The Genus Cuphea P. Browne as a Source of Biologically Active Phytochemicals for Pharmaceutical Application and Beyond—A Review

Cuphea P. Browne (Lythraceae) is a monophyletic taxon comprising some 240–260 species that grow wild in the warm, temperate, and tropical regions of South and Central America and the southern part of North America. They have been valued as traditional medicinal remedies for numerous indications, including treating wounds, parasitic infections, hypertension, digestive disorders, cough, rheumatism, and pain. Modern pharmacological research provides data that support many of these traditional uses. Such a wide array of medicinal applications may be due to the exceptionally rich phytochemical profile of these plants, which includes bioactive compounds classified into various metabolite groups, such as polyphenols, triterpenes, alkaloids, and coumarins. Furthermore, Cuphea seed oils, containing medium-chain fatty acids, are of increasing interest in various industries as potential substitutes for coconut and palm oils. This review aims to summarize the results of phytochemical and pharmacological studies on Cuphea plants, with a particular focus on the therapeutic potential and molecular mechanisms of the action of polyphenolic compounds (especially flavonoids and tannins), which have been the subject of many recently published articles.

The most numerous section is Euandra Koehne, which includes about 60 species [6]. Cuphea plants are native to South and Central America and the southern part of North America (southeastern USA; western and southern mountains of Mexico). Most species grow in Brazil, and 69 of the total 108 Brazilian species are endemics [7]. An exceptionally high diversity and abundance of Cupheas is observed in Brazilian cerrados and savannas in Bahia, Goiás, and Minas Gerais [6,8]. They grow in natural sites up to an altitude of 3000 m above sea level, usually in roadside, open, moist, mesophytic areas and pastures [1,9]. Some species have been introduced to Africa and Southeast Asia [10,11]. In some countries they are classified as invasive plants; e.g., C. ignea A.DC. in La Réunion [12,13]. On the other hand, in 2018, C. melvilla Lindl. was listed on the IUCN Red List of Threatened Species, although it is listed under the heading "least concern". It should be noted that several Cuphea species (C. glutinosa Cham. & Schltdl. and C. ignea A.DC. as examples) are cultivated as landscape and ornamental plants in gardens and can also be grown indoors [14,15].
Cuphea plants are widely used in traditional South American and Mexican medicine as anti-inflammatory, diuretic, antipyretic, antimicrobial, astringent, and hypotensive agents. Herbal teas, infusions, or decoctions are the most widespread traditional preparations, and are most often prepared from the aerial parts [16][17][18]. To date, only about a dozen species have been studied for their pharmacological activity. However, given their therapeutic potential and prospects for development, some of them have already attracted considerable interest as potential phytopharmaceuticals. These include, for example, C. aequipetala Cav., C. calophylla Cham. & Schltdl., C. carthagenensis (Jacq.) J.F.Macbr., C. glutinosa Cham. & Schltdl, C. ignea A.DC., and C. pinetorum Benth. However, no clinical trials evaluating their efficacy have been conducted to date.
For this reason, much attention has recently been given to the domestication of Cupheas suitable for large-scale cultivation [19]. However, this is not an easy task due to several characteristics typical of non-domesticated species that limit their agricultural suitability, such as an indeterminate pattern of continuous flowering, a hard seed coat and consequent dormancy, early seed shedding and shattering from maturing fruits, glandular trichomes on stems, and floral tubes that produce sticky/resinous substances [19,21]. For example, shattering of seed pods can lead to significant, almost 100%, seed loss [22]. Furthermore, many Cuphea species are entomophilous plants that attract bees or butterflies, which is another factor limiting their commercial production [23]. One of the recently explored ways to overcome this problem is the search for suitable pollinators to increase plant seed production. It appears that the subgenus Heterodon may provide the best candidates for agronomic crops due to its larger seeds, extremely abundant inflorescences, and considerable height [24].
Several successful attempts have been made to develop commercial Cuphea lines. To this end, the cultivar PSR23 (Partial Shatter Reduction line No. 23; PI606544, released by Knapp and Crane) was obtained through interspecific hybridization of Cuphea viscosissima Jacq. and C. lanceolata, f. silenoides W.T.Aiton as a potential feedstock for biodiesel production [25,26]. The term "partial seed reduction" stands for the fact that the seed capsules of line No. 23 do not split and spread as readily as those of other Cuphea lines. Cuphea PSR23 was the first cultivar in which seed loss was reduced to 20-30%, while having high oil content and non-dormant seeds [22].
Some Cuphea species are rich in polyphenols and can be considered as convenient sources of natural antioxidants in industrial processes [27]. For this reason, polyphenols are the most studied group of Cuphea phytoconstituents.

Botanical Characteristics
The name Cuphea comes from Greek κυϕóς, meaning stooping, bent forward, or hunched back [28]. The term probably refers to the shape of the fruiting capsule. In the Spanish-speaking world, Cuphea plants are also known by the generic name sete-sangrias (seven bleedings). They represent summer annual and perennial herbaceous plants or semi-shrubs that grow up to 2 m; however, most Cupheas are less than 1.5 m [1].
Cuphea species typically produce simple leaves with thin leaf blades, the arrangements of which are opposite or verticillate. In most species, the size of the leaf gradually decreases toward the top of the plant. Solitary flowers develop at the leaf nodes, forming raceme inflorescences. The flowers are hexamerous and zygomorphic, with an elongated tubular calyx terminated with six deltate petals, which are often small or vestigial [1,7]. The predomi-nant flower color is purple (e.g., C. lanceolata W.T.Aiton) to red (e.g., C. nudicostata Hemsl.), although some rare examples may develop yellow flowers (e.g., C. nudicostata S.A. Graham & T.B.Cavalc.) or bicolored floral tubes, e.g., C. annulata Koehne, C. cyanea Moc. & Sessé ex DC., and C. spectabilis S.A. Graham. Leaves, stems, and flowers are covered with sticky and glandular hair [2,3,29,30]. A couple of characteristics distinguish the genus from other members of the Lythraceae family: interpetiolar emergence of flowers, and the "disc"-a free-standing nectiferous organ at the base of the ovary. Other morphological synapomorphies include 11 stamens (rarely less), oblate pollen, and a unique seed dispersal mechanism [2,3]. Seeds are flattened and biconvex, with inverted, spiral, mucilaginous trichomes. They are attached through coordinated slits in the dorsal wall of the capsule and in the floral tube. A placenta exserted from the capsule allows seed dispersal.
One of the most important factors determining Cuphea seed production is temperature. Seed yields are reduced under hot and dry conditions. Seed production of the PSR23 cultivar is better adapted to cool and temperate climates and depends mainly on high water use [31,32]. Warm to hot weather conditions with sufficient humidity are optimal for vegetative growth of wild Cuphea species [9]. However, the vegetative biomass production of the PSR23 cultivar is not strictly dependent on temperature.
Storage temperature is one of the most important factors affecting seed viability, but its effect depends on the fatty acid composition of the triacylglycerols in individual Cuphea oils. In the case of a high concentration of lauric and/or myristic acids in the oil, a loss of viability can be observed when seeds are stored at −18 • C [33]. Seeds with a high content of capric, caprylic, or unsaturated fatty acids can withstand exposure to low temperatures much better.

Cuphea Seed Oil and Fatty Acids
As mentioned above, Cuphea plants are a rich source of MCFAs. About 50% of the species produce lauric acid, which is the predominant fatty acid in South American Cupheas, while oils from North American species are more diverse [34]. The average oil content of wild Cupheas seeds ranges from 30 to 35%, while the oil content in the seeds of PSR23 ranges from about 27 to 33% [35,36]. Seeds of the PSR23 cultivar were found to contain 4-5% more oil than the wild parents (C. lanceolata W.T.Aiton and C. viscosissima Jacq.) [37]. Furthermore, oil production in this variety may increase with increasing latitude.
There are several techniques for extracting oil from Cuphea seeds [38]. Standard procedure involves solvent extraction or mechanical extraction by screw pressing. The first method is more efficient, but exposure to solvents can be hazardous to workers and the environment. Screw pressing can extract only about 80% of the oil from the seeds [39]. The crude oil obtained by both methods must be properly refined by bleaching and deodorization (RBD). The undesirable high chlorophyll content in oil obtained by screw pressing can be reduced by dehulling Cuphea seeds prior to extraction [40]. Supercritical carbon dioxide (SC-CO2) extraction yields high-quality Cuphea seed oil with a much lower free fatty acid content and higher brightness than Cuphea oil obtained by RBD following solvent extraction [38]. Thus, this method is an economically viable alternative.
Some Cuphea oils can be relatively homogeneous and contain glycerides of a single fatty acid [33]. For example, C. wrightii A.Gray oil is rich in lauric acid (72.8%), C. llavea Lex. oil accumulates high levels of capric acid (92%) [41], while PSR23 oil contains a high amount of decanoic acid (65-73%), and its levels are generally greater in northern growing regions compared to southern ones [26,36]. On the other hand, longer-chain fatty acids predominate in some other species. For example, linoleic acid (18:2) is the main component of the seed oil of C. lindmaniana Koehne ex Bacig. and C. flavovirens S.A.Graham [42]. Table 1 lists Cuphea species according to the predominant fatty acid in the oil. The table was compiled on the basis of the data reported in: [34]; * [42]; ** [20]; *** [41]; **** [43].

Polyphenols
Many recent reports on Cuphea phytochemistry have been devoted to the characterization of various phenolic fractions: flavonoids (Figure 1), phenolic acids and their derivatives ( Figure 2), tannins ( Figure 3) and stilbenes ( Figure 4) [44]. Quercetin glycosides have been identified as major flavonoids, along with other flavonols: rhamnetin, isorhamnetin, and kaempferol; flavones: apigenin, and luteolin; isoflavone genistein; and their glycosides [45][46][47][48][49]. Sugar residues generally include galactose, glucose, rhamnose, arabinose, xylose, and glucuronic acid. In addition, the rare quercetin 3-sulfate has been identified in an aqueous extract of the aboveground parts of C. carthagenensis (Jacq.) J.F.Macbr. and a methanolic extract of C. ingrata Cham. & Schltdl. [47,50]. In addition to flavonoids, another class of polyphenols, the macrocyclic tannins, has received particular attention, among which the dimeric ellagitannins (cuphiin D 1 , cuphiin D 2 , oenothein B, and woodfordin) are of great interest due to their anticancer properties [51].      Most quantitative studies on Cuphea polyphenols provide data on the determination of total phenolic content (TPC) and total flavonoid content in extracts and fractions, usually calculated as gallic acid equivalents (GAE) and quercetin equivalents (QE), respectively. The results obtained by different authors vary considerably; these differences are mainly due to the study of different species and different parts of the plants as well as the use of different extraction solvents. For example, Krepsky et al. [45] observed a significant solvent-dependent effect when analyzing the phenolic content of different fractions of the ethanolic extract from aerial parts of C. carthagenensis (Jacq.) J.F.Macbr. The ethanolic extract, after concentration, was suspended in water and then sequentially extracted with nhexane, dichloromethane, ethyl acetate, and n-butanol. The aqueous part was divided into methanol-soluble and methanol-insoluble fractions. The highest content of phenols and tannins, expressed as percentage of dry material, w/w, was determined in the n-butanol fraction (87.6 ± 4.2% and 75.0 ± 0.9%, respectively). The emulsion formed during the partition of the ethanol extract with dichloromethane contained the highest level of proanthocyanidins (37.90 ± 0.50%) and flavonoids (5.80 ± 0.16%) [45]. More recently, Rather et al. [17] estimated the total phenolic and flavonoid content of a methanolic extract from   Most quantitative studies on Cuphea polyphenols provide data on the determination of total phenolic content (TPC) and total flavonoid content in extracts and fractions, usually calculated as gallic acid equivalents (GAE) and quercetin equivalents (QE), respectively. The results obtained by different authors vary considerably; these differences are mainly due to the study of different species and different parts of the plants as well as the use of different extraction solvents. For example, Krepsky et al. [45] observed a significant solvent-dependent effect when analyzing the phenolic content of different fractions of the ethanolic extract from aerial parts of C. carthagenensis (Jacq.) J.F.Macbr. The ethanolic extract, after concentration, was suspended in water and then sequentially extracted with nhexane, dichloromethane, ethyl acetate, and n-butanol. The aqueous part was divided into methanol-soluble and methanol-insoluble fractions. The highest content of phenols and tannins, expressed as percentage of dry material, w/w, was determined in the n-butanol fraction (87.6 ± 4.2% and 75.0 ± 0.9%, respectively). The emulsion formed during the partition of the ethanol extract with dichloromethane contained the highest level of proanthocyanidins (37.90 ± 0.50%) and flavonoids (5.80 ± 0.16%) [45]. More recently, Rather et al. [17] estimated the total phenolic and flavonoid content of a methanolic extract from Most quantitative studies on Cuphea polyphenols provide data on the determination of total phenolic content (TPC) and total flavonoid content in extracts and fractions, usually calculated as gallic acid equivalents (GAE) and quercetin equivalents (QE), respectively. The results obtained by different authors vary considerably; these differences are mainly due to the study of different species and different parts of the plants as well as the use of different extraction solvents. For example, Krepsky et al. [45] observed a significant solvent-dependent effect when analyzing the phenolic content of different fractions of the ethanolic extract from aerial parts of C. carthagenensis (Jacq.) J.F.Macbr. The ethanolic extract, after concentration, was suspended in water and then sequentially extracted with n-hexane, dichloromethane, ethyl acetate, and n-butanol. The aqueous part was divided into methanol-soluble and methanol-insoluble fractions. The highest content of phenols and tannins, expressed as percentage of dry material, w/w, was determined in the nbutanol fraction (87.6 ± 4.2% and 75.0 ± 0.9%, respectively). The emulsion formed during the partition of the ethanol extract with dichloromethane contained the highest level of proanthocyanidins (37.90 ± 0.50%) and flavonoids (5.80 ± 0.16%) [45]. More recently, Rather et al. [17] estimated the total phenolic and flavonoid content of a methanolic extract from leaves of the same species (C. carthagenensis) to be 43.13 ± 3.29 mg GAE/g and 24.13 ± 2.94 mg QE/g, respectively. A significantly higher phenolic content was found in the ethanol-water extract of C. calophylla Cham. & Schltdl. (180.51 ± 4.09 mg GAE/g) [52].
The effect of various extraction parameters (e.g., temperature, extraction duration, solvent concentration) on TPC levels in C. carthagenensis extracts was further investigated by Bergmeier et al. [27]. For ethanol extraction, different conditions resulted in a wide range of TPC values, from 7.64 to 42.16 mg GAE/g. The highest level of phenolics was recovered when extraction was carried out at 56 • C, for 110 min, in a 50:50 water/ethanol ratio. Acetone extraction yielded TPC values ranging from 4.63 to 37.99 mg GAE/g, with the highest content determined when the extraction was carried out at 40 • C, 110 min, and with a 50:50 water/solvent ratio.
The results of several studies have shown that the phenolic content in individual species tends to be organ specific. Cardenas-Sandoval et al. [53] determined TPC values in different organs of three plants of the genus Cuphea, including C. aequipetala Cav., C. aequipetala var. hispida Koehne, and C. lanceolata W.T. Aiton. The highest phenolic levels were found in the leaves of C. aequipetala and C. aequipetala var. hispida (55.62 ± 0.50 and 60.74 ± 0.23 mg GAE/g DW, respectively) and in the flowers of C. lanceolata (62.79 ± 0.05 mg GAE/g DW). In these three Cuphea species, the phenolic content was significantly lower in the underground parts compared to the aerial parts, while the stems in all cases were almost devoid of these compounds. Similarly, in C. aequipetala and C. aequipetala var. hispida, flavonoids were most abundant in the leaves (196.83 ± 2.94 and 124.74 ± 1.28 mg QE/g DW, respectively), while in C. lanceolata (135.81 ± 1.55 mg QE/g DW) in the flowers. In a study by Ismail et al. [54], similar organ-dependent differences in phenolic compound levels were observed for C. ignea A.DC. The ethanolic extract from leaves accumulated a higher phenolic content (212.98 ± 0.13 µg GAE/mg) than that obtained from flowers (188.25 ± 0.12 µg GAE/mg). In addition, both alcoholic and aqueous leaf extracts showed a higher flavonoid content (65.932 ± 0.084 µg/mg and 32.372 ± 0.44 µg/mg, respectively) calculated as QE, than the flower extracts. Phenolic content may also depend on cultivation conditions, as shown for greenhouse-grown and wild C. carthagenensis: wild-grown samples contained three times more phenolic compounds (30.81 mg GAE/g DW) than greenhouse-grown plants (9.66 mg GAE/g DW) [16].
In wild C. carthagenensis plants, the highest levels of phenolics were observed in the leaves (55.62 mg GAE/g DW), and the lowest in the stems (9.60 mg GAE/g DW), generally confirming the aforementioned organ specificity of the phenolic profiles of Cuphea plants. A similar trend was also observed for flavonoid content, which ranged from 53.38 g QE/g DW (stems) to 196.83 g QE/g DW (leaves) in wild-grown Cuphea, while it averaged 21.59 g QE/g DW in greenhouse-grown plants.

Cuphea Plants in Traditional Medicine
Plants belonging to the genus Cuphea are important components of the traditional materia medica of the regions where they grow in the wild. For example, some Cuphea species are used in traditional South American medicine as contraceptives. This has been recorded for the Kayapo Indians of Brazil's Amazon Basin [71]. In Argentina, C. glutinosa, C. longiflora, and C. racemosa are used as emmenagogues, and the latter also as an abortifacient.
Recently, an extract of C. aequipetala has been suggested as a potential antibacterial agent to be considered for the treatment of E. coli and Staphylococcus sp. infections in equine hospitals, particularly to avoid cross-transmission in horses and to reduce the risk of infections in equine workers [72]. The use of aerial parts of C. carthagenensis in animal self-medication has also been observed; for example, dogs have consumed the herb to relieve symptoms of diarrhea [73].
Traditional uses, forms of preparation, and routes of administration of Cuphea plants are presented in Table 3.  anti-hypertensive [87] C. urticulosa leaves ground up leaves (topically) rashes lice [88] The use of C. carthagenensis in traditional rituals has also been reported. In the Brazilian Kiki ritual performed for the Kaingang dead, graves are marked with pine and Cuphea branches [89,90]. Other examples of non-medical uses include the use of C. aequipetala herb to obtain pigment for painting [18].

Pharmacological Activity of Cuphea Plants and Phytochemicals
The pharmacological activity of plants of the genus Cuphea is multidirectional (Figure 8). Research was primarily inspired by the directions of traditional medicinal use, and focused on the evaluation of activity and mechanisms of action. The composition of the extracts and the presence of a number of bioactive phytochemicals justified the observed pharmacological activity. It should be emphasized that pharmacological studies confirmed most of the traditional uses of these plants. The results of pharmacological studies conducted on extracts and on partially purified fractions are presented in Table 4.           antitumor -pre-treatment with C. ignea extract was more effective then post-treatment and provided chemopreventive effect probably due to its potential to attenuate benzo(α)pyrene-induced oxidative stress in the lung tissues through the amelioration of the antioxidant defense system male Swiss albino mice in vivo benzo(α)pyreneinduced lung tumorigenesis mouse model; [105]   in vitro ACE-inhib. [66] Abbreviations: inhib.-inhibition/inhibitory; ↓-decrease/reduction; ↑-increase; ABTS-2,2 -azino-bis(3ethylbenzothiazoline-6-sulfonic acid); ACE-angiotensin-converting enzyme; CAT-catalase; DPPH-2,2diphenyl-1-picrylhydrazyl radical; FRAP-ferric reducing antioxidant power; IL-interleukin; LPSlipopolysaccharide; MDA-malondialdehyde; NBT-nitro-blue tetrazolium; ORAC-oxygen radical absorbance capacity; PMNs-polymorphonuclear neutrophils; PPL-porcine pancreatic lipase; QS-quorum sensing; ROSreactive oxygen species; SOD-superoxide dismutase; TEAC-trolox equivalent antioxidant capacity; TNF-αtumor necrosis factor α.

Hypotensive Activity of Cupheas
One of the most studied folk medicinal Cuphea species is C. carthagenensis, known as Colombian waxweed. Whole plants or aerial parts are commonly used as antihypertensives [76,103,111]. The species is also an antinociceptive, antiviral, antimicrobial, anti-inflammatory, and weight-reducing agent [112]. The in vitro ACE (angiotensin converting enzyme) inhibitory activity of an ethanolic leaf extract obtained from C. carthagenensis was determined by Santos et al. [59]. The extract, at a concentration of 100 ng/mL, reduced the enzyme activity by 32.41%. Other reports on the pharmacological activity of C. carthagenensis (Table 4) confirmed its cardioprotective, hypolipidemic, and antioxidant properties [17,45,79,[101][102][103]. The data from these studies showed that the traditional use of this plant in the treatment of cardiovascular problems is well founded.
In vitro ACE inhibitory properties were also reported for C. urbaniana Koehne leaf extracts collected in Unistalda and Barros Cassal [66]. Compared to C. carthagenensis, they were less effective-at a concentration of 100 ng/mL, they inhibited the enzyme by 22.82% (Unistalda) and 22.29% (Barros Cassal). C. glutinosa is another species known for its hypotensive activity [63]. The plant is used in traditional Brazilian medicine to treat various cardiovascular problems: abnormal heart rhythms, heart failure, hypertension, and atherosclerosis. Santos et al. [59] demonstrated the in vitro ACE inhibitory properties of extracts (at a concentration of 100 ng/mL) from C. glutinosa leaves collected in Alegrete (31.66%) and Unistalda (26.32%). The authors found that the inhibition of the enzyme was related to the presence of miquelianin (quercetin 3-O-glucuronide) and other phenolic compounds. The isolated miquelianin at a concentration of 100 ng/mL showed ACE-inhibitory properties of 32.41%. Another Cuphea species with in vitro ACE inhibitory activity is C. ignea-"the cigar plant" native to Mexico [54]. Ismail et al. [54] noted that the n-butanol and ethyl acetate fractions of the C. ignea leaf extract showed higher ACE inhibitory activity than the parent ethanolic extract: IC 50 0.084, 0.215 and 2.151 mg/mL, respectively.
However, not all studies confirm the antihypertensive effect of traditional Cuphea remedies. For example, an ethanol-soluble fraction obtained from an infusion of C. calophylla leaves and stems did not induce any pharmacological effects in rats (diuretic, hypotensive) after 7 days of administration [62]. However, a significant antioxidant effect was observed.
When considering the use of Cuphea extracts in the treatment of cardiovascular conditions, the risk of interactions with other drugs used or being investigated for use in the treatment of hypertension should be taken into account. Schuldt et al. [101] demonstrated that two possible mechanisms of the in vitro vasodilatory activity of an ethanolic extract of C. carthagenensis are involved: endothelium-dependent mechanism of action, which depends on the nitric oxide (NO˙)-cyclic guanosine 3 , 5 -monophosphate (cGMP) signaling, and an endothelium-independent mechanism (at higher doses; ≥100 µg/mL). Currently, the enzymes of the NO-cGMP signaling cascade are the identified drug targets in clinical trials of novel antihypertensive drugs [113]. Should such acting drugs be introduced into clinics, the possibility of synergism with Cuphea extracts will need to be considered. A similar caution extends to interactions between clinically used ACE inhibitors and compounds with such activity confirmed in pharmacological studies that are present in Cuphea extracts, namely miquelianin and other phenolic compounds [114].

Anti-Inflammatory Activity of Cupheas
Several Cuphea species (C. aequipetala, C. calophylla, and C. racemosa) have shown antiinflammatory effects in vitro and in vivo (Figure 9). C. aequipetala, commonly known as hierba del cáncer, cancer weed, and blow weed, is a perennial herb widely distributed in Mexico and is one of the few Cupheas found from Coahuila, Mexico, to Honduras [18,115]. Its leaves and stems are used to reduce fevers associated with measles and smallpox, as well as to treat inflammatory diseases or cancer [60,91,93,98]. The results of in vitro and in vivo studies of ethanolic extracts from the leaves and stems of C. aequipetala (Table 4) confirmed their anti-inflammatory activity, associated with up-regulation of IL-10 and down-regulation of IL-1β, IL-6, TNF-α, and PGE2 secretion [91].
The aqueous leaf extract of C. calophylla, as well as the isolated miquelianin, led to 100% inhibition of PMN migration at a concentration of 10 mg/mL. In contrast, C. racemosa extract had the same effect already at concentrations of 0.1, 0.01, and 0.001 mg/mL [96]. However, miquelianin alone does not have the potential to inhibit LPS-induced neuroinflammation, as it did not suppress the cytokine cascade and the release of IL-1β and TNF-α-proinflammatory cytokines responsible for the secretion of various proinflammatory mediators [116]. In contrast, 50% and 70% acetone extracts of the aerial parts of C. carthagenensis at a concentration of 500 µg/mL showed a significant inhibitory effect on TNF-α production in LPS-stimulated THP-1 monocytic cells (96.4 ± 0.2% and 99.9 ± 0.1%, respectively) [117]. An ethanolic extract of the same plant at a concentration of 62.5 µg/mL showed an inhibitory effect of 25.7 ± 0.6% on TNF-α release [118]. More importantly, higher concentrations of the extract (125 and 250 µg/mL) displayed lower inhibitory activity (9.8 ± 4.8% and 15.7 ± 3.0%, respectively).
Mousa et al. [58] have demonstrated the in vivo gastroprotective activity of an aqueousethanolic extract of aerial parts of C. ignea. At doses of 250 and 500 mg/kg, a significant decrease in gastric ulcer index was observed. In addition, the extract increased the pH value and decreased gastric volume. In an in vivo study, Madboli et al. [119] observed that, after a one-week treatment with C. ignea extract given before ethanol application, NF-κB synthesis increased, thus providing protection against EtOH toxicity.

Antiparasitic, Antibacterial, and Antiviral Effects
Some species of Cupheas are used to control parasitic infections, which are a serious problem in tropical and subtropical regions. A decoction prepared from the aerial parts of C. pinetorum Benth., known as Bakmomol and Vach′vet by the Tzeltal and Tzotzil Indians, is used in traditional Mayan medicine as an antidiarrheal and to treat dysentery [69]. The aerial parts and the whole plant of C. ingrata are used to potentiate the antimalarial activity of extracts from other plant species [120]. C. ingrata is also used in the treatment of syphilis and other venereal diseases [120]. Another species used against syphilis is C. dipetala, which grows naturally in central Colombia. In addition, this plant is also used as an astringent against oral and skin infections [121].
In a study of Hovoraková et al. [43], hydrolyzed C. ignea seed oil, which contains a high amount of capric acid, showed antibacterial activity against some pathogenic Gram-positive strains with an MIC value of 0.56-4.5 mg/mL. Most importantly, this hydrolyzed oil was not active toward beneficial commensal bacteria.
Cc-AgNPs (silver nanoparticles synthesized by green chemistry using an aqueous extract of C. carthagenensis leaves as a reducing agent) showed strong antibacterial activity against Gram-positive and Gram-negative bacteria with the lowest MIC (15 µg/mL) and MBC (25 µg/mL) values for Salmonella typhimurium [122]. AgNPs obtained using an aqueous extract of the leaves of C. procumbens were active against Escherichia coli and Staphylococcus aureus, with maximum inhibition zone at the concentration of 0.225 and 0.158 µg/mL, respectively [123].

Antiparasitic, Antibacterial, and Antiviral Effects
Some species of Cupheas are used to control parasitic infections, which are a serious problem in tropical and subtropical regions. A decoction prepared from the aerial parts of C. pinetorum Benth., known as Bakmomol and Vach vet by the Tzeltal and Tzotzil Indians, is used in traditional Mayan medicine as an antidiarrheal and to treat dysentery [69]. The aerial parts and the whole plant of C. ingrata are used to potentiate the antimalarial activity of extracts from other plant species [120]. C. ingrata is also used in the treatment of syphilis and other venereal diseases [120]. Another species used against syphilis is C. dipetala, which grows naturally in central Colombia. In addition, this plant is also used as an astringent against oral and skin infections [121].
In a study of Hovoraková et al. [43], hydrolyzed C. ignea seed oil, which contains a high amount of capric acid, showed antibacterial activity against some pathogenic Grampositive strains with an MIC value of 0.56-4.5 mg/mL. Most importantly, this hydrolyzed oil was not active toward beneficial commensal bacteria.
Cc-AgNPs (silver nanoparticles synthesized by green chemistry using an aqueous extract of C. carthagenensis leaves as a reducing agent) showed strong antibacterial activity against Gram-positive and Gram-negative bacteria with the lowest MIC (15 µg/mL) and MBC (25 µg/mL) values for Salmonella typhimurium [122]. AgNPs obtained using an aqueous extract of the leaves of C. procumbens were active against Escherichia coli and Staphylococcus aureus, with maximum inhibition zone at the concentration of 0.225 and 0.158 µg/mL, respectively [123].
A study by Andrighetti-Fröhner et al. [124], evaluated the antiviral activity of fractions derived from a hydroethanolic extract of aerial parts of C. carthagenensis. The ethyl acetate, dichloromethane and n-butanol fractions were active against herpes simplex virus type 1 (HSV-1) strain KOS with EC 50 (concentration required to inhibit viral cytopathic effect by 50%) values of 2 µg/mL, 4 µg/mL and 31 µg/mL, respectively. On the other hand, the fractions were inactive against the 29-R-acyclovir-resistant HSV-1 strain and the type 2 poliovirus (PV-2), a Sabin II vaccine strain. It should be noted that Mahmoud et al. [64] recently demonstrated antiviral activity of C. ignea formulations against SARS-CoV-2. Both the polyphenol-rich ethanolic leaf extract dissolved in DMSO and the self-nanoemulsifying formulation (composed of 10% oleic acid, 40% Tween 20 and propylene glycol 50%) showed antiviral activity with IC 50 values of 2.47 and 2.46 µg/mL, respectively. The C. ignea extract in the developed formulation reduced virus replication by 100% at a concentration of 5.87 µg/mL, obtained from dose-response measurements. The anti-SARS-CoV-2 activity of the ethanolic extract of C. ignea could be attributed to polyphenolic compounds, of which rutin, myricetin-3-O-rhamnoside, and rosmarinic acid showed the highest antiviral potential.

Antioxidant Activity
As mentioned above, Cupheas are rich in polyphenols that are well-known natural antioxidants [27]. For this reason, many studies have focused on the in vitro antioxidant activity of Cuphea plants [16,17,48,52,63,92,103]. The results of these studies are presented in Table 4. Most studies provide data on the radical scavenging properties of alcoholic or aqueous-ethanol extracts. Among these, several reports have shown that extracts from various organs of C. aequipetala, C. carthagenensis, C. calophylla, and C. hyssopifolia showed free radical scavenging activity against DPPH [16,17,48,63,92,97]. Recently, the antioxidant activity of methanolic extracts of the leaves of C. carthagenensis was also confirmed by the reduction of the ferricyanide complex (Fe 3+ ) to the ferrous form (Fe 2+ ) in the FRAP assay [17].
It should be noted that some Cuphea species possess the ability not only to scavenge free radicals, but also to inhibit the production of reactive oxygen species (ROS). For example, an ethanolic aqueous extract of the aerial parts of C. calophylla was found to significantly reduce ROS levels (26.2%) in LPS-induced macrophages ( Figure 9) [52].
It is known that overproduction of ROS can be detrimental to biomolecules and cell membranes. An aqueous-ethanolic extract and the ethyl acetate fraction of C. glutinosa reduced lipoperoxidation in rat brain homogenates induced by the pro-oxidant agents: sodium nitroprusside and hydrogen peroxide [63].
As indicated by most authors, the high antioxidant activity of Cuphea plant extracts is closely related to their high content of polyphenols.

Cytotoxic Activity of Cuphea Plants
C. hyssopifolia, a native plant of Mexico and Guatemala, known as false heather, has attracted much attention, mainly due to the presence of oligomeric tannins with reported cytotoxic activity. Chen et al. [125] isolated seven hydrolysable tannins, including cuphiins D 1 and D 2 , oenothein B, and woodfordin, which have since been extensively studied. Their in vitro cytotoxic activity against various human cancer cell lines (KB, HeLa, DU145, and Hep3B; Table 5) has been demonstrated [51]. It should be noted that all compounds tested were less cytotoxic than adriamycin against a normal cell line (WISH). Furthermore, all of these ellagitannins inhibited the viability of S-180 tumor cells, not only in vitro, but also in vivo. Oenothein B showed the highest cytotoxic activity in vitro (IC 50 = 11.4 µg/mL), while cuphiin D 1 prolonged the survival (%ILS = 84.1) of S-180 tumor-bearing ICR mice. Despite the cytotoxic potential of isolated compounds, extracts of C. hyssopifolia showed only moderate activity [48,126]. An aqueous methanolic extract of the aerial parts demonstrated cytotoxicity against MCF-7, Hep2, HCT-116 and HepG2 cell lines with IC 50 92.5, 84.9, 81, and 73.4 µg/mL, respectively [48].
Polyphenol rich n-butanol and ethyl acetate fractions, obtained from the methanolic extract of the aerial parts of C. ingrata, showed cytotoxic effects in several human melanoma cell lines (A375, HTB-140, WM793) [127]. It should be noted that their effect on highly metastatic HTB-140 melanoma cells was greater compared to doxorubicin. However, quantitative analysis showed that the observed activity was not related to the oenothein B content, either in the extract or in the fractions. Oenothein B alone showed moderate activity against human skin and prostate cancer cell lines (DU145, PC3).
Antiproliferative and apoptotic activities of methanolic and aqueous extracts of C. aequipetala have been reported for several cancer cell lines: B16F10, HepG2, and MCF-7 [128]. The methanolic extract induced cell accumulation in G1 phase, DNA fragmentation, and increased caspase-3 activity in B16F10 cells in vitro. In vivo experiments showed that the aqueous extract administered per os to C57BL/6 female mice for 14 days after melanoma induction had greater antitumor activity than the methanolic extract (tumor size reduction of up to 80% and 31%, respectively).
Data referring to cytotoxic activity are summarized in Table 5.   In addition to the previously mentioned possible interactions associated with the concomitant use of Cuphea extracts and blood pressure-lowering drugs, there are a number of other possible effects associated with the use of plant preparations. Particular attention should be paid to the polyphenolic compounds contained in them, for which agonistic or antagonistic effects towards nuclear receptors involved in xenobiotic metabolism have been repeatedly reported [132,133]. Interactions with the pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) are of particular relevance. It seems that at the cellular level, the effects induced by phytochemicals appear to be dual. On one hand, these compounds behave as agonists as they bind to the ligand-binding domain of the PXR; thereby, they can increase the transcriptional activity of downstream genes, especially CYP3A4, CYP2B, CYP2C, glutathione S-transferases, sulfotransferases, UGT, and drug transporters (OATP2, MDR1, MRP2 and MRP3) [132]. On the other hand, they may act as antagonists, either by inhibiting PXR transcription or by binding to the posttranslational active sites of mature CYPs to inhibit their catalytic activity.

Cuphea for Commercial Use
Plants of the Cuphea genus are of great interest, not only owing to their therapeutic value, but also their potential for non-medical use. Due to their ability to synthesize MCFAs, they are valuable crops for the chemical, cosmetic and food industries. Cuphea oils are used in the production of detergents, surfactants, anti-foaming agents, etc. [19]. Cuphea viscosissima seed oil (INCI), in cosmetic products, acts as a hair and skin conditioner, while Cuphea lanceolata/viscosissima seed oil (INCI) is used as a skin conditioner-emollient. Cuphea oil can be an ingredient in decorative cosmetics (e.g., lipsticks), body-care products (bath oils and creams) or hair-care cosmetics (lotions) [134]. Oils with high levels of decanoic acid, due to cross ketonisation reactions with acetic acid, are used in the production of 2-undecanone, which is a well-known aromatic compound and an insect repellent [135]. Cuphea oils are being investigated as a source of biobased lubricants [136]. Estolides synthesized by the reaction of Cuphea fatty acids with oleic acid (especially oleic-octanoate and oleic-decanoate estolide 2-ethyl esters) showed better lubricating properties than other vegetable oils [137,138]. In the food industry, Cuphea oil is used in the chewing gum manufacturing process instead of saturated fats and plasticizers such as glycerol. The oil is also used as a solvent and a release agent in the manufacture of candies.
The production of Cuphea seed oils generates significant amounts of by-products [139]. These are being considered as potential commercial plant growth regulators. Oil cake and pressing residues can be used as organic fertilizers and soil improvers. Cuphea seed oil fractions are potential biodegradable 'environmentally friendly' herbicides.
In addition, Cuphea seed oil can be used in the production of biodiesel and aviation fuel [140]. As a jet fuel additive, it can lower the fuel's freezing point.

Methods
Relevant information on the genus Cuphea was collected through electronic databases, including Scopus, PubMed, Web of Science, Google Scholar, ProQuest and other professional websites. Plant names were verified by The Plant List Database (http://www. theplantlist.org/, accessed on 12 September 2022).

Conclusions
Cuphea P. Browne is the largest genus of the Lythraceae family, comprising mainly herbs and shrubs typical of the warm temperate to tropical regions of the American continent. Several species, especially C. carthagenensis and C. aequipetala, are popular traditional medicines from which herbal teas, infusions, and decoctions are prepared. Diseases most commonly treated with Cuphea extracts include hypertension, gastrointestinal disorders, rheumatism, or infections.
Despite the wide use of Cuphea species in traditional medicine, the scientific literature provides relatively few pharmacological studies. However, data from these studies have shown that the traditional use of some species in the treatment of hypertension, inflammatory conditions, or parasitic infections is well supported. Alcoholic, hydroalcoholic, and water extracts are more frequently used in pharmacological studies than isolated fractions. Often, however, the phytochemical profile of the extracts studied is unknown. In recent years, however, there has been a rapid increase in the number of published reports on Cuphea species.
Initially, research focused on Cuphea seed oils, which contain medium-chain fatty acids, as potential replacements for coconut and palm oils. Today, Cuphea seed oils have gained particular attention as a source of biodiesel fuels and other industrial bioproducts. Therefore, the domestication of Cuphea plants suitable for large-scale cultivation is the subject of intensive agricultural research. Recent phytochemical studies of Cupheas have shown that these plants can be a rich source of various polyphenolic compounds: flavonoids, tannins, phenolic acids, and their derivatives, which are responsible for the hypotensive, antiparasitic, antiviral, and cytotoxic activity of Cuphea extracts, among others. However, further pharmacological research on Cupheas is undoubtedly needed to verify their biological effects and safety under in vivo conditions.

Conflicts of Interest:
The authors declare no conflict of interest.