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

Abstract

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.

1. Introduction

Cuphea P. Browne is an endemic American genus, the largest of the Lythraceae family [1,2]. This monophyletic taxon comprises approximately 240–260 species that grow wild in temperate, subtropical, and tropical regions [3,4]. The Cuphea genus is divided into two subgenera and 13 sections:

• -subgenus Cuphea Koehne (Lythrocuphea Koehne); sections: Archocuphea Koehne, Cuphea;
• -subgenus Bracteolatae S.A.Graham (Eucuphea Koehne); sections: Amazoniana Lourteig, Brachyandra Koehne, Diploptychia Koehne, Euandra Koehne, Heteranthus Koehne, Heterodon Koehne, Leptocalyx Koehne, Melicyathium Koehne, Melvilla Koehne, Pseudocircaea Koehne, Trispermum Koehne [3,5].

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.

Most plants of the genus Cuphea are valuable industrial oil crops due to their ability to synthesize medium-chain fatty acids (MCFAs), including caprylic (C8:0), capric (C10:0), lauric (C12:0), and myristic (C14:0) acids, which are stored in the seeds. Therefore, Cupheas are considered as potential replacements for currently exploited industrial sources of MCFA’s, such as Cocos nucifera L. (coconut) and Elaeis guineensis Jacq. (palm kernel) [19,20].

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.

2. Botanical Characteristics

The name Cuphea comes from Greek κυφός, 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 predominant 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. xanthopetala 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.

3. Phytochemistry

3.1. 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.

Table 1.

Percentage of the predominant fatty acid content in oils of different Cuphea species.

Dominant Fatty Acid	Cuphea Species	Total Fatty Acid Content in Oil (%)	Dominant Fatty Acid	Cuphea Species	Total Fatty Acid Content in Oil (%)
Caprylic (C8:0)	C. avigera var. pulcherrima (R.C.Foster) S.A.Graham	75–94	Lauric (C12:0)	C. laminuligera Koehne	63; 52–60 ***
	C. cordata Ruiz & Pav.	50		C. lobophora Koehne	66
	C. cyanea Moc. & Sessé	68		C. lutea Rose ex Koehne	38; 34–42 ***
	C. hookeriana Walp.	50		C. lutescens Pohl ex Koehne	66; 76; 66 *
	C. painteri Rose ex Koehne	65		C. melanium (L.) R.Br. ex Steud.	77; 86
	C. pinetorum Benth.	48		C. melvilla Lindl.	46; 52
Capric (C10:0)	C. angustifolia Jacq. ex Koehne	67–80		C. micrantha Kunth	43; 53
	C. avigera B.L.Rob. & Seaton	43		C. parsonsia (L.) R.Br. ex Steud.	74; 63 ***
	C. bustamanta Lex.	63		C. pohlii Lourteig	44
	C. caesariata S.A.Graham	86		C. polymorphoides Koehne	80
	C. calaminthifolia Schltdl.	44; 44 *		C. pseudovaccinium A.St.-Hil.	69; 83
	C. calcarata Benth.	64		C. pulchra Moric.	56
	C. cordata Ruiz & Pav.	50		C. retroscabra S.Watson	55
	C. crassiflora S.A.Graham	87		C. rupestris T.B.Cavalc. & S.A.Graham	54
	C. ferrisiae Bacig.	82; 82 *		C. sclerophylla Koehne	60; 67
	C. hookeriana Walp.	50		C. sessiliflora A.St.-Hil.	64; 37 *
	C. humifusa S.A.Graham	82		C. setosa Koehne	62
	C. ignea A.DC.	87; 54 ****		C. sincorana T.B.Cavalc.	39
	C. inflata S.A.Graham	86		C. spermacoce A.St.-Hil.	49
	C. koehneana Rose	92: 92 *		C. splendida Lourteig	51
	C. lanceolata W.T.Aiton	83; 78–91 ***		C. strigulosa Kunth	53 **
	C leptopoda Hemsl.	87		C. teleandra Lourteig	71
	C. llavea Lex.	86; 88; 83 ***; 92 ***		C. tolucana Peyr.	53; 46–64 ***
	C. lophostoma Koehne	62; 81		C. trochilus S.A.Graham	62; 62 *
	C. micropetala Kunth	26		C. thymoides Cham. & Schltdl.	56; 65
	C. nitidula Kunth	74		C. tuberosa Cham. & Schltdl.	56
	C. paucipetala S.A.Graham	87		C. urbaniana Koehne	48
	C. procumbens Ortega	80; 82; 81–89 ***		C. urens Koehne	76
	C. quaternata Bacig.	63; 63 *		C. vesiculigera R.C.Foster	71; 71 *
	C. schumannii Koehne	94		C. viscosa Rose ex Koehne	60; 60 *
	C. viscosissima Jacq.	76; 76 *		C. wrightii A.Gray	54; 54 **
Lauric (C12:0)	C. acinifolia A.St.-Hil.	65		C. wrightii var. wrightii	58–73 ***
	C. acinos A.St.-Hil.	64	Myristic (C14:0)	C. aequipetala Cav.	56
	C. adenophylla T.B.Cavalc.	73		C. epilobiifolia Koehne	55; 55 *
	C. appendiculata Benth.	73; 83; 83 *		C. palustris Koehne	64; 71
	C. bahiensis (Lourteig) S.A.Graham & T.B.Cavalc.	47		C. rasilis S.A.Graham	49
	C. brachiata Mart. ex Koehne	47		C. salvadorensis (Standl.) Standl.	65
	C. brachypoda T.B.Cavalc.	47		C. sessiifolia Mart.	37
	C. calophylla Cham. & Schltdl.	62–85; 85 *; 56–65 ***		C. strigulosa subsp. nitens Koehne	37
	C. calophylla subsp. calophylla	58–72 ***		C. strigulosa subsp. opaca Koehne	45; 45 *
	C. calophylla subsp. mesostemon (Koehne) Lourteig	59–70 ***		C. tetrapetala Koehne	51
	C. carthagenensis (Jacq.) J.F.Macbr.	61; 81; 59 **; 59–67 ***	Oleic (C18:1)	C. circaeoides Sm. ex Sims	48
	C. confertiflora A.St.-Hil.	73		C. denticulata Koehne	53
	C. diosmifolia A.St.-Hil.	64	Linoleic (C18:2)	C. decandra Dryand.	45
	C. egleri Lourteig	57		C. flavovirens S.A.Graham	23; 23 *
	C. ericoides Cham. & Schltdl.	43		C. fruticosa Spreng.	67
	C. ferrisiae Bacig.	35		C. linarioides Cham. & Schltdl.	34–62
	C. ferruginea Pohl ex Koehne	55		C. lindmaniana Koehne ex Bacig.	55; 55 *
	C. flava Spreng.	43		C. linifolia Koehne	49; 63
	C. gardneri Koehne	68		C. mimuloides Schltdl. & Cham.	30
	C. glareosa T.B.Cavalc.	49		C. pascuorum Mart. ex Koehne	53
	C. glossostoma Koehne	58 ***		C. purpurascens Bacig.	36; 36 *
	C. glutinosa Cham. & Schltdl.	50; 82; 54 ***		C. subuligera Koehne	29
	C. grandiflora Pohl ex Koehne	62		C. utriculosa Koehne	31
	C. heterophylla Benth.	48; 42 ***	Linolenic (C18:3)	C. spectabilis	31; 31 *
	C. hyssopifolia Kunth	79
	C. ingrata Cham. & Schltdl.	65; 69
	C. jorullensis Kunth	53; 53 *

The table was compiled on the basis of the data reported in: [34]; * [42]; ** [20]; *** [41]; **** [43].

3.2. 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 D₁, cuphiin D₂, oenothein B, and woodfordin) are of great interest due to their anticancer properties [51].

Figure 1.

Chemical structures of flavonoids and their derivatives of the genus Cuphea.

Figure 2.

Chemical structures of phenolic acids and their derivatives of the genus Cuphea.

Figure 3.

Chemical structures of tannins of the genus Cuphea.

Figure 4.

Chemical structures of stilbenes of the genus Cuphea.

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 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 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.

3.3. Other Phytochemicals

Other phytochemicals reported in various Cuphea species include triterpenes (e.g., carthagenol; Figure 5), sterols (Figure 6), alkaloids and coumarins (e.g., 5,7-dihydroxy-3-methoxycoumarin 5-O-β-glucopyranoside; Figure 7) [55,56,57,58].

Figure 5.

Chemical structures of triterpenes of the genus Cuphea.

Figure 6.

Chemical structures of sterols of the genus Cuphea.

Figure 7.

Chemical structures of (iso)coumarins of the genus Cuphea.

Table 2 summarizes the results of phytochemical research on the genus Cuphea.

Table 2.

Compounds reported in the genus Cuphea.

Cuphea Species	Compound	Reference	Cuphea Species	Compound	Reference
C. acinos A.St.-Hil. (a) leaves	Apigenin-C-glycoside Isorhamnetin-3-O-galactoside	[49]	C. appendiculata Benth. (a) aerial part	β-Amyrin Betulinic acid Epifriedelanol β-Sitosterol Stigmasterol Mannitol	[56]
C. adenophylla T.B.Cavalc. (a) leaves	Quercetin-3-O-arabinoside Quercetin-3-O-glucoside Quercetin-3-O-rhamnosylglucoside Quercetin-3-O-galactosylgalactosid	[49]	C. calophylla Cham. & Schltdl. (a) leaves	Quercetin Quercetin-3-(2-galloylglucoside) Quercetin-3-O-(6′′-O-α-L-rhamnose)-β-D-glucoside Quercetin-3-arabinoside Quercetin-3-O-α-L-rhamnoside Quercetin-3-O-β-glucoside Kaempferol Kaempferol-3-glucoside Kaempferol-galloyl-glucoside Kaempferol-3-xyloside Kaempferol-7-rhamnoside Myricetin-3-(2-galloyl-glucoside) Myricetin-3-glucoside Myricetin-3-xyloside Myricetin-3-O-α-L-rhamnoside	[59]
C. aequipetala Cav. (a) aerial parts (b) leaves	Mannitol Quercetin-3-β-D-glucoside	[60] [53]
C. aequipetala var. hispida Koehne (a) leaves	Quercetin-3-β-D-glucoside Sitotenone Stigmastenone	[53]
C. aperta Koehne (a) whole plant	Quercetin Kaempferol Gallic acid Methyl gallate Protocatechuic acid α-Amyrin, β-Amyrin Lupeol Stigmasterol β-Sitosterol Campestenone, Sitostenone, Stigmastenone	[61]	C. calophylla subsp. mesostemon (Koehne) Lourteig (a) fresh aerial parts	Kaempferol Gallic acid O-Galloylquinic acid Di-O-galloylquinic acid Brevifolincarboxylic acid Epigallocatechin Ellagic acid 3-O-Methyl ellagic acid 4′-sulfate 3-O-Methyl ellagic acid	[62]
C. carthagenensis (Jacq.) J.F.Macbr. (a) aerial parts (b) fresh aerial parts (c) aerial parts (d) leaves	β-Sitosterol, Stigmasterol Epifriedelanol Ergosterol, Carthagenol β-Amyrin Lauric acid, Myristic acid Betulinic acid, Ursolic acid Mannitol Quercetin-3-sulfate Quercetin-5-O-β -glucoside Quercetin-3-O-β-arabinofuranoside Quercetin-3-sulfate Quercetin Quercetin-5-O-β-glucoside Quercetin-3-O-(6′′-O-α-L-rhamnosyl)-β-D-glucoside Quercetin-3-O-β-D-glucuronide Quercetin-3-O-β-glucoside Quercetin-3-sulfate Quecertin-3-O-arabinofuranoside Kaempferol Kaempferol-rutinoside Kaempferol-3-glucoside Kaempferol 3,7-dirhamnoside Myricetin-glucoside Chlorogenic acid	[56] [50] [45] [60,62]	C. crulsiana Koehne (a) leaves	Quercetin Quercetin-3-O-arabinoside Quercetin-3-O-(glucose-rhamnose) Rhamnetin-3-O-glucoside Isorhamnetin-3-O-arabinoside	[49]
			C. diosmifolia A.St.-Hil. (a) leaves	Quercetin Quercetin-3-O-galactoside Quercetin-3-O-(glucose-glucuronic acid) Rhamnetin-3-O-galactoside Myricetin-3-O-galactoside Myricetin-3-O-glucoside	[49]
			C. disperma A.St.-Hil. (a) leaves	Apigenin-C-glycoside Quercetin-3-O-arabinoside Quercetin-3-O-galactoside Quercetin-3-O-glucosyl-glucosyl-glucoside	[49]
			C. epilobiifolia Koehne (a) aerial part	β-Sitosterol, β-Amyrin Epifriedelanol Betulinic acid Mannitol	[56]
C. cipoensis T.B.Cavalc. (a) leaves	Isorhamnetin-3-O-galactoside Myricetin-3-O-galactoside	[49]	C. ericoides Cham. & Schltdl. (a) leaves	Quercetin-3-O-galactoside Kaempferol-3-O-galactoside Myricetin-3-O-arabinosyl-arabinoside Myricetin-3-O-galactosyl-galactosyl-galactoside	[49]
C. glutinosa Cham. & Schltdl. (a) whole plant (b) leaves	Quercetin Quercetin-3-O-β-glucoside Kaempferol β-Sitosterol-3-O-β-glucoside Methyl gallate Gallic acid Quercetin Quercetin-3-O-β-D-glucuronide Quercetin-3-arabinoside Quercetin-3-O-α-L-rhamnoside Quercetin-acetyl-glucuronide Quercetin-3-O-β-glucoside Kaempferol Kaempferol-3-glucoside Kaempferol-3-glucuronide 6"-O-Galloylquercimeritrin Isorhamnetin Myricetin-3-O-glucuronide 3-Feruloylquinic acid	[63] [45,60]	C. hyssopifolia (a) aerial part (cont.)	Methyl gallate Epifriedelanol Ursolic acid Mannitol 1,3-O-Digalloyl-4-,6-hexahydroxydiphenoyl-β-D−4C1-glucoside Genistein-7-O-β-D-4C1-glucoside Myricetin-3-O-β-D-4C1-glucoside Valoneic acid dilactone Gallic acid 3,4,5-Trimethoxy benzoic acid Vanillic acid
C. hyssopifolia Kunth (a) aerial part	1,2,3,6-Tetra-O-galloyl-β-D-glucose 1,2,3,4,6-Penta-O-galloyl-β-D-glucose Myricetin 3-O-α-L-rhamnoside Tellimagrandin II Woodfordin C Oenothein B Cuphiin D1 Cuphiin D2 Quercetin Quercetin-3-O-α-rhamnoside	[47,64,65]	C. ignea A.DC. (a) fresh plant (b) leaves	7-Hydroxy-3-methoxycoumarin 5-O-β-glucoside Quercetin Quercetin-3-O-(6″-O-α-L-rhamnose)-β-D-glucoside Naringenin Myricetin-3-O-rhamnoside Catechin p-Coumaric acid o-Coumaric acid Gallic acid Caffeic acid Syringic acid Vanillic acid Cinnamic acid Rosmaric acid Chlorogenic acid Resveratrol	[57] [64]
C. ingrata Cham. & Schltdl. (a) leaves and thalli (b) aerial parts	Caffeine Quercetin Quercetin-3-O-(6′′-O-α-L-rhamnose)-β-D-glucoside Quercetin-3-O-β-D-glucoside Quercetin-3-O-β-D-glucuronide Quercetin-3-O-α-L-arabinoside Quercetin-3-O-α-L-arabinofuranoside Quercetin sulfate Quercetin-3-O-β-D-glucuronide butyl ester Kaempferol Kaempferol-3-O-(6′′-O-α-L-rhamnose)-β-D-glucoside Kaempferol-3-O-β-D-glucoside Methyl gallate, Gallic acid Protocatechuic acid p-Hydroxybenzoic acid Caffeic acid, Syringic acid Vanillic acid, p-Coumaric acid 1,3-Dicaffeoylquinic acid Ferulic acid Ellagic acid 1,5-Dicaffeoylquinic acid Oenothein B Cuphiin D2/Woodfordin C	[65] [47]	C. linarioides Cham. & Schltdl. (a) leaves	Myricetin-3-O-glucoside Myricetin-3-O-rhamnoside Myricetin-3-O-(glucose-rhamnose)	[49]
			C. lindmaniana Koehne ex Bacig. (a) leaves	Quercetin Quercetin 3-O-β-D-glucuronide Quercetin-3-arabinoside Quercetin-acetyl-glucuronide Quercetin-3-(4″-malonylrhamnoside) Quercetin-3-O-β-glucoside Kaempferol Kaempferol-3-xyloside Kaempferol-3-glucuronide 3-Methylellagic acid 8-rhamnoside Chlorogenic acid Chicoric acid	[66]
			C. lutea Rose ex Koehne (a) seed oil	Campesterol Stigmasterol β-Sitosterol Δ5-Avenasterol Δ7-Stigmastenol	[67]
C. lanceolata W.T.Aiton (a) seed oil (b) leaves	Campesterol Stigmasterol β-Sitosterol Δ5-Avenasterol Δ7-Stigmastenol Quercetin-3-β-D-glucoside	[67] [53]	C. lutescens Pohl ex Koehne (a) leaves	Quercetin-3-O-galactoside Quercetin-3-O-glucoside Quercetin-3-O-(arabinose-glucose) Isorhamnetin-3-O-(glucose-rhamnose) Myricetin-3-O-arabinoside Myricetin-3-O-galactoside Myricetin-3-O-(arabinose-galactose)	[49]
C. paucipetala S.A.Graham (a) seed oil	Campesterol Stigmasterol β-Sitosterol Δ5-Avenasterol Δ7-Stigmastenol	[67]	C. racemosa (L.f.) Spreng. (a) leaves	Quercetin Quercetin-3,7-diglucoside Quercetin-3-O-(6′′-O-α-L-rhamnose)-β-D-glucoside Quercetin-3-O-β-D-glucuronide Quercetin-3-arabinoside Quercetin-3-O-β-glucoside Kaempferol Kaempferol-3-O-rutinoside Kaempferol-3-glucuronide Myricetin-3-O-glucuronide Myricetin-3-O-glucoside Myricetin-3-O-α-L-rhamnoside Chlorogenic acid, 3-Feruloylquinic acid	[59]
C. pinetorum Benth. (a) roots (b) aerial part	Quercetin Kaempferol Quercetin Quercetin-3-O-α-rhamnoside Kaempferol Luteolin-7-O-β-D-glucoside Apigenin-7-O-α-rhamnoside Apigenin-7-O-β-D-glucoside Squalene, β-Sitosterol	[68] [69]	C. rubrovirens T.B.Cavalc. (a) leaves	Quercetin-3-O-galactoside Quercetin-3-O-(galactose-glucose) Rhamnetin-3-O-galactoside	[49]
C. pseudovaccinium A.St.-Hil. (a) leaves	Quercetin Quercetin-3-O-galactoside Quercetin-3-O-(galactose-rhamnose) Kaempferol-3-O-(galactose-glucose) Kaempferol-3-O-(glucose-rhamnose) Myricetin	[49]	C. sclerophylla Koehne (a) leaves	Quercetin Quercetin-3-O-galactoside Luteolin-7-O-galactoside Luteolin-7-O-(glucose-glucuronic acid) Myricetin-3-O-glucoside	[49]
C. pulchra Moric. (a) leaves	Quercetin-3-O-arabinoside Quercetin-3-O-galactosyl-galactoside Quercetin-3-O-rhamnosyl-glucoside Rhamnetin-3-O-glucoside Isorhamnetin-3-O-xyloside Myricetin	[49]	C. sessilifolia Mart. (a) leaves	Quercetin-3-O-arabinoside Quercetin-3-O-galactoside Quercetin-3-O-(galactose-glucose) Quercetin-3-O-(galactose-glucuronic acid) Quercetin-3-O-glucosyl-glucoside Quercetin-3-O-(glucose-glucuronic acid) Quercetin-3-O-rhamnosyl-glucoside Myricetin-3-O-galactoside	[49]
C. sperguloides A.St.-Hil (a) leaves	Myricetin-3-O-galactoside	[49]	C. viscosissima Jacq. (a) seed oil	Campesterol Stigmasterol β-Sitosterol Δ5-Avenasterol Δ7-Stigmastenol	[67]
C. teleandra Lourteig (a) leaves	Quercetin-3-O-arabinoside Quercetin-3-O-glucoside Quercetin-3-O-(glucose-rhamnose) Isorhamnetin-3-O-galactoside	[49]
C. urbaniana Koehne (a) leaves	Quercetin Quercetin-4′-galactoside Quercetin-3-O-(6′′-O-α-L-rhamnose)-β-D-glucoside Quercetin-3-O-β-D-glucuronide Quercetin-3-O-malonylglucoside Quercetin-galloyl rhamnoside Quercetin-3-O-α-L-rhamnoside Quercetin-3-O-β-glucoside Kaempferol Kaempferol-3-glucoside Apigenin-7-O-glucoside	[66]	C. wrightii A.Gray (a) seed oil (b) whole plant	Campesterol Stigmasterol β-Sitosterol Δ5-Avenasterol Δ7-Stigmastenol Quercetin-3-O-β-D-galactoside Luteolin-7-O-β-D-glucoside β-Sitosterol-3-O-β-D-glucoside Epifriedelanol Fernenol Germanicol Ursolic acid Mannitol	[67] [70]

4. 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.

Table 3.

Medicinal uses of Cuphea plants.

Species	Part of the Plant	Form (Route of Administration)	Traditional Use	Reference
C. aequipetala	aerial parts	decoction (topically; wound washing)	wound healing bumps bruises throat pain	[18]
		infusion	cough gastrointestinal disorders
		not mentioned	diarrhea stomachache	[74]
C. calophylla var. macrostemon	aerial parts	decoction	anti-hypertensive	[75]
C. carthagenensis	leaves, aerial parts	decoction (orally)	anti-hypertensive lipid-lowering	[76]
	whole plant leaves roots	maceration infusion	not mentioned	[77]
	roots	decoction (orally)	anti-hypertensive	[78]
	aerial parts	infusion (orally)	intestinal and heart problems	[79]
	stems and leaves	maceration in rum (topically)	sprains	[80]
		infusion (orally)	colds, chills
	not mentioned	not mentioned	digestive problems diarrhea stomachache bowel infections leg pain varicose veins	[81]
C. epilobiifolia	stems	decoction (orally)	rheumatism	[82]
	leaves	decoction (baths)	rheumatism
C. glutinosa	aerial parts	infusion (orally)	hypercholesteremia	[83]
C. hyssopifolia	leaves and flowers		cough fever as insecticide and tonic	[84]
C. ingrata	whole plant leaves stems	maceration infusion	cardiovascular system diseases musculoskeletal and joint diseases	[85]
C. lysimachioides	xylopodium	infusion	diarrhea as astringent	[86]
		decoction	throatache
C. pinetorum	aerial parts	decoction (orally)	diarrhea dysentery	[69]
C. racemosa	not mentioned	infusion decoction (orally)	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].

5. 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.

Figure 8.

Biological activity of Cuphea extracts.

Table 4.

The results of pharmacological studies on Cuphea sp.

Cuphea Species	Biological Activity Tested	Results	Assay/Model	References
C. aequipetala (ethanol extract from leaves and stems)	antinociceptive anti-inflammatory	- antinociception in the acetic acid test (dose-dependent ↓ in the number of abdominal constrictions, ED50 = 90 mg/kg) and in the second phase of the formalin test (ED50 = 158 mg/kg), probably due to the involvement of nitric oxide and ATP-sensitive K+ channels - no effect in hot-plate test (doses: 50–200 mg/kg) - inhib. of production of NO (IC50 = 420 μM/mL) and H2O2 (IC50 = 416 μM/mL) in LPS-treated macrophages in a concentration-dependent manner - significant ↑ in the production of IL-10 (EC50 = 10 pg/mL) - ↓ of ear oedema by 25.7% after topical application of 2 mg of the extract - ↓ of the levels of IL-1β, IL-6, TNF-α, and PGE2 induced by the extract at the concentration of 100 mg/kg and 200 mg/kg	male Balb/c mice in vivo acetic acid-induced writhing test in vivo formalin test in vivo hot plate test in vitro LPS-stimulated primary murine macrophages male Balb/c mice in vivo TPA-induced ear oedema male Balb/c mice in vivo carrageenan-induced mouse paw oedema	[91]
C. aequipetala (ethanol extract from shoots and leaves)	anti-lipase antioxidant	- non-competitive inhib. of porcine pancreatic lipase (PPL) up to 60% - effect on the kinetic parameters of PPL: Km (mM) 0.365 ± 0.014 at the concentration of 50 μg/mL 0.362 ± 0.019 at the concentration of 100 μg/mL - high antioxidant activity against the DPPH radical with IC50 = 6.5 μg/mL	in vitro inhib. of PPL in vitro DPPH assay	[92]
C. aequipetala (methanol extracts from leaves, stems and roots of wild-grown and greenhouse grown plants)	antioxidant	- free-radical scavenging activity of extracts [μM trolox/g DW] - from wild-grown plants: leaves 169.33 ± 2.10 stems 19.19 ± 0.10 roots 85.62 ± 0.48 leaves 494.37 ± 8.6 stems 106.71 ± 0.3 roots 209.38 ± 1.2 - from greenhouse grown plants: leaves 87.83 ± 0.8 stems 21.86 ± 0.3 roots 43.26 ± 0.2 leaves 119.50 ± 0.3 stems 117.74 ± 0.2 roots 43.38 ± 0.1	- in vitro DPPH assay - in vitro ABTS assay - in vitro DPPH assay - in vitro ABTS assay	[16]
C. aequipetala (extracts from leaves, flowers and stems)	antimicrobial	- no significant inhib. of bacteria and yeast cultures growth compared to common antibiotics: amoxicillin, ampicillin, carbenicillin, cephalotaxin, cephalothin, chloramphenicol, fosfomycin, gentamicin, penicillin, sulfamethoxazole, trimethopim	in vitro disc-diffusion method Staphyllococcus aureus, Staphyllococcus sp. coagulase-negative, Enterococcus faecalis, Escherichia coli, Candida albicans	[93]
C. aequipetala (methanol and aqueous extracts from aerial parts)	anti-Helicobacter pylori	- inhib. of the growth of H. pylori - aqueous extract: MIC 125 μg/mL - methanol extract: MIC >500 μg/mL	in vitro agar dilution method in vitro broth dilution method Helicobacter pylori	[74]
C. aequipetala (aqueous extracts from aerial parts prepared by infusion)	anti-Helicobacter pylori gastroprotective anti-inflammatory	- inhib. of the growth of H. pylori in a concentration dependent manner - promotion of bacterial lysis - MIC 125 μg/mL - ↓ of the ethanol-induced gastric lesions in a dose-dependent manner - 88% protective effect of the extract at the dose of 300 mg/kg, comparable to the effect (87%) of the reference drug carbenoxolone at the dose of 100 mg/kg - xylene-induced ear edema inhib. [%] after topical application of the extract 2.4 ± 2.7 at the dose of 0.1 mg of the extract 14.6 ± 2.5 at the dose of 0.25 mg 22.0 ± 4.0 at the dose of 0.5 mg - xylene-induced ear edema inhib. [%] after oral application of the extract 16.9 ± 4.4 at the dose of 10 mg/kg of the extract 36.4 ± 7.7 at the dose of 30 mg/kg 35.0 ± 3.0 at the dose of 100 mg/kg - TPA-induced ear edema inhib. [%] after topical application of the extract 10.4 ± 2.0 at the dose of 0.1 mg of the extract 14.3 ± 3.0 at the dose of 0.25 mg 23.7 ± 4.9 at the dose of 0.5 mg - TPA-induced ear edema inhib. [%] after oral application of the extract 12.2 ± 1.4 at the dose of 10 mg/kg of the extract 15.6 ± 2.2 at the dose of 30 mg/kg 27.3 ± 1.0 at the dose of 100 mg/kg	in vitro broth dilution method Helicobacter pylori male CD-1 mice in vivo ethanol-induced gastric ulcer model male CD-1 mice in vivo xylene and TPA-induced ear edema	[94]
C. aequipetala var. hispida (aqueous–ethanol extract)	antimicrobial antioxidant	- inhib. halo sizes [mm] (the preparation of 50% ethanolic extracts carried out with a 125 mg/mL dried matter plant concentration) L. monocytogenes 7.0 ± 0.0 Staphylococcus sp. 10 ± 1.0 E. coli 8 ± 0.03 S. enterica 8.0 ± 1.0 - free-radical scavenging activity [uM TEAC/g]—1756.59 ± 1.9	in vitro agar diffusion susceptibility test disc method Listeria monocytogenes (ATCC 19115), Staphylococcus sp., Escherichia coli (ATCC 25922), Salmonella enterica serotype Enteritidis (ATCC 13076) in vitro ABTS assay	[72]
C balsamona Cham. & Schltdl. (aqueous extract)	hypocholesteremic	- significant ↓ in cholesterol and triglycerides blood levels (vs. control) during chronic treatment with different concentrations of aqueous extract - 50 mg/L total cholesterol 500.0 ± 108.25 (vs. 857.81 ± 56.22) triglycerides 80.95 ± 27 (vs. 173.80 ± 63.35) HDL 38.65 ± 1.03 (vs. 69.32 ± 3.34) VLDL 16.31 ± 5.36 (vs. 34.75 ± 12.67) LDL 445.16 ± 101.71 (vs. 753.73 ± 55.17) - 100 mg/L total cholesterol 684.37 ± 98.22 (vs. 857.81 ± 56.22) triglycerides 61.90 ± 22.67 (vs. 173.80 ± 63.35) HDL 48.28 ± 7.33 (vs. 69.32 ± 3.34) VLDL 12.37 ± 4.53 (vs. 34.75 ± 12.67) LDL 623.72 ± 92 (vs. 753.73 ± 55.17)	young adult male Wistar rats submitted to a high cholesterol diet in vivo dyslipidemia model	[95]
C. calophylla (aqueous–ethanol extract of aerial parts)	antioxidant	- free-radical scavenging activity [μM ET/g] - 1761.92 ± 3.05 - 3756.65 ± 2.48	in vitro FRAP assay in vitro ORAC assay	[52]
C. calophylla (aqueous–ethanol extract of leaves)	anti-inflammatory	- significant ↓ in the ROS levels - no significant cytoprotective effect on the cell death induced by LPS and no effect on NO production in macrophages - inhib. activity against COX and LOX - 100% inhib. of PMNs migration at the concentration 10 μg/mL	in vitro inhib. of rat PMNs chemotaxis, employing a modified Boyden chamber	[96]
C. carthagenensis (ethanol–aqueous extract of leaves)	antihypertensive	- ACE-inhib. activity: 26.12% at the concentration of 100 ng/mL	in vitro ACE-inhib. assay	[59]
C. carthagenensis (dichloromethane– methanol extract of leaves)	antihypertensive	- ACE-inhib. activity: 50% at the concentration of 100 μg/mL	in vitro ACE-inhib. assay	[79]
C. carthagenensis (infusion of aerial parts and ethanol-soluble fraction)	diuretic antioxidant	- no changes in renal function or cortical blood flow - DPPH free radical scavenging of ethanol-soluble fraction: - IC50 = 18 ± 4.1 ug/mL - max activity—95 ± 1.8% at the concentration of 30 ug/mL - NO radical scavenging of ethanol-soluble fraction: - IC50 = 465 ± 4.1 ug/mL - max activity—68 ± 2.5% at the concentration of 1000 ug/mL	male Wistar rats in vivo laser-Doppler flowmetry in vitro DPPH assay in vitro nitric oxide radical assay	[97]
C. carthagenensis (aqueous extract of aerial parts and isolated fractions)	antinociceptive anti-inflammatory	- ↓ of the acetic acid-induced writhing in mice by aqueous extract (10 to 100 mg/kg) and semi-purified fraction (0.1 to 10 mg/kg) by 40 to 50% and by 46 to 70% of control, respectively; no effect in the tail flick response - the carrageenin-induced paw edema volume ↓ by semi-purified fraction at a dose of 100 mg/kg (p.o.) by 82% in the 1st hour after carrageenin injection and by 37% in the 3rd hour	adult albino male mice in vivo acetic acid-induced writhing test in vivo tail flick test in vivo carrageenan-induced rat paw oedema	[98]
C. carthagenensis (ethanol-soluble fraction of infusion of leaves)	serum lipid-lowering	- ↓ in oxidative stress and significant ↓ of the CAT (17,274.7 μM min mg) and ↑ of the SOD (3571.2 μM min mg) activities in liver after 4-weeks treatment with the ethanol-soluble fraction (100 mg/kg) - no significant change in the glutathione-S-transferase activity - ↓ of the serum triglycerides (TG), total cholesterol fractions (LDL-C and VLDL-C) levels and ↑ of the level of HDL-C after 4-weeks-treatment (vs. positive control) - at dose of 10 mg/kg TG 166 ± 35 (vs. 190 ± 28) LDL-C 166 ± 33 (vs. 185 ± 20) VLDL-C 78 ± 9.2 (vs. 81 ± 10) HDL-C 7.8 ± 0.8 (vs. 7.2 ± 0.3) - at dose of 30 mg/kg TG 140 ± 31 (vs. 190 ± 28) LDL-C 122 ± 15 (vs. 185 ± 20) VLDL-C 57 ± 6.9 (vs. 81 ± 10) HDL-C 8.2 ± 0.2 (vs. 7.2 ± 0.3) - at dose of 100 mg/kg TG 147 ± 25 (vs. 190 ± 28) LDL-C 117 ± 17 (vs. 185 ± 20) VLDL-C 56 ± 7.1 (vs. 81 ± 10) HDL-C 8.6 ± 0.4 (vs. 7.2 ± 0.3)	New Zealand (NZ) rabbits undergoing cholesterol-rich diet in vivo dyslipidemia and atherosclerosis model	[99]
C. carthagenensis (infusion of herb)	body weight control	- significant ↓ in cholesterolemia while chronic (4-weeks; infusion administrated to the rats ad libitum) treatment (vs. control) - cholesterol [mg/dL] 57 ± 9 (vs. 96 ± 23) - no significant effect on glycemic level, body weight and triglyceride level in comparison to control group	male Wistar rats undergoing a high calorie diet	[100]
C. carthagenensis (ethanol and aqueous extracts of aerial parts and derived fractions)	vasorelaxant	- vasodilatation on pre-contracted rat aortic rings probably associated with polyphenolic compounds - vasodilatation [pIC50] (max vasodilatation %): - ethanol extract 4.92 ± 0.11 (81.8 ± 5.1) - aqueous extract not calculated (46.8 ± 14.4) - n-butanol fraction 4.98 ± 0.06 (86.2 ± 1.6) - methanol-insoluble water fraction 4.53 ± 0.03 (94.8 ± 4.3) - methanol-soluble water fraction 4.85 ± 0.11 (89.1 ± 4.5) - emulsion 4.93 ± 0.07 (86.0 ± 7.1)	ex vivo aortic rings with functional endothelium, pre-contracted with phenylephrine, from male Wistar rats	[45]
C. carthagenensis (aqueous–ethanol-extract of aerial parts)	vasorelaxant	- the n-butanol fraction induced relaxation in rat aortic rings (IC50 = 6.85 μg/mL) through two separate mechanisms - endothelium-dependent: stimulation and/or potentiation of NO release and stimulation and/or potentiation of NO release - endothelium-independent: free radical-scavenging properties	ex vivo endothelium-intact rings of thoracic aorta from male Wistar rats	[101]
C. carthagenensis (ethanol-soluble fraction of aqueous extract from aerial parts)	cardioprotective	- inhib. of the progression of the cardiorenal disease while a 4-weeks treatment - modulation of the antioxidant defense system - NO/cGMP activation and K+ channel opening-dependent vasodilator effect	female Wistar rats in vivo two-kidney, one-clip (2K1C) model	[102]
C. carthagenensis (aqueous–ethanol extract of leaves and n-butanol and ethyl acetate fractions)	antioxidant	- inhib. of uric acid formation and inhib. of NBT ↓ by O2− - concentration-dependent inhib. of deoxyribose degradation - inhib. of lipid peroxidation induced by t-butyl-peroxide	in vitro xanthine/xanthine oxidase assay in vitro deoxyribose degradation assay in vitro lipid peroxidation assay	[103]
C. carthagenensis (methanol extract of leaves)	antioxidant anti-biofilm and QS-related virulence factors	- dose-dependent DPPH scavenging activity - max activity at 1.0 mg/mL (64.79 ± 0.83%) - ↓ of ferricyanide complex (Fe3+) to the ferrous form (Fe2+) - inhib. of biofilm formation at the concentration of 1 mg/mL by - 81.88 ± 2.57% (TCP method) - 72.14 ± 3.25% (tube method) - inhib. of production of QS-dependent virulence factors in Pseudomonas aeruginosa at sub-lethal concentrations of extract without affecting bacterial growth: - significant ↓ in pyocyanin production - max inhib. at the concentration of 1.0 mg/mL by 84.55 ± 1.63% - at the concentration of 0.25 mg/mL by 77.50 ± 2.10% - inhib. of violacein production (83.31 ± 2.77%) in Chromobacterium violaceum	in vitro DPPH assay in vitro FRAP assay in vitro tissue culture plate method (TCP) in vitro tube method microscopic techniques Chromobacterium violaceum ATCC12472, Pseudomonas aeruginosa MTCC 2297	[17]
C. glutinosa (aqueous–ethanol extract of leaves)	antihypertensive	- ACE-inhib. activity [%] of the extract of leaves collected in: - Alegrete 31.66 - Unistalda 26.32 - miquelianin 32.41	in vitro ACE-inhib.	[59]
C. glutinosa (aqueous and ethanol extracts of whole plant and derived fractions)	antioxidant inhibitory activity on Na+, K+-ATPAse	- DPPH scavenging activity [EC50 μg/mL] - aqueous extract 64.75 - ethyl acetate fraction 16.77 - ethanolic extract 42.17 - lower antioxidant capacity compared with the standard quercetin 2.059 - inhib. of the enzyme activity by the ethanolic extract at the concentration above 100 μg/mL with EC50 = 84.54 (48.77 to 146.6) μg/mL	in vitro DPPH assay in vitro ATPase extracted from male Wistar rat heart muscle membranes	[63]
C. glutinosa (roots and leaves infusions and macerations)	antifungal	- MIC [μg/mL] values: - roots infusion Trichosporon asahii TBE 23 7.8 T. asahii TAH 09 1.9 Candida parapsilosis RL 36 15.9 C. parapsilosis RL 07 62.5 Candida glabrata CG 08 >500 C. glabrata CG 10 >500 Candida tropicalis 102 A 62.5 C. tropicalis 72 A 62.5 - leaf infusion Trichosporon asahii TBE 23 1.9 T. asahii TAH 09 1.9 Candida parapsilosis RL 36 7.8 C. parapsilosis RL 07 31.25 Candida glabrata CG 08 >500 C. glabrata CG 10 >500 Candida tropicalis 102 A 62.5 C. tropicalis 72 A 62.5 - root maceration Trichosporon asahii TBE 23 3.9 T. asahii TAH 09 15.6 Candida parapsilosis RL 36 62.5 C. parapsilosis RL 07 62.5 Candida glabrata CG 08 >500 C. glabrata CG 10 >500 Candida tropicalis 102 A 62.5 C. tropicalis 72 A 62.5 - leaf maceration Trichosporon asahii TBE 23 1.9 T. asahii TAH 09 500 Candida parapsilosis RL 36 31.25 C. parapsilosis RL 07 31.25 Candida glabrata CG 08 62.5 C. glabrata CG 10 >500 Candida tropicalis 102 A 15.6 C. tropicalis 72 A 15.6	in vitro broth microdilution method Trichosporon asahii TBE 23, T. asahii TAH 09, Candida parapsilosis RL 36, C. parapsilosis RL 07, C. glabrata CG 08, C. glabrata CG 10, C. tropicalis 102 A, C. tropicalis 72 A	[46]
C. hyssopifolia (aqueous–methanol extract)	antioxidant	- inhib. of DPPH radical at 95.5% (IC50 = 12.34 μg/mL) compared to ascorbic acid—at 98.35% (IC50 = 1.82 μg/mL)	in vitro DPPH assay	[48]
C. hyssopifolia (methanol extract of leaves)	hepatoprotective	- changes in SOD, CAT, and MDA levels after pretreatment with the extract at the concentrations of 200 and 400 mg/kg, (vs. paracetamol-treated control) [IU/L] - 200 mg/kg SOD 0.25 ± 0.02 (vs. 0.27 ± 0.06) CAT 1.32 ± 0.06 (vs. 0.45 ± 0.09) MDA 0.45 ± 0.02 (vs. 0.72 ± 0.07) - 400 mg/kg SOD 0.32 ± 0.01 (vs. 0.27 ± 0.06) CAT 1.80 ± 0.01 (vs. 0.45 ± 0.09) MDA 0.45 ± 0.04 (vs. 0.72 ± 0.07)	adult Wistar rats in vivo paracetamol-induced hepatotoxicity rat model	[104]
C. ignea (aqueous–ethanol extract of aerial parts)	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)pyrene-induced lung tumorigenesis mouse model;	[105]
C. ignea (aqueous–ethanol extract of aerial parts)	antiulcerogenic, gastroprotective	- doses of 250 and 500 mg/kg bw administrated orally a week before ulcer induction, decreased the volume of gastric juice and gastric ulcer index, increased gastric pH value and pepsin activity - anti-ulcer activity comparable to that of ranitidine - anti-inflammatory, antioxidant, and curing effect on the hemorrhagic shock induced by ethanol toxicity	adult female Sprague-Dawley rats in vivo ethanol-induced gastric ulcers in rats	[58]
C. ignea (aqueous and ethanol extracts of leaves, flowers, stems; n-butanol and ethyl acetate fractions)	antihypertensive	- ACE inhib. activity IC50 [mg/mL] - aqueous extract of leaves 0.491 - ethanolic extract of leaves 2.151 - ethanolic extract of the flowers 1.748 - aqueous extract of stems 2.036 - ethanolic extract of stems 5.707 - n-butanol fraction of ethanol extract of leaves 0.084 - ethyl acetate fraction of ethanol extract. of leaves 0.215 - inhib. of renin activity [%] at the sample concentration of 10 mg/mL - ethanolic extract of leaves 94.82 - ethanolic extracts of stems 88.98 - ethanolic extract of flowers 86.65 - methylene chloride of the stems 98.14 - ethyl acetate fractions of leaves 93.09 - attenuation of elevated systolic blood pressure by ethanolic extract of leaves (at doses of 250 and 500 mg/kg b.wt.) similarly to standard lisinopril	in vitro ACE inhib. in vitro renin inhib. male Sprague-Dawley rats in vivo L-NAME-induced hypertension model	[54,106]
C. ignea (hydrolyzed seed oil)	antibacterial	- MIC [mg/mL] values: Enterococcus cecorum CCM 3659 2.25 CCM 4285 1.13 Clostridium perfringens CIP 105178 0.56 CNCTC 5454 4.5 UGent 56 2.25 Listeria monocytogenes ATCC 7644 1.13 Staphylococcus aureus ATCC 25923 2.25	in vitro broth microdilution method Enterococcus cecorum CCM 3659, CCM 4285 Clostridium perfringens CIP 105178, CNCTC 5454, UGent 56 Listeria monocytogenes ATCC 7644 Staphylococcus aureus ATCC 25923 Bifidobacterium animalis CCM 4988, MA5 B. longum TP 1, CCM 4990 Lactobacillus fermentum CCM 91 L. acidophilus CCM 4833	[43]
C. ingrata (5% tincture)	hypocholesteremic	- significant cholesterol level ↓, no significant effect on cholesterol absorption and triglyceride profile	in vivo male mice diet-induced hypercholesterolemia model	[107]
C. ingrata (methanol extract of aerial parts)	antimicrobial	- B. cereus and C. albicans growth inhib. with MIC 39 μg/mL	in vitro serial dilution assay Bacillus cereus, Candida albicans	[55]
C. ingrata (dichloromethane–methanol (1:1) and ethanol extracts of aerial parts)	trypanocidal	- 29% inhib. at a concentration of 100 μg/mL of the dichloromethane–methanol (1:1) extract - no effect of the aqueous extract	in vitro epimastigote assay Trypanosoma cruzi	[108]
C. lindmaniana (aqueous–ethanol extract of leaves)	anti-inflammatory antihypertensive	- 100% PMNs migration inhib. at the concentrations of 0.01–10.0 μg/mL of the extract - ACE-inhib. activity 19.58%	in vitro inhib. of rat PMNs chemotaxis, employing a modified Boyden chamber in vitro ACE-inhib.	[66]
C. pinetorum (dichloromethane– methanol extract of aerial parts)	antiprotozoal	- inhib. of the growth of trophozoites by isolated flavonoids with kaempferol as the most active compound against E. hystolitica (IC50 = 7 μg/mL) and G. lamblia (IC50 = 8.7 μg/mL)	in vitro susceptibility test using a subculture method Entamoeba histolytica HM1-IMSS, Giardia lamblia IMSS:0989:1	[69]
C. pinetorum (isolated flavonoids)	antiprotozoal	- antiprotozoal activity of isolated flavonoid compounds against Giardia lamblia with ED50 [μM/kg]: (-) epicatechin 0.072 kaempferol 2.057 tiliroside 1.429	suckling female CD-1 mice in vivo experimental infection of Giardia lamblia	[109]
C. pinetorum (methanol extracts of stems and leaves)	antimicrobial	- inhib. effect of the extracts at dose of 10 mg on S. aureus and C. albicans	in vitro disc-diffusion method Staphylococcus aureus ATCC 15006, Candida albicans ATCC 10231	[110]
C. subuligera (methanol extract of stems)	antimicrobial	- inhib. effect of the extract at dose of 10 mg on S. aureus (significant) and C. albicans	in vitro disc-diffusion method Staphylococcus aureus ATCC 15006, Candida albicans ATCC 10231	[110]
C. urbaniana (aqueous–ethanol extract of leaves collected in Unistalda and Barros Cassal)	anti-inflammatory antihypertensive	- 100% PMNs migration inhib. at the concentrations of 0.001–10.0 μg/mL of the extract - ACE-inhib. activity [%] of the extract of leaves collected in: - Unistalda 22.82 - Barros Cassal 22.29	in vitro inhib. of rat PMNs chemotaxis, employing a modified Boyden chamber. in vitro ACE-inhib.	[66]

Abbreviations: inhib.—inhibition/inhibitory; ↓—decrease/reduction; ↑—increase; ABTS—2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); ACE—angiotensin-converting enzyme; CAT—catalase; DPPH—2,2-diphenyl-1-picrylhydrazyl radical; FRAP—ferric reducing antioxidant power; IL—interleukin; LPS—lipopolysaccharide; MDA—malondialdehyde; NBT—nitro-blue tetrazolium; ORAC—oxygen radical absorbance capacity; PMNs—polymorphonuclear neutrophils; PPL—porcine pancreatic lipase; QS—quorum sensing; ROS—reactive oxygen species; SOD—superoxide dismutase; TEAC—trolox equivalent antioxidant capacity; TNF-α—tumor necrosis factor α.

5.1. 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: IC₅₀ 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].

5.2. Anti-Inflammatory Activity of Cupheas

Several Cuphea species (C. aequipetala, C. calophylla, and C. racemosa) have shown anti-inflammatory 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].

Figure 9.

Mechanism of anti-inflammatory and antioxidant activity of Cuphea extracts.

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 pro-inflammatory 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 aqueous–ethanolic 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.

5.3. 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].

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 EC₅₀ (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 IC₅₀ 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.

5.4. 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 (Fe³⁺) to the ferrous form (Fe²⁺) 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.

5.5. 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 D₁ and D₂, 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 (IC₅₀ = 11.4 μg/mL), while cuphiin D₁ 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 IC₅₀ 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.

Table 5.

In vitro cytotoxic activity of Cuphea plants.

Cuphea Species/Positive Control	Cell Line *	Cytotoxic Activity	Assay	References
C. aequipetala (acetone-aqueous extract of the whole plant) Colchicine	HEp-2 HCT-15 DU145 HEp-2 HCT-15 DU145	ED50 [μg/mL] >50 18.70 8.1 <0.006 0.006 0.099	Sulforhodamine B assay	[129]
C. aequipetala (chloroform extract of aerial parts)		% inhibition at the conc. of 6.25 μg/mL	Not mentioned	[130]
	HeLa	36.47 ± 4.04
	DU145	23.16 ± 9.21
C. aequipetala (methanol extract from leaves, flowers and stems)		ED50 [μg/mL]	Oyama and Eagle method	[93]
	UISO-SQC1	17.4
C. aequipetala (aerial parts) (a) methanol extract (b) aqueous extract		CC50 [mg/mL]	MTT assay	[128]
	B16F10	0.269
	HepG2	0.145
	MCF-7	0.096
	B16F10	0.364
	HepG2	0.212
	MCF-7	0.173
C. hyssopifolia (aqueous-methanol extract of aerial parts) Doxorubicin (positive control)		IC50 [μg/mL]	Sulforhodamine B assay	[48]
	MCF-7	92.5
	HEp-2	84.9
	HCT-116	81.0
	HepG2	73.4
	MCF-7
	HEp-2	3.7–5
	HCT-116
	HepG2
C. hyssopifolia (methanol extract) (a) aerial parts (b) roots		EC50 [μg/mL]	MTT assay	[126]
	MK-1	50–100
	HeLa	25–50
	B16F10	50–100
	MK-1	25–50
	HeLa	50–100
	B16F10	50–100
Compounds isolated from C. hyssopifolia Cuphiin D1 Cuphiin D2 Oenothein B Woodfordin C Adriamycin (positive control)		IC50 [μg/mL]	MTT assay	[51]
	KB	20.0
	DU145	51.4
	HeLa	36.5
	Hep3B	54.2
	S-180	39.2
	WISH	100.0
	KB	20.7
	DU145	74.0
	HeLa	28.5
	Hep3B	55.0
	S-180	24.5
	WISH	69.0
	KB	26.8
	DU145	54.5
	HeLa	29.0
	Hep 3B	19.0
	S-180	11.4
	WISH	67.2
	KB	28.9
	DU145	70.5
	HeLa	34.1
	Hep 3B	34.0
	S-180	24.7
	WISH	102.5
	KB	<0.15
	DU145	<0.15
	HeLa	<0.15
	Hep3B	<0.15
	S-180	<0.15
	WISH	<0.15
Compound isolated from C. hyssopifolia Cuphiin D1		IC50 [μM]	MTT assay	[131]
	HL-60	16
C. ignea (aqueous–ethanol extract of aerial parts)		IC50 [μg/mL]	MTT assay NRU assay	[105]
	A549	376
	A549	369.6
C. ignea (aqueous–ethanol extract of whole plant) 7-hydroxy 3-methoxy coumarin 5-O-β-glucopyranoside		IC50 [μg/mL]	NRU assay	[57]
	HaCaT	397.34 ± 19.83
	HCT-116	70.88 ± 0.62
	HuH-7	98 ± 2.91
	MRC-9	83.65 ± 13.43
	NCI-H460	37.76 ± 3.41
	NCI-H23	32.44 ± 5.23
	HaCaT	220.52 ± 28.83
	HCT-116	59.29 ± 6.21
	HuH-7	66.39 ± 2.39
	MRC-9	340.67 ± 22.21
	NCI-H460	45.56 ± 1.61
	NCI-H23	40.38 ± 2.75
C. ingrata (methanol extract of the aerial parts) (ethyl acetate fraction) (n-butanol fraction) Doxorubicin (positive control)		IC50 [μg/mL]	LDH assay	[127]
	A375	36.07
	HTB-140	>100
	WM793	43.37
	HaCaT	9.18
	DU145	>100
	PC3	>100
	PNT2	>100
	A375	15.90
	HTB-140	3.40
	WM793	18.75
	HaCaT	6.12
	DU145	>100
	PC3	>100
	PNT2	>100
	A375	22.60
	HTB-140	5.65
	WM793	29.39
	HaCaT	7.23
	DU145	>100
	PC3	>100
	PNT2	>100
	A375	0.59
	HTB-140	5.71
	WM793	>40
	HaCaT	4.68
	DU145	3.18
	PC3	>50
	PNT2	1.38
C. procumbens (aqueous extract of leaves)		IC50 [μg/mL]	MTT assay	[123]
	MCF-7	>100
	MDA-MB-468	>100
	A375	>100
	HCT-116	>100

* human cancer cell lines: breast: MCF-7, MDA-MB-468; cervix: HeLa, KB (a subline of the ubiquitous KERATIN-forming tumor cell line HeLa), UISO-SQC1; colon: HCT-116, HCT-15; larynx: HEp-2; leukemia: HL-60; liver: Hep3B, HepG2, HuH-7; lung: A549, NCI-H23, NCI-H460; melanoma: A375, HTB-140, WM793; prostate: DU145, PC3; stomach: MK-1; human normal cell lines keratinocytes: HaCaT; fibroblasts: MRC-9; amniotic epithelial cells: WISH (HeLa derivative); prostate epithelial cells: PNT2; animal cancer cell lines: murine melanoma: B16F10, murine sarcoma S-180.

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.

6. 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.

7. 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).

8. 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.

Author Contributions

Conceptualization, D.S., K.M. and I.P.; methodology, D.S. and K.M.; investigation, D.S., D.W.-B. and K.G.; resources, D.S.; writing—original draft preparation, D.S., K.M., I.P., D.W.-B. and K.G.; writing—review and editing, D.S., K.M., I.P., D.W.-B., K.G., M.A.O. and A.O.-J.; visualization, K.M. and D.W.-B.; supervision, I.P. and M.A.O. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research was funded by the Jagiellonian University, Medical College, project number N42/DBS/000204 and Medical University of Lodz, grant number 503/3-022-01/503-31-001.