A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”

Assis de Andrade, Evelyn; Machinski, Isadora; Terso Ventura, Ana Carolina; Barr, Sarah Ainslie; Pereira, Airton Vicente; Beltrame, Flávio Luís; Strangman, Wendy Karen; Williamson, Robert Thomas

doi:10.3390/molecules28145574

Open AccessReview

A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”

¹

Pharmaceutical Science Graduate Program, State University of Ponta Grossa, Ponta Grossa 84030-900, PR, Brazil

²

Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28409, USA

^*

Author to whom correspondence should be addressed.

Molecules 2023, 28(14), 5574; https://doi.org/10.3390/molecules28145574

Submission received: 19 June 2023 / Revised: 15 July 2023 / Accepted: 19 July 2023 / Published: 21 July 2023

(This article belongs to the Special Issue Analysis and Identification of Natural Product Extracts for Use in Medicine, Public Health and Agriculture)

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Abstract

:

Species of the genus Kalanchoe have a long history of therapeutic use in ethnomedicine linked to their remarkable healing properties. Several species have chemical and anatomical similarities, often leading to confusion when they are used in folk medicine. This review aims to provide an overview and discussion of the reported traditional uses, botanical aspects, chemical constituents, and pharmacological potential of the Kalanchoe species. Published scientific materials were collected from the PubMed and SciFinder databases without restriction regarding the year of publication through April 2023. Ethnopharmacological knowledge suggests that these species have been used to treat infections, inflammation, injuries, and other disorders. Typically, all parts of the plant are used for medicinal purposes either as crude extract or juice. Botanical evaluation can clarify species differentiation and can enable correct identification and validation of the scientific data. Flavonoids are the most common classes of secondary metabolites identified from Kalanchoe species and can be correlated with some biological studies (antioxidant, anti-inflammatory, and antimicrobial potential). This review summarizes several topics related to the Kalanchoe genus, supporting future studies regarding other unexplored research areas. The need to conduct further studies to confirm the popular uses and biological activities of bioactive compounds is also highlighted.

Keywords:

traditional use; chemical composition; botanical description; pharmacological activities; natural products; bioactive compounds; Kalanchoe; Crassulaceae

1. Introduction

The Crassulaceae J. St.-Hil. family is composed of 36 genera [1]. Species of this family are distributed in Africa and Asia, predominantly in Madagascar and Arabia [2,3] but are also found in the Americas and in Australia (Figure 1) [4].

The genus Kalanchoe Adans (Heterotypic Synonyms: Baumgartenia Tratt., Bryophyllum Salisb., Crassuvia Comm. ex Lam., Geaya Costantin and Poiss., Kitchingia Baker, Meristostylus Klotzsch, Physocalycium Vest, and Vereia Andrews) belongs to the Crassulaceae family and comprises 179 accepted species [5]. The synonyms (according to Plants of the World Online, facilitated by the Royal Botanic Gardens) and number of occurrences worldwide (according to Global Biodiversity Information Facility) of the accepted species are shown in Table 1.

The term Kalanchoe was originally used by Michel Adanson in 1763 and it refers to the phonetic transcription of the Chinese term “Kalan Chauhuy”, which means “what falls and grows”. The name Kalanchoe describes the propagation of leaf embryos. Another explanation for the name relates it to the words “kalanka” and “chaya”, which are used by Brazilian indigenous people and, respectively, mean stain/rust and shine, alluding to the reddish roots and shiny leaves [3,6]. Figure 2 shows the distribution of the native and introduced species of the genus Kalanchoe around the world [7].

Species of this genus are popularly known as “mother-of-thousands” or “mother-of-millions” due to their propagation by leaf embryos [8]. Some members of the genus Kalanchoe have a long history of therapeutic use and are known as “miracle leaf” because of their remarkable healing properties and traditional use in the treatment of several diseases and disorders [6,9,10,11,12]. Some of these biological activities have been correlated with specific classes of secondary metabolites already described in the Kalanchoe species. Examples include cardioactive glycosides and phenolic compounds (phenolic acids, flavonoids, and tannins) [13].

However, a detailed literature search revealed that only a limited number of species described as “miracle leaf” have anatomical and structural similarities and are used in folk medicine to treat a variety of health problems and disorders. Consequently, this review provides a critical overview of the main aspects published in the literature regarding the traditional uses, botanical characteristics, chemical composition, and pharmacological activity of species of the Kalanchoe genus, and aims to contribute to the knowledge of this genus, discussing important biological and chemical aspects described in these studies, and providing material for new evaluation.

2. Results and Discussion

2.1. Traditional Uses

The genus Kalanchoe is widely used in folk medicine to treat different health diseases and disorders. Thus far, only 21 of the 133 species of the genus Kalanchoe have been reported regarding their popular uses, as described in Table 2.

From these 21 species, there exists a broad ethnopharmacological knowledge of four species that are more often cited as medicinal plants (K. pinnata, K. laciniata, K. crenata, and K. daigremontiana), suggesting that they can be adopted to treat wounds, cancer, diabetes, infections, and inflammation. However, there are no reports in the scientific literature that describe the amounts of plant or dosages for ethnomedicinal uses.

All parts of the Kalanchoe species are traditionally used for medicinal purposes, but the juice or crude extract preparations (produced by maceration) are cited as the primary forms of administration [6,8,11,15,18,20,21,28,37,43,49,63,65,70,78,79,81].

In the cases of K. × houghtonii, K. flammea, K. gastonis-bonnieri, and K. integra, the literature does not describe which parts of the plant, method of preparation, or the dosage are popularly recommended for medicinal use. As is the case with many medicinal plants, folk-information related to traditional use of medicinal plants contributes to the search for scientific basis in these treatment regimens. These data, and the important lack thereof in most cases, reinforce the importance of additional investigations into the chemistry and bioactivity of this genera.

2.2. Botanical Description

Species of the Crassulaceae family are herbaceous or sub-shrubs, usually succulent, opposite, or alternate, and exstipulate. The flowers are actinomorphic, hermaphrodite, and usually cymose [5]. Species of the Kalanchoe genus are herbaceous or sub-woody; they have small branches and can reach from 1 to 1.5 m in height, especially during their flowering stage. Its leaves are opposite, succulent, oval, and have crenated margins, which are 10 to 20 cm long. Flowers can measure up to 5 cm in length, are pendant, and are arranged in inflorescences. Fruits are membranous, and the seeds are ellipsoid. The stem has thin-walled cells located deep in the epidermis. These cell walls are impregnated with resin, forming a thin layer that can reduce liquid evaporation [94,95,96].

These species adapt well and tolerate extreme conditions, such as lighting and water scarcity. One feature of this plant is a compartment in the leaves and stem tissues that can store and inhibit water loss [2,96,97]. This physical adaptation works in tandem with crassulacean acid metabolism (CAM), a metabolic adaptation to perform photosynthetic CO₂ fixation and water loss reduction. During the night, and at low temperatures, the stomata open, and the plant can assimilate atmospheric CO₂. However, daylight closes the stomata structure and CO₂ fixation occurs [98,99,100]. The stomatas have been described in detail and can be considered anatomical markers of the family [101].

Species of the genus Kalanchoe are popularly known due to their propagation by leaf embryos, and these propagules (also called leaf bulbs or bulbils) from the margins of the leaves are responsible for their tremendous invasiveness. New plants can be produced from parts of the mother plant, especially by clonal growth through the bulbs that arise from the leaf margins. In suitable open places (such as rocky or sandy environments) these populations can quickly form dense stands. This feature is the primary reason they are popularly known as “mother-of-thousands” or “mother-of-millions” [8,12,102].

Only 16 of the 133 species of the genus Kalanchoe have had their botanical aspects formally described in the literature (Table 3). More specifically, 11 of them have a macroscopic description (K. blossfeldiana; K. marmorata; K. beharensis, K. laxiflora, K. orgyalis, K. rhombopilosa, K. synsepala, K. tetraphylla, K. tomentosa, and K. × houghtonii), and only 5 have additional botanical evaluation/microscopical analysis of the plants (K. daigremontiana, K. delagoensis, K. laciniata, K. pinnata, and K. pumila).

In the case of K. blossfeldiana, five genotypes were also distinguished by morphological characterization (assessing the flower’s anatomical aspects and plant height), and molecular profiling (random amplified polymorphism DNA (RAPD), inter-simple sequence repeats (ISSR), and start codon targeted (SCoT)-polymerase chain reaction (PCR) tools) [103].

Table 3. Botanical aspects of Kalanchoe species.

Species	Macro Aspects	Micro Aspects	References
K. beharensis	The largest species of the genus, with 3 m in height; unbranched stems; leaves crowded at the branch tips; lobed, covered in a dense felt; ranging from 12–35 cm in length and 7–35 cm in width.		[6]
K. blossfeldiana	Dark green, succulent, and perennial plant, with scallop-edged leaves and large umbels of flower clusters held above the foliage. The fleshy, dark shiny green leaves have lobed edges and can reach 7.7 cm in length and 3.8 cm in width. Floral colors range from traditional red to yellow, orange, salmon and pink.		[104]
K. daigremontiana	Perennial short-lived succulent herb; monocarpic multi-annuals. The most characteristic feature of the species is its method of asexual reproduction by auto-propagation. Flowering tends to be sporadic, in winter, and, when it occurs, the main stalk elongates vertically, developing a terminal inflorescence of small, bell-shaped, pendulous flowers with a pinkish or purple corolla. The stem is unbranched, up to 1.5 m in height. The leaves are thick, fleshy, lanceolate, tapered at the apex and serrated in the margins, dark green colored, and have purple-brown spots on the abaxial side. The apex bears hydathodes and adventitious buds, from which propagules are formed and developed.	The epidermis is single-layered, with parenchymatic cells, convex outer walls surface, wax patches in cuticles, is smooth-undulating, and striated only on subsidiary cells. The leaves are amphistomatic, with anisocytic stomata. The subepidermal mesophyll consists of one or several layers of small, closely adherent cells. The central vascular bundles are surrounded by perivascular sheaths composed of mesophyll cells. Between the epidermis and mesophyll in the petioles there are 1–3 layers of compact angular collenchyma. The vascular bundles are collateral. In the central veins in the petiole and the leaf are three large bundles. The cross-sections show fine lateral vascular bundles surrounding large bundles in the petioles and leaf blades. The different tissues of the leaf contain numerous phenolic idioblasts, accumulating phenolic compounds in their vacuoles, present in epidermal cells, in the subepidermal layer, near the vascular elements, around the large vascular bundles in the leaf petioles, and surrounding the smaller vascular bundles, dispersed in the parenchyma as single cells or form multicellular aggregates.	[6,12,29,97,105,106]
K. delagoensis	It has dark purplish, speckled, tubular leaves, which are filled with plantlets. It typically grows to about 1 m in height before blooming. It overwinters as a terminal inflorescence bearing orange or red pendant bell-shaped flowers and then dies.	The leaves are tubular and have 6–8 apical buds. The epidermal cells are uniseriate with sinuous anticlinal walls. The leaves are amphistomatic with anisocytic stomata. The mesophyll has regular chlorenchyma. The vascular system has collateral bundles distributed in the form of an arc. Anthocyanin idioblasts occur throughout the leaf blade, in the epidermis; hypodermis; layer beneath the hypodermis; scattered in the chlorenchyma; surrounding the vascular bundles; vascular tissues; and apical buds.	[6,107]
K. ceratophylla	Perennial, succulent, and glabrous species.		[16]
K. laciniata	Perennial or biennial herb that grows from 30 cm to 1.5 m in height. Its leaves are oval, opposite, fleshy, simple, short-petiolate, glossy, and pale green to dark green in color. They have dentate to crenate leaf margins, with a cylindrical herbaceous stem and fleshy petiole.	The secretory structures found in the stems, petioles and leaf blades consist of idioblasts that contain anthocyanins. The epidermis of K. laciniata is a single layer with adhering and oblong cells. The outer cell wall is convex and covered with cuticles. The leaves are amphistomatic and the chlorenchyma tissue is uniform. The cells of the chlorenchyma tissue have irregular, spherical-ellipsoidal shapes. The vacuoles of some mesophyll cells located near the epidermis, vascular bundles, and hydathodes contain phenolic compounds. The leaves show the presence of adaptive traits that enable them to survive in dry environments	[42,44,108]
K. laxiflora	Perennial species with multicolored leaves, that are crenate, green in shady settings, and pink or purple in bright sun. The flower buds are almost transparent but when they open, they turn orange.		[6]
K. marmorata	The leaves are large, oval, blue-green colored, with purple markings, arranged in stacked, opposite pairs to a height of 30 cm. The brown spots become brighter during summer dormancy and in strong sunlight; during winter they become pale or disappear altogether.		[3,6]
K. orgyalis	It is a much-branched slow-growing shrub that can reach approximately 1–2 m in height. It has spoon-shaped leaves, which are bronze to gray on the underside, and felted on the top of each leaf, with cinnamon-toned fuzz. Late winter or early spring brings bright yellow flowers in terminal clusters at the branch tips.		[6]
K. pinnata	An erect, succulent, perennial and glabrous plant that grows up to 1.5 m in height. The species reproduces through seeds and from leaf bulbils. The freshly dark green leaves are large (12–18 cm and 6–8 cm in size), simple, opposite, ovate, or elliptic, have serrate-crenate margins with buds, an obtuse apex, asymmetric base, reticulate venation, and long petiole. The flowers are pendulous, dark, and bell-like. The stems are tall, hollow, obtuse, and four-angled. The fruits are enclosed in the calyx and corolla. The seeds are small, smooth, oblong-ellipsoid, rarely striate, and smooth.	The leaves are broadly shallow on the adaxial side and convex on the abaxial side. The epidermal layer is thin, with small prominent cells on the adaxial side and less distinct on the abaxial side. The ground tissue of the midrib is parenchymatous and homogenous. The cells are circular or angular and compact. The vascular strand is single, collateral, small, and hemispherical; it consists of a thick horizontal band of xylem and a wide band of phloem. The lamina is uniformly flat with an even surface. The mesophyll tissue is not differentiated into palisade and spongy parenchyma. The stomata are anisocytic. The leaf petiole shows prismatic crystals of calcium oxalate embedded in parenchymatous cells, and annular and spiral vessels. In the powder, part of the vascular bundle, epidermis, annular and spiral xylem vessels were observed. The secretory structures found in the stems, petioles, and leaf blades consisted of idioblasts containing anthocyanins.	[12,42,44,63,78,79,106,109]
K. pumila	It is a 30 cm high shrublet with small, fleshy leaves covered with powdery deposits formed by calcium carbonate sediments. The leaves are obovate (2.8 cm long, 1.7 cm wide, and 2.5 mm thick), opposite, wedge-shaped, and have a sinuate basis and dentate-serrate margins.	The reddish-brown or purple color appears along the leaf margins after exposure to sunlight due to the presence of anthocyanins in the epidermal cells and mesophyll vacuoles. The epidermal cells are polygonal–isodiametric or slightly oblong; they are more numerous on the abaxial surface. The anticlinal walls are curved or straight and are convex on the outer walls. The walls are thickened due to the presence of wax. The cuticula is smooth or slightly undulating, elevated or with striae, with sparse white or gray irregularly shaped and sized wax structures on the surface. The leaves are amphistomatic, with anisocytic stomata. The vascular bundles are collateral and closed. The sheath cells, or phloem, xylem parenchyma cells, subepidermal ground tissue, mesophyll tissue, and chlorenchyma tissue cells may contain tannin substances.	[110]
K. rhombopilosa	Small plant (no more than 10 cm tall), which blooms in spring. The leaves are hard and triangular, with a pale and wavy margin and green-yellow flowers with red lines.		[6]
K. synsepala	One of the more unusual species of the genus because it is one of the few that produces stolon (lateral spreading stems). The leaves are arranged in rosettes and are thick, succulent, smooth, shiny, and green, with violet-red marks along the margins. This species is dormant in winter. The flowers are small, hairy, tubular, numerous, and pink.		[6]
K. tetraphylla	The leaves are silvery pale green, which turn red in bright sun and revert to green in active growth. It has a large rosette of rounded or wavy leaves. The inflorescence is terminal and erect, with densely clustered panicles of greenish, waxy, narrow, urn-shaped flowers.		[6]
K. tomentosa	The leaves are silvery, about 30 cm tall, reflecting the sun’s rays, lessening the chances of leaves overheating.	Its dense trichomes arise in triplets and perform a vital function in dry environments, helping to reduce the transpiration of water from the leaf surface	[6]
K. × houghtonii	A perennial erect herb, monocarpic, and can reach a height of up to 1.5 m. The leaves are opposite or verticillate, petiolate, with the leaf blade simple. The leaves vary from triangular to narrowly lanceolate, are serrate and mottled. The species forms corymbiform inflorescences of more than 100 pendulous, tetra or pentameric, dark-red flowers.		[102]

These data demonstrate that even with some similarities between the species, an adequate morpho-anatomical study of the material can allow the correct identification of the studied species and validation of the scientific data (biological or chemical study). In this review, species identification errors that could disavow the scientific data obtained have been identified [29,106].

2.3. Chemical Composition

There have been 124 chemical metabolites reportedly isolated from Kalanchoe species (Table 4, Table 5 and Table 6 and Figure 3, Figure 4 and Figure 5). The most common are cardiac glycosides (compounds 1–39, in Table 4 and Figure 3) and flavonoids (compounds 40–78, in Table 5 and Figure 4). The primary species from which these compounds have been reported are K. daigremontiana, K. pinnata, K. delagoensis, and K. ceratophylla. Cardiac glycosides (such as the bufadienolide class) have been identified in the species K. ceratophylla, K. daigremontiana, K. delagoensis, K. hybrida, K. lanceolata, and K. pinnata (compounds 1–39, in Table 4 and Figure 3).

Table 4. Cardiac glycosides from Kalanchoe species.

Extract and/or Plant Part	Compound Name	Species	References
Dichloromethane extract; methanol extract of aerial parts; flowers	bryophyllin A (bryotoxin C) (1)	K. daigremontiana; K. pinnata; K. delagoensis; K. ceratophylla	[11,32,86,111,112,113,114,115]
Aqueous extract from the roots or whole plant; methanol extract of aerial parts	bryophyllin B (2)	K. daigremontiana; K. ceratophylla; K. delagoensis; K. pinnata	[30,111,113,114,116]
Leaves, dichloromethane extract; methanol extract of the leaves; dichloromethane fraction from methanol extract	bryophyllin C (3) daigremontianin (4) methyl daigremonate (5)	K. daigremontiana; K. pinnata	[11,112,117]
Dichloromethane extract; aqueous extract from the roots	bersaldegenin-1,3,5-orthoacetate (6)	K. daigremontiana; K. pinnata; K. delagoensis	[11,30,32,86,116]
Aqueous extract from the roots; ethanol and dichloromethane extracts from the roots; leaves	bersaldegenin 1-acetate (7)	K. daigremontiana; K. pinnata; K. delagoensis	[11,30,32,86]
Leaves; ethanol and dichloromethane extracts from the leaves	bersaldegenin 3-acetate (8)	K. pinnata	[11,86,114]
Aqueous extract from the roots	bersaldegenin (9)	K. daigremontiana	[30]
Ethanol and dichloromethane extracts from the leaves	bufalin (10)	K. pinnata	[86]
Flower heads	bryotoxin A (11)	K. delagoensis	[111]
Aqueous extract from the roots; flowers	bryotoxin B (12)	K. daigremontiana; K. delagoensis; K. pinnata	[30,111,115,116]
Aqueous leaf extract; leaves	bufadienolide A (13) bufadienolide B (14)	K. daigremontiana	[118]
Aqueous extract from the roots	daigredorigenin 3-acetate (15)	K. daigremontiana	[30,116]
Aqueous extract from the roots	11α,19-dihydroxytelocinobufagin (16)	K. daigremontiana	[30,116]
Methanol extract of aerial parts	hellebrigenin (17)	K. ceratophylla	[113]
Methanol extract of aerial parts	hellebrigenin-3-acetate (18)	K. ceratophylla; K. daigremontiana	[113,116]
Methanol extract of aerial parts	kalanchoside A (19) kalanchoside B (20) kalanchoside C (21)	K. ceratophylla	[113]
Methanol extract of aerial parts	thesiuside (22)	K. ceratophylla	[113]
Ethanol extract; whole plant	kalantuboside A (23) kalantuboside B (24)	K. delagoensis	[32]
Aqueous extract from the roots	1β,3β,5β,14β,19-pentahydroxybufa-20,22-dienolide (kalandaigremoside A) (25) 19-(acetyloxy)-1β,3β,5β,14β-tetrahydroxybufa-20,22-dienolide (kalandaigremoside B) (26) 3β-(O-α-L-rhamnopyranosyl)-5β,11α,14β,19-tetrahydroxybufa-20,22-dienolide (kalandaigremoside C) (27) 19-(acetyloxy)-3β,5β,11α,14β-tetrahydroxybufa-20,22-dienolide (kalandaigremoside D) (28) 3β,5β,11α,14β,19-pentahydroxy-12-oxo-bufa-20,22-dienolide (kalandaigremoside E) (29) 19-(acetyloxy)-3β,5β,11α,14β-tetrahydroxy-12-oxo-bufa-20,22-dienolide (kalandaigremoside F) (30) 19-(acetyloxy)-1β,3β,5β,11α,14β-pentahydroxy-12-oxo-bufa-20,22-dienolide (kalandaigremoside G) (31) 1β-(acetyloxy)-3β,5β,11α,14β,19-pentahydroxy-12-oxo-bufa-20,22-dienolide (kalandaigremoside H) (32)	K. daigremontiana	[30]
Ethyl acetate extract of the fresh; whole plant	lanceotoxin A (33) lanceotoxin B (34)	K. lanceolata	[119]
Methanol extract; whole plant	kalanhybrin A (35) kalanhybrin B (36) kalanhybrin C (37)	K. hybrida	[120]
Ethanol extract of the whole plant	kalantubolide A (38) kalantubolide B (39)	K. delagoensis	[32]

Flavonoids have been identified in aqueous, hydroalcoholic, and alcoholic extracts from the leaves of K. blossfeldiana, K. crenata; K. daigremontiana, K. delagoensis, K. fedtschenkoi, K. laciniata, K. marmorata, K. mortagei, and K. pinnata (compounds 40–78, Table 5 and Figure 4). The most common flavonoids/glycosylated flavonoids described from these species are derivatives of quercetin (40), patuletin (69–71), eupafolin (64), and kaempferol (48–62).

Table 5. Flavonoids from Kalanchoe species.

Extract and/or Plant Part	Compound Name	Species	References
Flower; ethanol leaf extractFlowers; Leaves	quercetin (40)	K. pinnata K. delagoensis K. blossfeldiana; K. mortagei; K. fedtschenkoi; K. daigremontiana; K. longiflora K. ceratophylla	[32,37,121,122,123,124,125,126,127]
Flower extractFlowers	Quercetin 3-O-β-glucoside (quercetin 3-O-glucoside; isoquercetin; isoquercetrin) (41)	K. pinnata; K. blossfeldiana; K. daigremontiana; K. delagoensis	[49,122,123,127,128]
Flower extractFlowers	quercetin 3-O-β-d-glucuronopyranoside (miquelianin) (42)	K. pinnata	[122]
Aqueous and methanolic leaf extractsLeaves	quercetin 3-O-rhamnoside (quercitrin) (43)	K. pinnata; K. delagoensis; K. longiflora; K. ceratophylla	[42,82,122,123,125,126,129,130]
Flowers, Aqueous leaf extractFlower, Leaves	quercetin-3-O-β-d-xylopyranosyl (1→2)-α-L-rhamnopyranoside (44)	K. blossfeldiana K. daigremontiana	[118,127]
Aqueous and methanolic leaf extracts; flower extractFlowers, Leaves	quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (45)	K. pinnata	[8,82,83,122,129,130]
Methanol leaf extractLeaves	quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside-7-O-β-d-glucopyranoside (46)	K. pinnata	[129]
Ethanol leaf extractLeaves	quercetin 3-O-rutinoside (rutin) (47)	K. pinnata	[121]
Methanolic and hydroethanolic extracts from the leavesLeaves	kaempferol (48)	K. delagoensis; K. pinnata; K. fedtschenkoi; K. longiflora; K. ceratophylla	[2,37,43,123,125,126,129,131]
Water and ethanol extracts Leaves	kaempferol 3,7-O-dirhamnoside (kaempferitrin) (49) kaempferol 3-O-β-d-xylopyranosyl-(1→2)-α-L-rhamnopyranoside-7-O-β-d-glucopyranoside (daigremontrioside) (50)	K. daigremontiana	[49]
Leaves	kaempferol 7-O-rhamnoside (51)	K. delagoensis; K. longiflora	[123,125]
Methanol leaf extractLeaves	kaempferol 3-O-β-d-xylopyranosyl-(1→2)-α-l-rhamnopyranoside (kaempferol 3-O-xylosyl-rhamnoside) (52)	K. pinnata; K. daigremontiana	[49,118,129]
Leaves	kaempferol 3-O-galactoside (trifolin) (53)	K. delagoensis	[123]
Leaves	kaempferol 3-rutinoside (nicotiflorin) (54)	K. pinnata; K. longiflora	[70,125]
Leaves	kaempferol- 3-O-robinoside-7-O- rhamnoside (robinin) (55)	K. delagoensis; K. longiflora	[123,125]
Aqueous and methanolic leaf extractsLeaves	kaempferol 3-O-α-l-arabinopyranosyl (1→2)-α-l-rhamnopyranoside (kapinnatoside) (56)	K. pinnata	[83,129,130]
Ethyl acetate extract of the wholeWhole plant	kaempferol 3-O-α-l-(2-O-acetyl)rhamnopyranoside 7-O-α-l-rhamnopyranoside (57) kaempferol 3-O-α-l-(3-O-acetyl)rhamnopyranoside 7-O-α-l-rhamnopyranoside (58) kaempferol 3-O-α-l-(4-O-acetyl)rhamnopyranoside 7-O-α-l-rhamnopyranoside (59) kaempferol 3-O-α-d-glucopyranoside 7-O-α-l-rhamnopyranoside (60) afzelin (kaempferol 3-O-α-l-rhamnopyranoside) (61) α-rhamnoisorobin (kaempferol 7-O-α-l-rhamnopyranoside) (62)	K. pinnata	[132]
Aqueous leaf extractLeaves	4′,5-dihydroxy-3′,8-dimethoxyflavone 7-O-β-d-glucopyranoside (63)	K. pinnata	[130]
Aerial parts; methanol extract from the stemsStems	eupafolin (6-methoxyluteolin) (64)	K. ceratophylla	[17,126]
Aerial parts	eupafolin 4′-O-rhamnoside (65)	K. ceratophylla	[126]
Ethanol extract of the wholeWhole plant	4′-methoxyherbacetin (66)	K. delagoensis	[32]
Stems and leaves; Leaves	kalambroside A (67) kalambroside B (68) kalambroside C (69) patuletin 3-O-(4′-O-acetyl-α-l-rhamnopyranosyl)-7-O-(3′-O-acetyl-α-l-rhaminopyranoside) (70) patuletin 3-O-α-l-rhamnopyranosyl-7-O-(3′-O-acetyl-α-L-rhaminopyranoside) (71)	K. laciniata	[133]
Stems and leaves; hydroethanolic extract from leavesStems; Leaves	patuletin 3-O-α-l-rhamnopyranosyl-7-O-α-l-rhamnopyranoside (72)	K. laciniata	[40,44,133]
Methanol leaf extract Leaves	myricetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (73) myricitrin (myricetin 3-O-α-l-rhamnopyranoside) (74) diosmine (diosmetin 7-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside) (75) acacetin 7-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (76)	K. pinnata	[129]
Ethanol leaf extractLeaves	luteolin (77)	K. ceratophylla; K. pinnata	[121,126]
Ethanol leaf extractLeaves	luteolin 7-O-β-d-glucoside (78)	K. pinnata	[121]

Recently, a comprehensive approach encompassing metabolomics and machine learning techniques was implemented [134] to investigate K. daigremontiana, K. × houghtonii, and K. delagoensis plant tissue cultures. By employing untargeted metabolomics, a remarkable total of 460 phenolic compounds were identified. Among them, the elicitation process significantly influenced the biosynthesis of 164 compounds. Through the utilization of neuro fuzzy logic, the study successfully predicted the impact and interactions involved in plant cell growth as well as the biosynthesis of various subfamilies of polyphenols. The findings highlight the distinct genotype-dependent role of salicylic acid in eliciting Kalanchoe cell cultures, while methyl jasmonate emerged as a secondary contributing factor.

Several other secondary metabolites (steroids, triterpenes, coumarins, and others) have also been isolated from different species of Kalanchoe and are described in the literature (compounds 79–124, in Table 6 and Figure 5).

Table 6. Other compounds isolated and identified from Kalanchoe species.

Class	Extract and/or Plant Part	Compound Name	Species	References
Aurone	Aqueous root extractRoots	hovetrichoside C (79)	K. daigremontiana	[116]
Coumarin	Aerial parts	7-hydroxycoumarin (80)	K. ceratophylla	[126]
Glycoside	Roots	KPB 100 (81) KPB 200 (82) schisandriside (83)	K. pinnata K. daigremontiana	[69,116]
Glycoside	Aqueous root extract	schisandriside (83)	K. daigremontiana	[116]
Lipid	Ethanol extract of the wholeWhole plant	taurolipid C (84)	K. delagoensis	[32]
Megastigmane	Ethanol extract of the wholeWhole plant	(6S,7R,8R,9S)-6- oxaspiro-7,8-dihydroxymegastigman-4-en-3-one (tubiflorone) (85)	K. delagoensis	[32]
Organic/ phenolichenolic acid	Leaves, ether leaves extract	ferulic acid (86)	K. delagoensis; Kalanchoe sp. K.daigremontiana K. pinnata;	[29,123,135,136]
	Ethanol extract of the wholeWhole plant; leavesLeaves	gallic acid (87)	K. delagoensis; Kalanchoe sp.; K. daigremontiana	[29,32,123,135]
	Leaves; ether leaves extract	caffeic acid (88)	K. delagoensis; Kalanchoe sp.; K. longiflora; K. daigremontiana K. pinnata	[29,123,125,135,136]
	Leaves	protocatechuic acid (89)	K. delagoensis; Kalanchoe sp.; K. daigremontiana	[29,123,135]
	Ethanol extract of the whole plant; leaves; ether leaves extractWhole plant; Leaves	syringic acid (90)	K. delagoensis; Kalanchoe spp.; K. pinnata	[32,123,135]
	Leaves	sinapic acid 91)	Kalanchoe sp.	[135]
	Ethanol extract of the wholeWhole plant; leavesLeaves	vanillic acid (92)	K. delagoensis; Kalanchoe sp.	[32,135,136]
	Leaves	chlorogenic acid (93)	Kalanchoe sp.; K. longiflora	[125,135]
	Leaves; ether leaves extract	p-Coumaric acid (94)	Kalanchoe sp.; K. longiflora; K. daigremontiana K. pinnata	[29,125,135,136]
	Leaves	β- resorcylic acid (95)	Kalanchoe sp.	[135]
		γ-resorcylic acid (96)
	Ethanol extract of the wholeWhole plant	cinnamic acid (97) 4-O-ethylgallic acid (98) methyl gallate (99)	K. delagoensis	[32]
Phenolic compounds	Whole plant	4-O-ethylgallic acid (98) methyl gallate (99) 3,4-dimethoxyphenol (100) phloroglucinol (101) 3,4-dihydroxyallylbenzene (102)	K. delagoensis	[32]
Phenanthrene	Leaves	bryophollenone (103) 2(9-decenyl) phenanthrene (104)	K. pinnata	[137]
Steroid	Leaves	bryophyllol (105) 24-ethyl-25-hydroxycholesterol (106)	K. pinnata	[137]
		24-ethyl-25-hydroxycholesterol (106)
	Ethanol extract of the wholeWhole plant	stigmasterol-O-d-glucoside (107)	K.delagoensis	[32]
Tocochromanol	Hexane leaf extractLeaves	α-tocopherol (108) γ-tocopherol (109) δ-tocopherol (110) β-tocomonoenol (111) γ-tocomonoenol (112) δ-tocomonoenol (113)	K. daigremontiana	[138]
iterpeneTriterpene	Aerial parts; petroleum ether extract from flowers; methanol extract Flowers	friedelin (114)	K. fedtschenkoi; K. marnieriana; K. daigremontiana K. integra	[136,139,140]
		glutinone (115)	K. miniata	[139]
		glut-5-en-3- β-ol (glutinol) (116)	K. fedtschenkoi; K. daigremontiana K. integra	[136,139,140,141]
	Leaves	18α-oleanane (117) α-amyrin acetate (118)	K. pinnata	[137]
	Leaves	α-amyrin acetate (118)
	Leaves	β-amyrin acetate (119)	K. pinnata; K. miniata	[137,139]
	Leaves; methanol extract	α-amyrin (120)	K. pinnata K. daigremontiana	[137,141]
	Leaves; methanol extract	β-amyrin (121)	K. pinnata;	[137,140,141]
	Leaves, petroleum ether extract from flowers; Flowers	bryophynol (122) Ψ-taraxasterol (123) bryophollone (124)	K. daigremontiana K. pinnata K. integra	[136,137]

Until now, of the four species most reported as medicinal plants with ethnopharmacological use (K. pinnata, K. laciniata, K. crenata, and K. daigremontiana), only two had cardiac glycosides identified in published studies (K. pinnata and K. daigremontiana). In contrast, compounds from the flavonoid class were identified in all four species. Additionally, although the juice or crude extract (produced by maceration) is the ethnomedicinal form of use in the literature, phytochemical studies are generally based on polar organic extracts (ethanol, methanol) prepared from leaves, stems, roots, flowers, and whole plant. Few studies using nonpolar or aqueous solvents have been identified. This is an important observation because it is known that popular knowledge needs to be confirmed, and the presence of the biological compounds in an extract are related to the solvent and the procedure used to obtain it.

2.4. Pharmacological Activities

In folk medicine, the use of Kalanchoe species is related to several disease conditions. Due to its widely distributed and popular use, experiments have been performed to corroborate the pharmacological potential activities and to prove the therapeutic potential of different species of Kalanchoe. So far, only 16 of the 133 species of the genus Kalanchoe have been analyzed to assess various pharmacological activities. The primary activities studied have been antioxidant, anti-inflammatory, cytotoxic, and antimicrobial properties. Of these sixteen species, four are not reported in the literature regarding their popular uses, but their pharmacological activities were tested (K. blossfeldiana, K. longiflora, K. scapigera, and K. rhombopilosa).

Kalanchoe blossfeldiana methanolic extract (ME) showed biofilm formation and demonstrated anticytokine properties [128]. Its aqueous extract (AE) in zinc oxide nanoparticles showed promising antibacterial and antifungal potential and a potent cytotoxic effect against a HeLa cell line [142]. In comparison with two other species (K. daigremontiana and K. pinnata), the ethanolic extract (EE) of K. blossfeldiana exhibited the most potent cytotoxic activity (IC₅₀: < 19 µg/mL for HeLa and SKOV-3 cells) and the strongest antibacterial effects (MIC: 8.45, 8.45, 0.25, and <33.75 µg/mL for S. aureus, S. epidermidis, and E. hirae, respectively) but this extract did not contain bufadienolides, which are known to elicit these biological effects (cytotoxic and antibacterial) [11].

Kalanchoe ceratophylla stems ME has been suggested to provide analgesic and anti-inflammatory effects, with its anti-inflammatory mechanisms being well discussed. Eupafolin (64) demonstrated good pharmacological activity, and the antioxidant potential and efficacy of this species may be largely attributed to polyphenolic compounds [16,17]. The antiviral effects of the leaf extract from this species were investigated against RNA enteroviruses, specifically enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). The extract showed little cytotoxicity and exhibited concentration-dependent antiviral activities, including reductions in cytopathic effects, plaque formation, and virus yield. Furthermore, the extract demonstrated greater potency in antiviral activity compared to ferulic acid, quercetin, and kaempferol, significantly inhibiting the in vitro replication of EV71 (IC₅₀: 35.88 μg/mL) and CVA16 (IC₅₀: 42.91 μg/mL). As such, this extract may be considered a safe anti enteroviral agent [143].

Kalanchoe crenata ME was non-toxic when administered orally for animals over a period of 14 days. The ME and its fractions showed fold decreases in IC₅₀ for fractions regarding CYP3A4; phytoconstituents in the ME were a reversible and time-dependent inhibitor of CYP3A4, and the methanol fraction is a potential source of a new oral anti-nephropathic drug [18,20,22]. The cytotoxicity of ME leaves was highlighted in comparison with five other species, with reported IC₅₀ values that ranged from 2.33 μg/mL (SPC212, mesothelioma) to 28.96 μg/mL (HepG2, hepatocarcinoma), and apoptosis induction via ROS production [23]. Its AE were quantitatively assessed for significant elements, and the amounts of Ca, K, and Mg detected could be correlated to its traditional usage in cases of hypertension and arrhythmia. However, the presence of heavy metals (Pb and As inorganic) may be a major health concern [39]. The AE antidepressant potential could be possibly mediated by a complex interplay between serotoninergic, opioidergic, and noradrenergic systems [75]. The EE showed no genotoxic potential and possessed cardioprotective effects against DOX-induced cardiotoxicity in Sprague-Dawley rats [19]. The methylene chloride/methanol extract and its hexane, methylene chloride, ethyl acetate, n-butanol fractions, and aqueous residue were evaluated for their analgesic effects and anticonvulsant activity. The results suggested the presence of peripheral and central analgesic activities, along with an anticonvulsant effect [144].

Bufadienolide-rich fractions (BRF) isolated from the roots of K. daigremontiana presented antioxidant activity against DPPH radicals (EC₅₀: 21.80 µg/mL); moderate activity for peroxynitrite-induced oxidative stress; protective levels of 3-nitrotyrosine and thiol groups (50 µg/mL); effective antioxidant potential for hydroperoxides and TBARS generation (1–5 and 25–50 µg/mL, respectively); uncompetitive inhibitory effect on the enzymatic properties of a serine proteinase-thrombin (1–50 µg/mL) (IC₅₀: 2.79 µg/mL); and of plasmin (0.05–50 µg/mL). No effects were observed to prevent the oxidation of low-molecular plasma thiols, and no cytotoxicity was observed. Docking studies suggested that only some compounds (mostly bersaldegenin 1-acetate (7), bryotoxins (1,11–12), and hovetrichoside C (78)) were bound to plasminogen/plasmin, depending on the presence or absence of the substrate in the active site, suggesting allosteric regulation of plasminogen activation and plasmin activity by components of the examined fraction [14,15,116]. Additionally, root extracts of K. daigremontiana was also evaluated [145] in comparison to other plants (Cyphomandra betacea, Robinia pseudoacacia, Nothofagus pumilio, and Rosmarinus officinalis) in a set of in vitro assays and, regarding the cytotoxic assays, K. daigremontiana was the only species considered to be highly toxic.

The anti-inflammatory activity of AE, EE, and petroleum ether (PEE) extracts obtained from the leaves of K. pinnata and K. daigremontiana were compared and the AE and PEE of K. daigremontiana showed the highest anti-inflammatory effects (−105.69 ± 0.40 and −79.95 ± 0.37, respectively) [106]. Crude extracts from the leaves of K. daigremontiana can contribute to antiviral activity [118] and, most prominently, to high antibacterial activity [10] against E. coli and S. aureus. A macerated ME from the leaves of K. daigremontiana demonstrated high antiparasitic activity against E. histolytica and T. vaginalis (IC₅₀: 70.71 ± 3.08 and 105.27 ± 5.19 μg/mL, respectively) [124]. Antioxidant properties of nanovesicle preparations of K. daigremontiana compared to Artemisia absinthium, Hypericum perforatum, Silybum marianum, Chelidonium majus, and Scutellaria baicalensis demonstrated that the activities are specific to plant species, but K. daigremontiana and S. marianum nanoparticle showed similar characteristics, suggesting future analysis to test the complementary/synergic effects between them [146].

The cytotoxic effects of K. daigremontiana were investigated in relation to human adenocarcinoma (HeLa), ovarian (SKOV-3), breast (MCF-7) and melanoma (A375) cells [49,147], and human multiple myeloma cells [28]. The dichloromethane fraction (DF) showed strong activity against all cell lines (IC₅₀ ≤ 10 µg/mL), and it could be related to the presence of bersaldegenin-1,3,5-orthoacetate (6). The AE reduced the viability of tumor cells by 13% and, in combination with doxorubicin, showed an additive synergism of action, which enhanced this effect. The intracellular glutathione level decreased by 25%, mitochondrial membrane potential decreased by 19%, and ATPase activity increased 50%, which shows that this extract affects the metabolism of tumor cells and contributed to their death and antitumor activity. The AE elevated the oxidative stress levels in SKOV-3 cells as well as exhibited notable antiproliferative and cytotoxic effects, leading to the depolarization of the mitochondrial membrane and causing a significant cell cycle arrest in the S and G2/M phases of this cell line. The non-activation of caspases 3, 7, 8, and 9 suggests a non-apoptotic mode of cell death. Additionally, real-time PCR analysis suggested that the AE may induce cell death through the involvement of TNF receptor (tumor necrosis factor receptor) superfamily members 6 and 10.

The K. delagoensis n-hexane and ethanol extracts suggested wound-healing potential [34]. Its n-butanol-soluble fraction was able to inhibit cell proliferation and reduce cell viability by two mechanisms exclusively involved with cell division (inducing multipolarity and disrupting chromosome alignment during metaphase) [31]. The AE of this species promoted cell cycle arrest and senescence-inducing activities in A549 cells, and tumor growth was effectively inhibited, suggesting that this extract is an antitumor agent [148]. Compounds isolated from the EE of this species were evaluated for anti-inflammatory and cytotoxic activities [32,33]. Some compounds (quercetin (40), syringic acid (84), 3,4-dimethoxyphenol (94), 3,4-dihydroxyallylbenzene (96), and tubiflorone (120)) possessed NO inhibitory activity (IC₅₀ 15.1/0.9–98.9/1.3 mM). The biological evaluation indicated that some cardenolides (kalantubolide A (38) and kalantubolide B (39)) and bufadienolide glycosides (bryophyllin A (1), bersaldegenin-1,3,5-orthoacetate (6), bersaldegenin 1-acetate (7), kalantuboside A (23), kalantuboside B (24)) demonstrated strong cytotoxicity against four human tumor cell lines (A549, Cal-27, A2058, and HL-60) (IC₅₀ 0.01–10.66 µM). In addition, these compounds blocked the cell cycle in the G2/M-phase and induced apoptosis in HL-60 cells.

The ethyl acetate extract (EAE) of K. flammea is non-genotoxic and exhibits selective cytotoxic activity against several cell lines of prostate cancer, with mechanisms of induced apoptosis by the intrinsic pathway, significant downregulation of apoptosis-related proteins, induced DNA fragmentation, and cell cycle arrest. Additionally, a fraction rich in coumaric acid and palmitic acid, obtained from the EAE, demonstrated selective cytotoxic activity against PC-3 cells [36]. Similarly, fraction rich in fatty acids obtained from the EE of K. pinnata demonstrated inhibited lymphocyte proliferation in vitro and showed in vivo immunosuppressive activity [149].

Kalanchoe fedtschenkoi and K. mortagei were studied to compare their antibacterial potential [37], and K. fedtschenkoi extracts demonstrated growth inhibitory effects against A. baumannii, P. aeruginosa, and S. aureus, and its stem extracts exhibited the best inhibitory activity against A. baumannii (IC₅₀ 128 µg/mL). Four treatments (250 µg/mL for 72 h) with different parts of the AE of K. gastonis-bonnieri inhibited the proliferation of benign prostatic hyperplasia (BPH) cells (13.5–56.7%), and the AE of underground parts was the most active, stimulating changes in the BPH cells and modulating crucial processes such as proliferation, viability, and apoptosis [38].

In a study that compared 57 extracts obtained from 18 plants, K. glaucescens possessed the second-highest antioxidant activity and considerable cytotoxicity against leukemia cells [150]. The K. laciniata extracts from leaves picked before and during blooming (BB and DB, respectively) were tested to assess anti-inflammatory effects and both extracts presented no acute toxicity in mice (0.25 to 5 g/kg). Oral doses of the BB (0.25, 0.5, and 1.0 g/kg) significantly inhibited paw edema during the first four hours after injection of 2% carrageenan but oral doses of the DB (0.5, 1.0 and 2.0 g/kg) had no inhibitory activity [81]. The AE of K. laciniata also displayed thyroid peroxidase inhibition [151], immunomodulatory and anti-inflammatory properties [152,153]. The aqueous-methanol (AM) and n-hexane (NH) extracts of this species showed significant mutagenicity and cytotoxicity, and the NH extract treatment was more sensitive than others to E. coli [47,48]. Hydroethanolic extracts (HEE) obtained from K. laciniata leaves indicated dose-dependent cytotoxic activity against a 3T3 cell line (normal) and the 786–0 line (kidney carcinoma) (92.23% cell inhibition). In an in vivo experiment, the extract showed only liver changes and damage related to acute toxicity, and no significant toxicity. The HEE was able to reduce Salmonella growth rate, and the cell number was reduced with the release of the bacterial content. This species is confirmed as a natural source of antioxidant agents [45,154].

The gastroprotective activity of the leaf juices of K. laciniata was evaluated and compared with K. pinnata, and both species showed gastroprotective effects; however, the K. laciniata extract reduced the lesions in all the tested doses [43]. Other authors [155] determined the effect of aqueous, ethanol, and hexane extracts of K. laciniata leaves in comparison to other plants (Drymoglossum piloselloides leaves and Aegle marmelos flowers) against CaOx urolithiasis in vitro and the results clearly demonstrated that all species have the capacity to inhibit the nucleation, growth, and aggregation of CaOx crystals. Preliminary phytochemical screening also revealed the presence of reducing sugars, proteins, flavonoids, tannins, and polyphenol compounds in K. laciniata.

Kalanchoe longiflora was evaluated and compared to eight species of Kalanchoe in relation to antitrypanosomal, antimalarial, antileishmanial, cytotoxic, and antimicrobial activities [125]. This study revealed that K. longiflora leaf extracts showed activity against T. brucei with an inhibition concentration of sample at 50% (IC₅₀ 17.6 µg/mL). To determine the mechanism of action of K. longiflora extract as a potent anti-trypanosomal and cytotoxic agent, the authors investigated the ability to inhibit topoisomerase I enzyme and found the K. longiflora extract showed the best activity (IC₅₀ 0.148 µg/mL).

The antioxidant potential of various extracts of K. pinnata were evaluated and significant dose-dependent antioxidant activity was demonstrated in all of them. The antioxidant activities of the AE from the leaves improves the antioxidant potential in various organs (mainly the aorta), prevents adverse changes due to CCl4 intoxication in rats by pre-treatment (25 and 50 mg/kg b.w.), and the inhibits arginase II, as well as increasing antioxidant status in CCl4-intoxicated rats, which suggests a protection of the kidneys against CCl4-induced oxidative damage [59,63,65,83]. The EE from its stem/bark was evaluated by DPPH and exhibited high antioxidant activity (IC₅₀ 37.28 µg/mL). In comparison with other extracts (AE and PEE) obtained from the leaves, the EE showed the greatest radical inhibitory effect by DPPH, reaching a maximum inhibitory effect of 49.5 ± 5.6% (2000 µg/mL) [106,156]. The antioxidant property of ME from leaves showed 69.77% of free radical inhibition (100 µg/mL) of DPPH [62].

The concentration of vitamin C in AE of two Kalanchoe species (K. daigremontiana and K. pinnata) was evaluated and compared [12]; the amount of vitamin C was highest for the AE of K. pinnata (81 mg/100 g). Four major flavonoids obtained from HEE of K. pinnata leaves were evaluated by xanthine oxidase (XO) inhibition and antioxidant activity (DPPH and ABTS). It was found that kaempferol and quercetin derivatives moderately inhibited XO, while only quercetin derivatives displayed average radical scavenging activity, suggesting that quercetin 3-O-α-L-arabinopyranosyl-(1→2)-α-L-rhamnopyranoside (45) can be indicated as a specific marker of this species [71].

The K. pinnata AE and quercetin (40) inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcRI crosslinking in vitro: they decreased the development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia, and production of IL-5, IL-13, and TNF in vivo. In contrast, treatment with quercitrin (43) did not affect the tested parameters [42]. Additionally, the AE and quercitrin showed protective effects in fatal anaphylactic shock [157].

The antinociceptive, antiedematogenic, and anti-inflammatory potential as well as the possible mechanisms of action of the subcutaneous administration of K. pinnata AE of flowers, its ethyl acetate (EAF), and butanol (BF) fractions, and the main flavonoid (45) were investigated in a mouse model; the AE and its main flavonoid produced antinociceptive, antiedematogenic, and anti-inflammatory activities through COX inhibition and TNF-𝛼 reduction [8]. The flowers AE also are described as a rich source of T-suppressive flavonoids that may be therapeutically useful against inflammatory diseases [122]. The AE and the EE of K. pinnata leaves were found to be effective as hepatoprotective, and the AE was more effective [158]. The AE of the K. pinnata leaves were also examined [159] to investigate the ulcer healing properties and gastroprotective activity. The results indicate that treatment with the AE exhibited a higher inhibition percentage compared to pretreatment with an isolated quercetin derivative. This suggests that while the isolated flavonoid may possess gastroprotective activity, other compounds present in K. pinnata could potentially act synergistically to enhance its effect.

Studies comparing the anti-inflammatory [131] and the anti-ophidic [44] activities of K. laciniata and K. pinnata have been performed. The anti-inflammatory activity of topical formulations containing AE of both species showed good results; however, K. laciniata was most effective, with excellent results on the formulation containing a low concentration of its AE (5%). On the other hand, even though HE extracts from both species significantly reduced the hemorrhagic activity of B. jararaca venom in pre-treatment protocol, only K. pinnata was active in the post-treatment protocol and in the anti-edematogenic activity assay. It was also more active in the phospholipase test. Continuing the study, the authors conducted a study [160] to evaluate the healing properties and mechanism of action of the topical formulation of K. pinnata, which demonstrated the ability to stimulate the healing of skin wounds, leading to a reduction in wound area. Additionally, it exhibited a notable decrease in inflammatory infiltrate, as well as lowered levels of IL-1β and TNF-α. Moreover, the formulation induced angiogenesis by increasing the expression of VEGF, similar to the effects of Fibrinase. These findings highlight the significant potential of this formulation as a novel active ingredient in the development of pharmaceuticals for wound healing. The EE of K. pinnata also shows wound healing activity [161].

A method for targeting and identifying molecules with antimicrobial activity was implemented, which could potentially replace chemical preservatives in cosmetic applications [70]. An in vitro evaluation of the antimicrobial activity of different extracts (petroleum ether, chloroform, methanol, and aqueous) produced from K. pinnata roots was performed against E. coli, S. aureus, P. aeruginosa, and C. albicans [78], and the ME presented as an effective antibacterial, while none of the extracts showed activity against C. albicans. The EE of stem bark was tested against antimicrobial activity [156]; it inhibited the growth of microorganisms such as B. cereus, E. coli, S. aureus, P. aeruginosa, K. pneumoniae, and A. niger, while the extract was inactive against S. typhi and C. albicans.

The AE of K. pinnata displayed a significant reduction in hepatic and splenic parasite burden, indicating that the oral efficacy of this species extends to visceral leishmaniasis caused by L. chagasi [73,162]. The antileishmanial activity of three flavonoid glycoside and free quercetin (40) (isolated from the AE of K. pinnata) were also demonstrated [82,130], with a low toxicity profile. The anthelmintic capacity of the PEE and ME of K. pinnata was explored [163]. Both extracts were investigated in different concentrations for anthelmintic activity against P. posthuma and they exhibited no anthelmintic activity even at the highest concentration (200 mg/mL); the conclusion was that they had no vermicide activity. Two compounds (KPB-100 (122) and KPB-200 (123)) identified from K. pinnata are promising targets for synthetic optimization and in vivo study against human alpha herpesvirus 1 and 2 and vaccinia virus. KPB-100 (122) inhibited all the tested viruses [69]. The bryophyllin A (1) (isolated from K. pinnata), bersaldegenin 1,3,5-orthoacetate (6) and daigremontianin (4) (isolated from K. x houghtonni) showed good inhibitory potential on the Epstein-Barr virus, but bryophyllin A (1) was the most effective (IC₅₀: 0.4 µM) [112]. Additionally, both bryophyllin A and C isolated from a ME of the leaves of K. pinnata showed strong insecticidal activity against third instar larvae of the silkworm.

The EE of K. pinnata shows great hypoglycemic effect and the improvement of the number of pancreatic Langerhans beta cells at medium-dose treatment (11.6 mg/kg); it has a hypoglycemic effect through the improvement of the number of pancreatic Langerhans beta-cells. On the other hand, the DF from AE of K. pinnata demonstrates a dose-dependent insulin secretagogue action; reducing fasting blood glucose values (from 228 mg/dL to 116 mg/dL, on 10 mg/kg); improving the glycated hemoglobin to 8.4% (compared with 12.9% in diabetic controls); and restoring insulin level and lipid profile values close to normal [87,90]. The antioxidant effects of combined preparations of K. pinnata and metformin were investigated [164]. The treatment with K. pinnata alone (400 µg/mL), resulted in a significant increase in catalase activity in both non-diabetic and diabetic human skeletal muscle myoblasts, as well as in a human skeletal muscle myoblast cell line subjected to H₂O₂-stress-induced stress. Simultaneously, K. pinnata treatment led to a significant reduction in malondialdehyde levels. Notably, the combination of K. pinnata and metformin appeared to modulate antioxidant responses by increasing the enzymatic activity of superoxide dismutase, elevating the levels of reduced glutathione, and reducing glutathione levels in both non-diabetic and diabetic human skeletal muscle myoblasts, as well as in the H₂O₂-stress-induced human skeletal muscle myoblasts, which demonstrates the potential of these treatment in addressing the pathophysiological complications linked to oxidative stress in individuals with type II diabetes.

Investigations of the in vitro cytotoxicological and genotoxicological effects of K. pinnata were performed using its AE [85], leaf juice [64], and EE [165]. All the results indicated significantly lower results than those found for a positive control, suggesting a weak genotoxic response or a non-genotoxic effect. Hence, these extracts of K. pinnata can be used, but not for long durations or at higher doses, which indicates that this material may cause DNA damage and/or may have mutagenic effects. Consequently, its use should be restricted. Its chloroform extract (CE) obtained from the leaves demonstrated potential as anticancer and anti-HPV therapeutic for treatment of HPV infection and cervical cancer [166]. The cytotoxic activities of the EE of K. pinnata leaves were compared with the EE of three other species of the genus (K. daigremontiana, K. milloti, K. nyikae). The EE of K. pinnata showed the highest cytotoxicity against a lymphoma cell line, in a dose-dependent manner [135]. The anticancer mechanisms were revealed through a molecular approach [167] to support the use of K. pinnata as an adjuvant in cancer treatment. Gallic acid, caffeic acid, coumaric acid, quercetin, quercitrin, isorhamnetin, kaempferol, bersaldegenin, bryophyllin A, bryophyllin C, bryophynol, bryophyllol, bryophollone, stigmasterol, and campesterol were identified as bioactive compounds which participate. Some compounds were identified as bioactive, participating in the regulation of proliferation, apoptosis, cell migration, angiogenesis, metastasis, oxidative stress, and autophagy, with the potential to act as epigenetic drugs by reverting the acquired epigenetic changes associated with tumor resistance to therapy—such as the promoter methylation of suppressor genes, inhibition of DNMT1 and DNMT3b activity, and HDAC regulation—through methylation, thereby regulating the expression of genes involved in the PI3K/Akt/mTOR, Nrf2/Keap1, MEK/ERK, and Wnt/β-catenin pathways. Bryophyllin A, bryophyllin B, and bersaldegenin-3-acetate isolated from AE of K. pinnata are well known regarding their cytotoxic effects against A-549, HCT-8, P-388, and L-1210 tumor cells [114].

Two creams containing the AE of K. pinnata leaves (6%) and its major flavonoid quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (45) (0.15%) were developed and compared [67]. Both creams were topically evaluated and resulted in better re-epithelialization and dense collagen fibers. The flavonoid plays a fundamental role in wound healing but similar results that were found for both creams indicate that the use of the AE could be more profitable than the isolated compound. This extract of the AE also significantly prevented the increase of systolic and diastolic arterial pressures in salt hypertensive rats, and the concomitant administration of high-salt + the AE significantly prevented salt-induced hypertension in rats [65].

The effects of pressed juice (PJ), flavonoid-enriched fractions (FEF), bufadienolide-enriched fractions (BEF), and a flavonoid aglycone mixture (FAM) on detrusor contractility were investigated as a major target in overactive bladder disease [60]. The PJ increased the contraction force of muscle strips, the FEF had almost no effect on contractility, while the BEF and FAM led to a dose-dependent lowering of contraction force. The data indicated that several components of the PJ may contribute to the inhibitory effect on detrusor contractility, which in turn provides support for overactive bladder treatment. Other authors aimed to substantiate the use of the PJ [89] and AE in the treatment of premature labor [168] and in the uterine contractility [169]. In the first case, several fractions and compounds obtained from the PJ led to a dose-dependent decrease of oxytocin signaling (induced by an increase in free calcium concentration), but none was as strong as the PJ. However, the combination of a BEF and a FEF was as effective as the PJ, and the combination had a synergistic effect. The PJ inhibited oxytocin-driven activation, and this effect was comparable to that of the Atosiban oxytocin-receptor antagonist and tocolytic agent. In the second case, the AE showed to be as effective as beta-agonists, but significantly better tolerated. The antioxidant activity of 34 juices of species of the Kalanchoe genus were also compared, and the species K. scapigera and K. rhombopilosa showed the highest antioxidant activity (1981 mg/L and 1911 mg/L, respectively) [170]. A market product from PJ of K. pinnata was tested in prospective-observational studies in pregnancy [171], in patients with cancer and suffering from sleep problems [172], and the results suggested that these tablets can be a suitable treatment in both conditions.

The anticonvulsant activity from the ME of roots and stems of K. pinnata decreased with increased doses of the ME of roots, whereas the effect of the ME of stems was dose-dependent (it increased with higher doses) and this effect was preserved when the mixture of chloroform and ethyl acetate were tested. The dose of 400 mg/kg of the ME significantly improved the memory and learning of mice [62,80]. A study utilizing a larval zebrafish model was conducted to assess the potential of the AE obtained from K. pinnata leaves; the results indicated that the AE exhibited both anxiolytic and psychoactive effects, in a dose-dependent manner [173]. The findings of this study contribute to a deeper understanding of the underlying mechanisms responsible for these behavioral effects, thereby providing valuable insights that support the safe and effective utilization of AE in the treatment of mood disorders.

There are few studies about the isolation and characterization of bioactive molecules from Kalanchoe species correlated to their pharmacological potential. Detailed information regarding the studies reported in the literature can be observed in Table 7.

3. Methodology

This literature review used published scientific materials collected from the PubMed^® and SciFinder^® databases without restriction regarding the year of publication and includes literature published through April of 2023. The search term used was “Kalanchoe”. The chemical names agree with the original references.

4. Conclusions and Future Perspectives

This review describes the popular uses, anatomical, and biological aspects of the Kalanchoe species, a plant genus widely prescribed in folk medicine and popularly known as the “miracle leaf”. Even though the Kalanchoe genus has 133 accepted species names, only 19 species with popular uses have been described in the literature; 16 species have received botanical and pharmacological evaluation and only 6 species have received some chemical research in relation to isolated compounds. The species are mainly used in folk medicine to treat wounds, cancer, diabetes, infections, and inflammation. However, in the pharmacological evaluation, these species were not always studied in these models. Of the four species with the highest incidence of popular medicinal use, only K. pinnata was tested in relation to cutaneous wounds and the re-epithelialization process, and diabetes. The others (K. crenata, K. laciniata, and K. daigremontiana) have not yet been studied, but are popularly reported with these uses. Kalanchoe crenata, for example, has only been evaluated for cytotoxicity so far, but is often recommended for wound treatment as well as for diabetes, infections, and inflammation. All parts of the plant are utilized but the juice or crude extract are most widely used. The most utilized species are K. pinnata, K. crenata, K. laciniata, and K. daigremontiana. The literature does not describe which parts of the plant or methods of preparation are popularly recommended for medicinal use in relation to K. × houghtonii, K. flammea, K. gastonis-bonnieri, and K. integra. Several species have structural similarities, although few of them have macroscopic or microscopic information described in the literature. Further studies are necessary to differentiate the species. One hundred and twenty-three compounds were isolated from the Kalanchoe genus, mainly phenols, cardiac glycosides, and triterpenes. Most of the compounds were isolated from K. daigremontiana, K. pinnata, K. delagoensis, and K. ceratophylla. Pharmacological studies have validated antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities, some of which are related to ethnopharmacological uses. Of the sixteen studied species four are not reported in the literature regarding their popular uses; however, they have been tested regarding pharmacological activities (K. blossfeldiana, K. longiflora, K. scapigera, and K. rhombopilosa). More in vivo studies should be conducted to obtain information about the bioavailability of the chemical compounds present in the extracts, and to propose active doses of these extracts that could be used in vivo to promote the expected biological activities. These experiments could also help to determine the toxicity of these doses, and the possible adverse effects that might be related to these bioactive compounds. Analytical experiments to standardize the extracts and identify possible chemical markers that could be used for quality control are also required. Finally, the authors consider that pharmacological studies dealing with yet unexplored areas should be encouraged to increase other possible medicinal uses of the extracts of these species of Kalanchoe.

Author Contributions

Data curation, E.A.d.A. and I.M.; original draft preparation, E.A.d.A.; tables preparation, E.A.d.A., I.M., A.C.T.V. and S.A.B.; chemical structures preparation, E.A.d.A. and S.A.B.; review and editing, A.V.P., F.L.B., W.K.S. and R.T.W.; supervision and project administration, F.L.B., W.K.S. and R.T.W. All authors have read and agreed to the published version of the manuscript.

Funding

The scholarship of E.A.A. was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88881.689971/2022-01).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are grateful to the State University of Ponta Grossa and University of North Carolina Wilmington for the partnership.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Sample Availability

Not applicable.

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Figure 1. Distribution of the species of the family Crassulaceae (yellow spots).

Figure 2. Distribution of the native (green) and introduced (purple) species of the genus Kalanchoe.

Figure 3. Chemical structures of cardiac glycosides from Kalanchoe species.

Figure 4. Chemical structures of flavonoids from Kalanchoe species.

Figure 5. Chemical structures of other secondary metabolites from Kalanchoe species.

Table 1. Kalanchoe species, synonyms, and number of occurrences.

Scientific Name	Synonym	Occurrences
Kalanchoe adelae Raym.-Hamet	Bryophyllum adelae (Raym.-Hamet) A.Berger, Kalanchoe floribunda Tul.	2
Kalanchoe aliciae Raym.-Hamet	Bryophyllum aliciae (Raym.-Hamet) A.Berger, Kalanchoe miniata var. tsinjoarivensis H.Perrier, Kalanchoe pubescens var. brevicalyx Boiteau and Mannoni, Kalanchoe pubescens var. grandiflora Boiteau and Mannoni	4
Kalanchoe alternans (Vahl) Pers.	Cotyledon alternans Vahl, Vereia alternans (Vahl) Spreng.	56
Kalanchoe alticola Compton	-	5
Kalanchoe ambolensis Humbert	-	10
Kalanchoe angolensis N.E.Br.	-	1
Kalanchoe antennifera Desc.	-	2
Kalanchoe arborescens Humbert	-	43
Kalanchoe aromatica H.Perrier	-	27
Kalanchoe aubrevillei Raym.-Hamet ex Cufod.	-	12
Kalanchoe × auriculata (Raadts) V.V.Byalt	Kalanchoe nyikae subsp. auriculata Raadts	47
Kalanchoe ballyi Raym.-Hamet ex Cufod.	-	27
Kalanchoe beauverdii Raym.-Hamet	Bryophyllum beauverdii (Raym.-Hamet) A.Berger, Kalanchoe beauverdii var. typica Boiteau and Mannoni	152
Kalanchoe beharensis Drake	Kalanchoe vantieghemii Raym.-Hamet	386
Kalanchoe benbothae Gideon F.Sm. and N.R.Crouch	-	6
Kalanchoe bentii C.H.Wright ex Hook f.	-	37
Kalanchoe berevoensis Rebmann	-	-
Kalanchoe bergeri Raym.-Hamet and H.Perrier	Bryophyllum bergeri (Raym.-Hamet and H.Perrier) Govaerts, Kalanchoe bergeri var. typica Boiteau and Mannoni, Kalanchoe bergeri var. glabra Boiteau and Mannoni	27
Kalanchoe bhidei T.Cooke	-	16
Kalanchoe bipartita Chiov.	-	14
Kalanchoe blossfeldiana Poelln.	Kalanchoe coccinea (H.Perrier) Boiteau, Kalanchoe coccinea var. blossfeldiana (Poelln.) Boiteau, Kalanchoe globulifera var. coccinea H.Perrier	493
Kalanchoe bogneri Rauh	Bryophyllum bogneri (Rauh) V.V.Byalt	10
Kalanchoe boisii Raym.-Hamet and H.Perrier	-	2
Kalanchoe boranae Raadts	-	10
Kalanchoe bouvetii Raym.-Hamet and H.Perrier	Bryophyllum bouvetii (Raym.-Hamet and H.Perrier) A.Berger	16
Kalanchoe bouvetii Raym.-Hamet and H.Perrier	Kalanchoe baumii Engl. and Gilg, Kalanchoe multiflora Schinz, Kalanchoe pruinosa Dinter, Kalanchoe pyramidalis Schönland	16
Kalanchoe bracteata Scott Elliot	Kalanchoe bracteata var. aurantiaca Rauh and Hebding, Kalanchoe bracteata var. glabra Rauh and Hebding, Kalanchoe bracteata subsp. glabra Rauh and Hebding, Kalanchoe bracteata var. longisepala Boiteau ex L.Allorge, Kalanchoe bracteata var. pubescens Rauh and Hebding, Kalanchoe bracteata var. virescens Desc., Kalanchoe nadyae Raym.-Hamet	88
Kalanchoe brevicalyx (Raym.-Hamet and H.Perrier) Gideon F.Sm. and Figueiredo	Kalanchoe pinnata var. brevicalyx Raym.-Hamet and H.Perrier	1
Kalanchoe briquetii Raym.-Hamet	-	2
Kalanchoe campanulata (Baker) Baill.	Bryophyllum campanulatum (Baker) V.V.Byalt, Udalova and I.M.Vassiljeva, Kitchingia campanulata Baker, Kalanchoe amplexicaulis (Baker) Baill., Kalanchoe campanulata subsp. orthostyla Boiteau and Mannoni, Kalanchoe panduriformis (Baker) Baill., Kalanchoe parviflora (Baker) Baill., Kitchingia amplexicaulis Baker, Kitchingia panduriformis Baker, Kitchingia parviflora Baker	80
Kalanchoe ceratophylla Haw.		111
Kalanchoe chapototii Raym.-Hamet and H.Perrier		2
Kalanchoe cherukondensis Subba Rao and Kumari	Vereia ceratophylla (Haw.) D.Dietr.	-
Kalanchoe chevalieri Gagnep.	Kalanchoe integra var. chevalieri (Gagnep.) H.H.Pham	9
Kalanchoe citrina Schweinf.	Kalanchoe citrina var. ballyi Raym.-Hamet ex Wickens, Kalanchoe citrina var. erythreae Schweinf.	102
Kalanchoe costantinii Raym.-Hamet	Bryophyllum costantinii (Raym.-Hamet) A.Berger	1
Kalanchoe craibii Raym.-Hamet	-	1
Kalanchoe crenata (Andrews) Haw.	Cotyledon crenata (Andrews) Vent., Cotyledon verea Jacq., Kalanchoe afzeliana Britten, Kalanchoe crenata var. verea Cufod., Kalanchoe integra var. crenata (Andrews) Cufod., Kalanchoe integra var. varea Cufod., Kalanchoe verea Pers., Vereia crenata Andrews	1320
Kalanchoe crouchii Gideon F.Sm. and Figueiredo	-	3
Kalanchoe crundallii I.Verd.	-	6
Kalanchoe curvula Desc.	Bryophyllum curvulum (Desc.) V.V.Byalt	16
Kalanchoe cymbifolia Desc.	Bryophyllum cymbifolium (Desc.) V.V.Byalt	-
Kalanchoe daigremontiana Raym.-Hamet and H.Perrier	Bryophyllum daigremontianum (Raym.-Hamet and H.Perrier) A.Berger	768
Kalanchoe darainensis D.-P.Klein and Callm.	-	22
Kalanchoe decumbens Compton	-	-
Kalanchoe deficiens (Forssk.) Asch. and Schweinf.	Cotyledon deficiens Forssk., Kalanchoe glaucescens var. deficiens (Asch. and Schweinf.) Senni	342
Kalanchoe delagoensis Eckl. and Zeyh.	Bryophyllum delagoense (Eckl. and Zeyh.) Druce, Bryophyllum tubiflorum Harv., Kalanchoe tubiflora (Harv.) Raym.-Hamet, Bryophyllum verticillatum (Scott Elliot) A.Berger, Geaya purpurea Costantin and Poiss., Kalanchoe verticillata Scott Elliot	5341
Kalanchoe densiflora Rolfe	-	687
Kalanchoe × descoingsii Shtein, Gideon F.Sm. and J.Ikeda	-	-
Kalanchoe dinklagei Rauh	Kalanchoe brevisepala (Humbert) L.Allorge, Kalanchoe millotii var. brevisepala Humbert	14
Kalanchoe dyeri N.E.Br.	-	21
Kalanchoe elizae A.Berger	Cotyledon elizae (A.Berger) Raym.-Hamet, Cotyledon insignis N.E.Br., Kalanchoe insignis (N.E.Br.) N.E.Br., Kalanchoe laurensii Raym.-Hamet	80
Kalanchoe eriophylla Hils. and Bojer ex Tul.	Cotyledon pannosa Baker	43
Kalanchoe × estrelae Gideon F.Sm.	-	-
Kalanchoe fadeniorum Raadts	-	8
Kalanchoe farinacea Balf.f.	-	55
Kalanchoe faustii Font Quer	Kalanchoe laciniata subsp. faustii (Font Quer) Maire	33
Kalanchoe fedtschenkoi Raym.-Hamet and H.Perrier	Bryophyllum fedtschenkoi (Raym.-Hamet and H.Perrier) Lauz.-March., Kalanchoe fedtschenkoi var. isalensis Boiteau and Mannoni	514
Kalanchoe fernandesii Raym.-Hamet	-	4
Kalanchoe × flaurantia Desc.	-	-
Kalanchoe gastonis-bonnieri Raym.-Hamet and H.Perrier	Bryophyllum gastonis-bonnieri (Raym.-Hamet and H.Perrier) Lauz.-March., Kalanchoe adolphi-engleri Raym.-Hamet, Kalanchoe gastonis-bonnieri var. ankaizinensis Boiteau ex L.Allorge	173
Kalanchoe germanae Raym.-Hamet ex Raadts	-	16
Kalanchoe gideonsmithii N.R.Crouch and Figueiredo	-	1
Kalanchoe glaucescens Britten	Kalanchoe beniensis De Wild., Kalanchoe elliptica Raadts, Kalanchoe flammea Stapf, Kalanchoe holstii Engl., Kalanchoe magnidens N.E.Br., Kalanchoe marinellii Pamp., Kalanchoe ndorensis Schweinf. ex Engl.	379
Kalanchoe globulifera H.Perrier	-	15
Kalanchoe gracilipes (Baker) Baill.	Bryophyllum gracilipes (Baker) Eggli, Kitchingia gracilipes Baker	89
Kalanchoe grandidieri Baill.	-	64
Kalanchoe grandiflora Wight and Arn.	Vereia grandiflora (Wight and Arn.) D.Dietr.	77
Kalanchoe guignardii Raym.-Hamet and H.Perrier	Kalanchoe beauverdii var. guignardii (Raym.-Hamet and H.Perrier) Boiteau and Mannoni	1
Kalanchoe × gunniae Gideon F.Sm. and Figueiredo	-	-
Kalanchoe hametiorum Raym.-Hamet	-	4
Kalanchoe hauseri Werderm.	-	-
Kalanchoe hildebrandtii Baill.	Kalanchoe gomphophylla Baker, Kalanchoe hildebrandtii var. glabra Rauh and Hebding	95
Kalanchoe hirta Harv.	-	13
Kalanchoe × houghtonii D.B.Ward	Bryophyllum × houghtonii (D.B.Ward) P.I.Forst.	1650
Kalanchoe humifica Desc.	Bryophyllum humificum (Desc.) V.V.Byalt	1
Kalanchoe humilis Britten	-	30
Kalanchoe hypseloleuce Friis and M.G.Gilbert	-	1
Kalanchoe inaurata Desc.	Bryophyllum inauratum (Desc.) V.V.Byalt	-
Kalanchoe integra (Medik.) Kuntze	Cotyledon integra Medik., Bryophyllum serratum Blanco, Cotyledon acutiflora (Haw.) W.T.Aiton, Cotyledon hybrida Dum.Cours., Cotyledon spathulata (DC.) Poir., Echeveria spathulata (DC.) W.Bull ex É.Morren, Kalanchoe acutiflora (Andrews) Haw., Kalanchoe annamica Gagnep., Kalanchoe corymbosa Wall., Kalanchoe dixoniana Raym.-Hamet, Kalanchoe garambiensis Kudô, Kalanchoe hybrida Desf. ex Steud., Kalanchoe integra var. annamica (Gagnep.) H.H.Pham, Kalanchoe nudicaulis Buch.-Ham. ex C.B.Clarke, Kalanchoe schumacheri Koord., Kalanchoe spathulata DC., Kalanchoe spathulata var. annamica (Gagnep.) H.Ohba, Kalanchoe spathulata var. baguioensis H.Ohba, Kalanchoe spathulata var. ciliata, Kalanchoe spathulata var. dixoniana (Raym.-Hamet) H.Ohba, Kalanchoe spathulata var. garambiensis (Kudô) H.Ohba, Kalanchoe spathulata var. schumacheri (Koord.) H.Ohba, Kalanchoe spathulata var. simlensis H.Ohba, Kalanchoe spathulata var. staintonii H.Ohba, Kalanchoe subamplectens Wall., Kalanchoe varians Haw., Kalanchoe yunnanensis Gagnep., Vereia acutiflora Andrews, Vereia spathulata (DC.) D.Dietr.	289
Kalanchoe integrifolia Baker	Kalanchoe bitteri Raym.-Hamet and H.Perrier, Kalanchoe heckelii Raym.-Hamet and H.Perrier, Kalanchoe integrifolia var. bitteri Raym.-Hamet and H.Perrier, Kalanchoe integrifolia var. flava Boiteau	85
Kalanchoe jongmansii Raym.-Hamet and H.Perrier	Bryophyllum jongmansii (Raym.-Hamet and H.Perrier) Govaerts, Kalanchoe jongmansii subsp. ivohibensis Humbert	54
Kalanchoe klopperae Gideon F.Sm. and Figueiredo	-	-
Kalanchoe laciniata (L.) DC.	Cotyledon laciniata L., Vereia laciniata (L.) Willd., Kalanchoe angustifolia A.Rich., Kalanchoe biternata Wight ex Wall., Kalanchoe carnea N.E.Br., Kalanchoe gloveri Cufod., Kalanchoe lentiginosa Cufod., Kalanchoe petitiaesii Rich. ex Jacques, Kalanchoe rohlfsii Engl., Kalanchoe rosea A.Chev., Kalanchoe schweinfurthii Penz., Kalanchoe teretifolia Haw.	430
Kalanchoe laetivirens Desc.	Bryophyllum laetivirens (Desc.) V.V.Byalt	223
Kalanchoe lanceolata (Forssk.) Pers.	Cotyledon lanceolata Forssk., Vereia lanceolata (Forssk.) Spreng., Cotyledon amplexicaulis B.Heyne ex C.B.Clarke, Cotyledon corymbosa Rottler ex Wight and Arn., Cotyledon heterophylla Roxb., Cotyledon hirsuta B.Heyne ex C.B.Clarke, Cotyledon paniculata Rottler ex Wight and Arn., Kalanchoe amplexicaulis B.Heyne, Kalanchoe brachycalyx A.Rich., Kalanchoe crenata var. collina Engl., Kalanchoe ellacombei N.E.Br., Kalanchoe floribunda Wight and Arn., Kalanchoe floribunda var. glabra C.B.Clarke, Kalanchoe glandulosa Hochst. ex A.Rich., Kalanchoe glandulosa var. benguellensis Engl., Kalanchoe glandulosa var. rhodesica Baker f., Kalanchoe glandulosa var. tomentosa Keissl., Kalanchoe goetzei Engl., Kalanchoe gregaria Dinter, Kalanchoe heterophylla (Roxb.) Wight and Arn., Kalanchoe heterophylla (Roxb.) Prain, Kalanchoe homblei De Wild., Kalanchoe homblei f. reducta De Wild., Kalanchoe junodii Schinz, Kalanchoe laciniata var. brachycalyx (A.Rich.) Chiov., Kalanchoe lanceolata var. glabra (C.B.Clarke) S.R.Sriniv., Kalanchoe lanceolata var. glandulosa (Hochst. ex A.Rich.) Cufod., Kalanchoe modesta Kotschy and Peyr., Kalanchoe pentheri Schltr., Kalanchoe pilosa Baker, Kalanchoe platysepala Welw. ex Britten, Kalanchoe pubescens R.Br. ex Britten, Kalanchoe ritchieana Dalzell, Kalanchoe spathulata Wall., Kalanchoe wightianum Wall., Meristostylus macrocalyx Klotzsch, Vereia floribunda (Wight and Arn.) D.Dietr., Vereia heterophylla (Wight and Arn.) D.Dietr.	893
Kalanchoe lateritia Engl.	-	284
Kalanchoe latisepala N.E.Br.	-	31
Kalanchoe laxiflora Baker	Bryophyllum laxiflorum (Baker) Govaerts, Bryophyllum crenatum Baker, Kalanchoe crenata (Baker) Raym.-Hamet, Kalanchoe laxiflora subsp. stipitata Boiteau and Mannoni, Kalanchoe laxiflora subsp. subpeltata Boiteau and Mannoni, Kalanchoe laxiflora subsp. violacea Boiteau and Mannoni, Kalanchoe tieghemii Raym.-Hamet	469
Kalanchoe leblanciae Raym.-Hamet	-	17
Kalanchoe lindmanii Raym.-Hamet	Kalanchoe gossweileri Croizat, Kalanchoe humbertii Guillaumin, Kalanchoe pearsonii N.E.Br.	16
Kalanchoe linearifolia Drake	Kalanchoe bonnieri Raym.-Hamet	118
Kalanchoe lobata R.Fern.	-	6
Kalanchoe × lokarana Desc.	Bryophyllum × lokarana (Desc.) V.V.Byalt	2
Kalanchoe longiflora Schltr.	-	35
Kalanchoe longifolia E.T.Geddes	-	2
Kalanchoe lubangensis R.Fern.	-	1
Kalanchoe luciae Raym.-Hamet	Kalanchoe albiflora H.M.L.Forbes	60
Kalanchoe macrochlamys H.Perrier	Bryophyllum macrochlamys (H.Perrier) A.Berger	12
Kalanchoe mandrarensis Humbert	-	7
Kalanchoe manginii Raym.-Hamet and H.Perrier	Bryophyllum manginii (Raym.-Hamet and H.Perrier) Nothdurft	67
Kalanchoe marmorata Baker	Kalanchoe grandiflora A.Rich., Kalanchoe macrantha Baker ex Maire, Kalanchoe macrantha var. marmorata (Baker) Maire, Kalanchoe macrantha var. richardiana Maire	264
Kalanchoe marnieriana H.Jacobsen ex L.Allorge	Bryophyllum marnierianum (H.Jacobsen ex L.Allorge) Govaerts, Kalanchoe humbertii Mannoni and Boiteau	46
Kalanchoe maromokotrensis Desc. and Rebmann	-	5
Kalanchoe migiurtinorum Cufod.	-	7
Kalanchoe millotii Raym.-Hamet and H.Perrier	-	82
Kalanchoe miniata Hils. and Bojer ex Tul.	Bryophyllum miniatum (Hils. and Bojer ex Tul.) A.Berger, Kalanchoe miniata var. typica H.Perrier, Kitchingia miniata (Hils. and Bojer ex Tul.) Baker	252
Kalanchoe mitejea Leblanc and Raym.-Hamet	-	29
Kalanchoe montana Compton	Kalanchoe luciae subsp. montana (Compton) Toelken	2
Kalanchoe mortagei Raym.-Hamet and H.Perrier	Bryophyllum mortagei (Raym.-Hamet and H.Perrier) Wickens, Kalanchoe poincarei var. mortagei (Raym.-Hamet and H.Perrier) Boiteau	42
Kalanchoe ndotoensis L.E.Newton	-	1
Kalanchoe neglecta Toelken	Kalanchoe rotundifolia f. peltata R.Fern.	7
Kalanchoe nyikae Engl.	Kalanchoe hemsleyana Cufod.	53
Kalanchoe obtusa Engl.	-	39
Kalanchoe olivacea Dalzell	-	10
Kalanchoe orgyalis Baker	Kalanchoe antanosiana Drake	162
Kalanchoe paniculata Harv.	Sedum harveyanum Kuntze, Kalanchoe oblongifolia Harv.	193
Kalanchoe pareikiana Desc. and Lavranos	-	2
Kalanchoe peltata (Baker) Baill.	Bryophyllum peltatum (Baker) V.V.Byalt, Udalova and I.M.Vassiljeva, Kitchingia peltata Baker	152
Kalanchoe peltigera Desc.	Bryophyllum peltigerum (Desc.) V.V.Byalt	5
Kalanchoe perrieri Shtein, Gideon F.Sm. and D.-P.Klein	-	-
Kalanchoe peteri Werderm.	-	35
Kalanchoe petitiana A.Rich.	-	95
Kalanchoe pinnata (Lam.) Pers.	Bryophyllum pinnatum (Lam.) Oken, Cotyledon pinnata Lam., Crassula pinnata (Lam.) L.f., Kalanchoe pinnata var. genuina Raym.-Hamet, Vereia pinnata (Lam.) Spreng., Baumgartenia sobolifera Tratt., Bryophyllum calcicola (H.Perrier) V.V.Byalt, Bryophyllum calycinum Salisb., Bryophyllum germinans Blanco, Bryophyllum pinnatum simplicifolium Kuntze, Cotyledon calycina (Salisb.) B.Heyne, Cotyledon calyculata Sol. ex Sims, Cotyledon rhizophylla Roxb., Crassuvia floripendia Comm. ex Lam., Kalanchoe calcicola (H.Perrier) Boiteau, Kalanchoe floripendula Steud, Kalanchoe pinnata var. calcicola H.Perrier, Kalanchoe pinnata var. floripendula Pers.	7288
Kalanchoe × poincarei Raym.-Hamet and H.Perrier	Bryophyllum poincarei (Raym.-Hamet and H.Perrier) Govaerts	10
Kalanchoe porphyrocalyx (Baker) Baill.	Bryophyllum porphyrocalyx (Baker) A.Berger, Kalanchoe porphyrocalyx var. typica Boiteau and Mannoni, Kitchingia porphyrocalyx Baker	187
Kalanchoe prasina N.E.Br.	Kalanchoe figuereidoi Croizat	-
Kalanchoe prittwitzii Engl.	Kalanchoe dielsii Raym.-Hamet, Kalanchoe lugardii Bullock, Kalanchoe robynsiana Raym.-Hamet, Kalanchoe secunda Werderm.	136
Kalanchoe prolifera (Bowie ex Hook.) Raym.-Hamet	Bryophyllum proliferum Bowie ex Hook., Bryophyllum cochleatum Lem., Kalanchoe cochleatum (Lem.) B.D.Jacks.	180
Kalanchoe pseudocampanulata Mannoni and Boiteau	Bryophyllum pseudocampanulatum (Mannoni and Boiteau) Govaerts, Kalanchoe miniata var. decaryana H.Perrier	5
Kalanchoe pubescens Baker	Bryophyllum pubescens (Baker) Govaerts, Kalanchoe pubescens var. typica Boiteau and Mannoni	162
Kalanchoe pumila Baker	Kalanchoe brevicaulis Baker, Kalanchoe multiceps Baill., Kalanchoe pumila f. venustior Boiteau	71
Kalanchoe quadrangularis Desc.	-	3
Kalanchoe quartiniana A.Rich.	-	23
Kalanchoe rebmannii Desc.	-	1
Kalanchoe × rechingeri Raym.-Hamet ex Rauh and Hebding	Bryophyllum × rechingeri (Raym.-Hamet ex Rauh and Hebding) V.V.Byalt	2
Kalanchoe rhombopilosa Mannoni and Boiteau	Kalanchoe rhombopilosa var. argentea Rauh, Kalanchoe rhombopilosa var. viridifolia Rauh	30
Kalanchoe × richaudii Desc.	-	2
Kalanchoe robusta Balf.f.	Kalanchoe abrupta Balf.f.	7
Kalanchoe rolandi-bonapartei Raym.-Hamet and H.Perrier	Bryophyllum rolandi-bonapartei (Raym.-Hamet and H.Perrier) Govaerts, Bryophyllum tsaratananense (H.Perrier) A.Berger, Kalanchoe tsaratananensis H.Perrier	16
Kalanchoe rosea C.B.Clarke	-	-
Kalanchoe rosei Raym.-Hamet and H.Perrier	Bryophyllum rosei (Raym.-Hamet and H.Perrier) A.Berger, Kalanchoe bouvieri Raym.-Hamet and H.Perrier	74
Kalanchoe rotundifolia (Haw.) Haw.	Crassula rotundifolia Haw., Sedum subrotundifolium (Haw.) Kuntze, Vereia rotundifolia (Haw.) D.Dietr., Kalanchoe guillauminii Raym.-Hamet, Kalanchoe integerrima Lange, Kalanchoe luebbertiana Engl., Kalanchoe rotundifolia var. guillauminii (Raym.-Hamet) Raym.-Hamet, Kalanchoe rotundifolia f. tripartita R.Fern., Kalanchoe seilleana Raym.-Hamet, Kalanchoe stearnii Raym.-Hamet, Meristostylus brachycalyx Klotzsch	623
Kalanchoe rubella (Baker) Raym.-Hamet	Bryophyllum rubellum Baker	23
Kalanchoe salazarii Raym.-Hamet	-	2
Kalanchoe sanctula Desc.	Bryophyllum sanctulum (Desc.) V.V.Byalt	2
Kalanchoe scandens H.Perrier	Bryophyllum scandens (H.Perrier) A.Berger, Kalanchoe beauverdii var. parviflora Boiteau and Mannoni	7
Kalanchoe scapigera Welw. ex Britten	-	15
Kalanchoe schimperiana A.Rich.	Cotyledon deficiens Hochst. and Steud. ex A.Rich.	78
Kalanchoe schizophylla (Baker) Baill.	Bryophyllum schizophyllum (Baker) A.Berger, Kitchingia schizophylla Baker	48
Kalanchoe schliebenii Werderm.	-	3
Kalanchoe serrata Mannoni and Boiteau	Bryophyllum lauzac-marchaliae V.V.Byalt, Bryophyllum serratum (Mannoni and Boiteau) Lauz.-March.	36
Kalanchoe sexangularis N.E.Br.	-	130
Kalanchoe stenosiphon Britten	-	9
Kalanchoe streptantha Baker	Bryophyllum streptanthum (Baker) A.Berger	28
Kalanchoe suarezensis H.Perrier	Bryophyllum suarezense (H.Perrier) A.Berger, Kalanchoe poincarei var. suarezensis (H.Perrier) L.Allorge	20
Kalanchoe subrosulata Thulin	-	4
Kalanchoe synsepala Baker	Kalanchoe brachycalyx Baker, Kalanchoe gentyi Raym.-Hamet and H.Perrier, Kalanchoe trichantha Baker	214
Kalanchoe tachingshuii S.S.Ying	-	-
Kalanchoe tashiroi Yamam.	-	4
Kalanchoe teixeirae Raym.-Hamet ex R.Fern.	-	3
Kalanchoe tenuiflora Desc.	-	3
Kalanchoe tetramera E.T.Geddes	-	2
Kalanchoe tetraphylla H.Perrier	-	30
Kalanchoe thyrsiflora Harv.	Kalanchoe alternans Eckl. and Zeyh. ex Harv.	251
Kalanchoe tomentosa Baker	Bryophyllum triangulare Blanco	179
Kalanchoe torrejacqii Shtein and Gideon F.Sm.	-	3
Kalanchoe tuberosa H.Perrier	-	11
Kalanchoe uniflora (Stapf) Raym.-Hamet	Bryophyllum uniflorum (Stapf) A.Berger, Kitchingia uniflora Stapf, Bryophyllum ambrense (H.Perrier) A.Berger, Kalanchoe ambrensis H.Perrier, Kalanchoe uniflora var. brachycalyx Boiteau and Mannoni	97
Kalanchoe usambarensis Engl. and Raym.-Hamet	-	16
Kalanchoe variifolia (Guillaumin and Humbert) Shtein, D.-P.Klein and Gideon F.Sm.	Kalanchoe rosei var. variifolia (Guillaumin and Humbert) J.M.H.Shaw, Kalanchoe rosei subsp. variifolia Guillaumin and Humbert	13
Kalanchoe velutina Welw. ex Britten	-	56
Kalanchoe viguieri Raym.-Hamet and H.Perrier	Kalanchoe viguieri var. latisepala Raym.-Hamet and H.Perrier	68
Kalanchoe waldheimii Raym.-Hamet and H.Perrier	Bryophyllum waldheimii (Raym.-Hamet and H.Perrier) Lauz.-March.	50
Kalanchoe waterbergensis van Jaarsv.	-	3
Kalanchoe welwitschii Britten	-	17
Kalanchoe wildii Raym.-Hamet ex R.Fern.	Kalanchoe aleuroides Stearn	2
Kalanchoe winteri Gideon F.Sm., N.R.Crouch and Mich.Walters	-	3
Kalanchoe yemensis (Deflers) Schweinf.	Kalanchoe brachycalyx var. yemensis Deflers	17

Table 2. Traditional uses of Kalanchoe species.

Species	Traditional Uses	Form of Use and Plant Part	References
K. ceratophylla	To treat injuries, pain, fever, and inflammation.	Internal or external administration of crude extracts or plant juice.	[14,15,16,17]
K. crenata	Antidiabetic, anti-inflammatory, antimicrobial, vermifuge, and anti-infective agent; to treat wounds, abscesses, abdominal pain, asthma, headache, convulsion, smallpox, peptic ulcer, upper respiratory tract infections, coughs, otitis, palpitations, cancer (or disease states with symptoms related to cancer), diabetes, swollen areas for muscle sprain and myalgia; and to heal umbilical cord wounds in newborns.	Internal administration of crude extracts, plant juice, leaves juice, or chew the leaves; external administration of crude extracts or plant juice and from macerating the leaves into a cream. Use of roots.	[6,14,15,16,18,19,20,21,22,23,24,25,26,27]
K. daigremontiana	Anticancer, anti-inflammatory, antimicrobial, antiseptic, carminative and cardioactive agent; to treat skin injuries and wounds; to staunch bleeding; to treat infections, rheumatism, earache, burns, arthritis, gastric and menstrual disorders, cough, fever, cardiovascular dysfunction, diabetes, psychic agitation, restlessness and anxiety, some cancers; a chemo preventive.	Internal or external administration of crude extracts or plant juice and use of roots.	[9,10,11,12,15,21,28,29,30]
K. delagoensis	To treat wounds, epilepsy, neoplastic diseases, fever, abscesses, bruises, pneumonia, coughs, stomachache, and as a vermifuge.	Internal or external administration of crude extracts or plant juice and use of roots.	[14,15,21,31,32,33,34]
K. densiflora	To treat wounds and skin disorders, rheumatism, hemorrhoids, eye problems, joint and muscle pains, stomach and liver problems, umbilical cord, cardiac disorders, edema, poisonous, abortifacient.	Internal or external administration of crude extracts or plant juice.	[15,24,27,35]
K. flammea	To treat fever, wounds, inflammation, and cancer.		[36]
K. fedtschenkoi	Analgesic, cytotoxic, and antimicrobial treatments.	Internal or external administration. Use of leaves and roots.	[21,37]
K. gastonis-bonnieri	To treat genital-urinary and vaginal infections and as a vaginal contraceptive.		[38]
K. germanae	After removal of ganglions the leaves are used to treat the affected area.	Internal or external administration of crude extracts or plant juice.	[15]
K. glaucescens	To treat coughs and rheumatism.	Internal or external administration of crude extracts or plant juice.	[15,24]
K. integra	Antihypertensive.		[39]
K. laciniata	As an anti-inflammatory, astringent, and antiseptic; to treat wounds, inflammation, headache, diabetes, heart discomfort, gastric disorders, lithiasis, diarrhea, fever, cough, snakebites, erysipelas, boils, and human prostate cancer.	Internal administration of crude extracts, plant juice, leaves juice or chew the leaves; external administration of crude extracts or plant juice and from macerating the leaves into a cream.	[6,11,15,40,41,42,43,44,45,46,47,48,49]
K. lanceolata	To treat dysentery, rheumatism, hemorrhoids, splenomegaly, hepatomegaly, and pains.	Internal or external administration of crude extracts or plant juice.	[15,24,27,35]
K. marmorata	To treat wounds, boils, bruises, periodontal disease, cracked lips, arthritis, gastric ulcers, ear diseases, eye infections, dysentery, fever, common cold, coughs, cholera, urinary diseases, stiff muscles, liver problems, and headaches.	Internal or external administration of crude extracts or plant juice.	[15,24,50,51,52]
K. mortagei	As an antimicrobial; to treat digestive disorders, parasites, and neoplastic diseases orally; and as a local remedy for cancer.	Internal or external administration. Use of leaves and roots.	[21,37]
K. obtusa	Children’s diseases and as pesticide.	Use the whole plant.	[24]
K. petitiana	To treat epilepsy, trachoma, allergies, intestinal parasites, gonorrhea, bone setting after fractures, wound healing, breast tumors, skin cancer, swelling of gland/lymph adenitis, toothache, dysentery, liver problems, stomachache, tonsillitis, gastritis, peptic ulcer disease, and foot problems (fungal nails, corns, and calluses, athlete’s foot, plantar warts).	Internal or external administration of crude extracts or plant juice.	[15,53,54,55,56]
K. pinnata	Antipyretic, antibacterial, antiseptic, antimalaria, anti-inflammatory, and antipsychotic agent. To treat the following: wounds, burns; cardiovascular dysfunctions; cancer; rheumatoid arthritis; digestive, menstrual and psychiatric disorders; hypertension; skin, respiratory and genitourinary infections; kidney, liver and urinary disorders; ear, head and toothache; insect, snake and scorpion bites; muscle bruises; cholera; leishmania; leprosy; lithiasis; viruses; restlessness; biostimulator during skin transplantation; to prevent premature labor and help women recover after childbirth; diabetes; cold, whooping cough, bone fracture, Chikungunya virus, and against COVID-19 symptoms.	Internal administration of crude extracts, whole plant, or leaves juice, chew the leaves or leaves infusion; external administration of crude extracts or plant juice and from macerating the leaves into a cream. Use of roots.	[6,8,9,14,15,21,41,42,43,44,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]
K. prittwitzii	Stiff joints and rheumatism.	Use of leaves.	[24]
K. serrata	To treat pain, inflammation, fever, and viruses.	Use of leaves and roots.	[21]
K. x houghtonii	To treat infections, rheumatism, coughs, fever, and inflammation.		[30]

Table 7. Biological activities of compounds isolated from Kalanchoe species.

Species Plant Part	Compound Tested	Pharmacological Activity	Results	Mechanisms of Action	References
K. delagoensis Whole plant	quercetin (40) (6S,7R,8R,9S)-6-oxaspiro-7,8-dihydroxymegastigman-4-en-3-one (tubiflorone) (85) syringic acid (90) 4-O-ethylgallic acid (98) 3,4-dimethoxyphenol (100) phloroglucinol (101) 3,4-dihydroxyallylbenzene (102)	Anti-inflammatory Lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells	The compounds demonstrated dose-dependent relationships for LPS-induced NO production. The MTT assay showed high cell viability in the presence of LPS in the culture medium at various concentrations. The results showed that quercetin (40), and 3,4-dihydroxyallylbenzene (102) possessed NO inhibitory activities, whereas (6S,7R,8R,9S)-6-oxaspiro-7,8-dihydroxymegastigman-4-en-3-one (85), syringic acid, and 3,4-dimethoxyphenol (100) exhibited weak activities.	Not reported	[32]
K. delagoensis Whole plant	kalantubolide A (38) kalantubolide B (39) kalantuboside A (23) kalantuboside B (24) bryotoxin C (1) bersaldegenin-1,3,5-orthoacetate (6) bersaldegenin-1-acetate (7) taurolipid C (84) gallic acid (87) cinnamic acid (97) ferulic acid (86) stigmasterol-O-d-glucoside (107)	Cytotoxicity In vitro cytotoxicity assay, cell cycle analysis, and apoptosis assay	Cardenolides (kalantubolide A (38) and kalantubolide B (39)) and bufadienolide glycosides (kalantuboside A (23), kalantuboside B (24), bryotoxin C (1), bersaldegenin-1,3,5-orthoacetate (6), bersaldegenin-1-acetate (7)) showed strong cytotoxicity against four human tumor cell lines (A549, Cal-27, A2058, and HL-60) with IC₅₀ values ranging from 0.01 µM to 10.66 µM. Cardenolides (kalantubolide A (38) and kalantubolide B (39)) also displayed significant cytotoxicity toward HL-60 tumor cell line. In addition, kalantuboside A (23), kalantuboside B (24), bryotoxin C (1), bersaldegenin-1,3,5-orthoacetate (6), and bersaldegenin-1-acetate (7) blocked the cell cycle in the G2/M-phase and induced apoptosis in HL-60 cells.	Not reported	[33]
K. pinnata Whole plant	bryophyllin A (1) bryophyllin B (2) bersaldegenin-3-acetate (8)	Cytotoxicity In vitro cytotoxicity assay	Bryophyllin A (1), bryophyllin B (2), and bersaldegenin-3-acetate (8) showed potent cytotoxicity effects.	Not reported	[114]
K. pinnata Roots	KPB-100 (81) KPB-200 (82)	Antivirus Virus spread inhibition and virus yield reduction assays of vaccinia virus, and viral cytopathic effect inhibition assay of HHV-2-TK-mutant and VYR assay of HHV-1 wild type	Both compounds are promising targets for synthetic optimization and in vivo study against human alpha herpesvirus 1 and 2 and vaccinia virus. KPB-100 (122) strongly inhibited all the tested viruses.	The authors consider that further studies are required to establish the mechanism of action of these compounds.	[69]
K. pinnata Flowers	quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (45)	Anti-inflammatory Acetic acid-induced abdominal writhing	The flavonoid (1, 3, and 10 mg/kg) produced a dose-related inhibition of the number of acetic acid-induced writhing by 20.5% (44.2 ± 3.1 w), 35.8% (35.7 ± 4.5 w), and 50.5% (27.5 ± 3.5 w), respectively (ID₅₀ 9.4 mg/kg), when compared with the vehicle group (55.6 ± 3.3 w). The positive control indomethacin (10 mg/kg) reduced the number of writhings by 56.5% (24.2 ± 3.5 w).	The aglycone quercetin present in the chemical structure of the isolated compound proved to be an anti-inflammatory and immunosuppressive agent. This flavonol has a well-known immunomodulatory effect through the regulation of inflammatory mediators, such as inhibiting cytokine and inducible nitric oxide synthase expression via inhibition of the NF-κβ pathway.	[8]
		Anti-inflammatory Carrageenan-induced pleurisy	The flavonoid (0.3, 1.0, and 3.0 mg/kg) exhibited a dose-related reduction of leukocyte migration by 8.0% (6.9 ± 0.6 leukocytes × 106/mL), 38.8% (4.6 ± 0.2 leukocytes × 106/mL), and 57.2% (3.2 ± 0.3 leukocytes × 106/mL), respectively (ID50 2.0 mg/kg), whereas the treated with dexamethasone (2 mg/kg), positive control group, inhibited by 71.9% (2.1 ± 0.2 leukocytes × 106/mL) when compared with the vehicle-treated group (7.5 ± 0.6 leukocytes × 106/mL).	The reduction in the total leukocyte migration to the pleural cavity induced by carrageenan is dependent on the synthesis/release of the chemoattractant mediators leukotrienes such as LTB4, cytokines IL-1 and TNF-α, and chemokines.
		Anti-inflammatory Croton oil-induced mice ear edema	Pretreatment with the flavonoid (0.3, 1.0, or 3.0 mg/kg, s.c.) produced a dose-related antiedematogenic effect by 38.2% (=4.2 ± 0.4 mg), 54.4% (=3.1 ± 0.4 mg), and 70.6% (=2.0 ± 0.4 mg), respectively, whereas the treatment with dexamethasone (2 mg/kg) reduced the ear edema by 85.3% (=1.0 ± 0.4 mg) when compared with the vehicle group (=6.8 ± 0.6 mg), with ID50 0.76 mg/kg.	The edema formation is initially mediated by histamine and serotonin and later by the release of prostaglandins. Prostaglandins play an important role in the setting of the cardinal signs of inflammation, pain, heat, redness, edema, and loss of function. The biosynthesis of PGE2, the main inflammatory prostaglandin, involves three key enzymes, phospholipase A2 (PLA2), cyclooxygenase (COX), and PGE synthase (PGES).
		Anti-inflammatory TNF-α ex vivo measurement	The flavonoid (3.0 mg/kg, s.c.) decreased the TNF-α concentration in pleural exudates by 66.6% (22.6 ± 3.1 pg/mL) when compared to the vehicle group (67.5 ± 4.9 pg/mL), whereas dexamethasone (2 mg/kg, s.c.) reduced the TNF-α concentration by 74.5% (17.2 ± 3.2 pg/mL).	Pretreatment reduced the TNF-α concentration in pleural exudates, suggesting that they produce an anti-inflammatory effect, at least in part, by TNF-α inhibition.
		Anti-inflammatory In vitro cyclooxygenase (COX) inhibition assay	The flavonoid inhibited both COX-1 and COX-2 in vitro activities (COX-1 IC₅₀ = 3.8 × 10⁻⁵ M (22.1 μg/mL) and COX-2 IC₅₀ ≥ 8.4 × 10⁻⁵ M). The selectivity index was <0.44. The positive control indomethacin also inhibited both COX-1 and COX-2 activities (IC₅₀ for COX-1 and COX-2 was 5.9 and 31.2 μg/mL, resp., and SI was 0.19).	Some flavonoids may reduce PGE2 synthesis by inhibiting the activity of these enzymes or by inhibiting the expression of the inflammatory-induced enzymes, COX-2, or microsomal PGES-1.
K. pinnata Leaves	quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (45)	Wound healing In vivo rat excision model	A cream containing quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-L rhamnopyranoside (45) (0.15%) was developed and topically compared to a cream containing the aqueous extract. Both creams showed a better re-epithelialization and dense collagen fibers compared to control groups.	Wound healing agents can act in the inflammation, cellular proliferation and/or remodeling phases of wound healing. Classic symptoms of inflammation are caused by the release of prostaglandins, leukotrienes and reactive oxygen and nitrogen species. The strong antioxidant activity and in vivo anti-inflammatory activity exhibited by quercetin 3-O-α-L-arabinopyranosyl-(1→2)-α-L rhamnopyranoside (45) might explain its healing performance, being considered the main responsible for the wound healing activity of this species.	[67]
	quercetin 3-O-α-l-arabinopyranosyl-(1→2)-O-α- L-rhamnopyranoside (45) kaempferol 3-O-α-l-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside (56)	Antioxidant In vitro DPPH and ABTS assays	Kaempferol and quercetin derivatives moderately inhibited XO, while only quercetin derivatives displayed average radical scavenging activity, suggesting that quercetin 3-O-α-l-arabinopyranosyl-(1→2)-α-l-rhamnopyranoside (45) can be indicated as a specific marker of this species.	Not reported	[71]
		Anti-inflammatory Xanthine oxidase (XO) inhibition assay		Not reported	[71]
	quercitrin (43)	Antianaphylactic Mouse hypersensitization and antigen challenge, OVA-specific IgE measurement, T cell proliferation, cytokine production, mast cell degranulation in the mesentery, and histamine release assay.	Pretreatment with the flavonoid quercitrin (43) showed protective effects in death caused by anaphylactic shock. In this study, the treatment conferred resistance to fatal anaphylactic shock in 75% of the animals.	The mechanism by which quercitrin acts its still unknown.	[157]
		Anti-inflammatory Mast cell activation in vitro and allergic airway disease model in vivo	Treatment with quercitrin (43) did not affect the tested parameters.		[68]
		Antileishmanial In vitro antiamastigote and antipromastigote acitivity assays	Antiamastigote activity-guided fractionation of ethyl acetate fraction led to the isolation of quercitrin (43), which inhibited 93.9% of amastigote growth (100 µg/mL (223 µM). The compound exhibited significant antileishmanial activity.		[130]
	bryophyllin A (1) bryophyllin C (3)	Insecticidal Third instar larvae of silkworm bioassay	Bryophyllin A (1) and bryophyllin C (3) showed strong insecticidal activity against third instar larvae of the silkworm (Bombyx mori).	The authors suggest that the 1,3,5-orthoacetate moiety played an important role in exhibiting the insecticidal activity.	[112]
	bryophyllin A (1) bryophyllin B (2) bryophyllin C (3)	Antivirus Tumor promoter-induced Epstein-Barr virus (EBV) activation assay	Bryophyllin A (1), bersaldegenin 1,3,5-orthoacetate (6) and daigremontianin (4) showed good inhibitory potential on the Epstein-Barr virus, but bryophyllin A (1) was the most effective (IC₅₀: 0.4 µM). These results strongly suggest that bufadienolides are potential cancer chemopreventive agents.	Tumor promoters possibly induce EBV activation through the activation of protein kinase C and mitogen-activated protein kinase.	[174]
K. × houghtonni Leaves	daigremontianin (4) bersaldegenin 1,3,5-orthoacetate (6)				[174]

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Assis de Andrade, E.; Machinski, I.; Terso Ventura, A.C.; Barr, S.A.; Pereira, A.V.; Beltrame, F.L.; Strangman, W.K.; Williamson, R.T. A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”. Molecules 2023, 28, 5574. https://doi.org/10.3390/molecules28145574

AMA Style

Assis de Andrade E, Machinski I, Terso Ventura AC, Barr SA, Pereira AV, Beltrame FL, Strangman WK, Williamson RT. A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”. Molecules. 2023; 28(14):5574. https://doi.org/10.3390/molecules28145574

Chicago/Turabian Style

Assis de Andrade, Evelyn, Isadora Machinski, Ana Carolina Terso Ventura, Sarah Ainslie Barr, Airton Vicente Pereira, Flávio Luís Beltrame, Wendy Karen Strangman, and Robert Thomas Williamson. 2023. "A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”" Molecules 28, no. 14: 5574. https://doi.org/10.3390/molecules28145574

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A Review of the Popular Uses, Anatomical, Chemical, and Biological Aspects of Kalanchoe (Crassulaceae): A Genus of Plants Known as “Miracle Leaf”

Abstract

1. Introduction

2. Results and Discussion

2.1. Traditional Uses

2.2. Botanical Description

2.3. Chemical Composition

2.4. Pharmacological Activities

3. Methodology

4. Conclusions and Future Perspectives

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Acknowledgments

Conflicts of Interest

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