBA); hydroxyl radical averting capacity (HORAC); reducing power method (RP), and the ferric thiocyanate method (FTC) ^{[105][106][107][108][109][110]}[119,120,121,122,123,124]. In most of these studies, the concentration of polyphenols, capsaicinoids, and other compounds, such as carotenoids, is directly related to the antioxidant activity present in chili and peppers. 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. ^[111][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. ^[112][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. ^[113][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.

3.2. 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 ^[114][115][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. ^[59][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.

3.3. 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][60][15,63]. In a study by Spiller et al. ^[60][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 carrageenan-induced 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 immune-induced 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. ^[116][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. ^[117][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.

3.4. 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 ^[118][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. ^[111][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, 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.