Systematics, Phytochemistry, Biological Activities and Health Promoting Effects of the Plants from the Subfamily Bombacoideae (Family Malvaceae)

Plants belonging to the subfamily Bombacoideae (family Malvaceae) consist of about 304 species, many of them having high economical and medicinal properties. In the past, this plant group was put under Bombacaceae; however, modern molecular and phytochemical findings supported the group as a subfamily of Malvaceae. A detailed search on the number of publications related to the Bombacoideae subfamily was carried out in databases like PubMed and Science Direct using various keywords. Most of the plants in the group are perennial tall trees usually with swollen tree trunks, brightly colored flowers, and large branches. Various plant parts ranging from leaves to seeds to stems of several species are also used as food and fibers in many countries. Members of Bombacoides are used as ornamentals and economic utilities, various plants are used in traditional medication systems for their anti-inflammatory, astringent, stimulant, antipyretic, microbial, analgesic, and diuretic effects. Several phytochemicals, both polar and non-polar compounds, have been detected in this plant group supporting evidence of their medicinal and nutritional uses. The present review provides comprehensive taxonomic, ethno-pharmacological, economic, food and phytochemical properties of the subfamily Bombacoideae.


Introduction
The plant group Bombacoideae is a subfamily of Malvaceae (kapok, cotton family). The subfamily contains about 304 species, most of them with high economical and medicinal values. Considering their importance, some of the plants are given special cultural status. For instance, the Ceiba pentandra tree is the national tree of Guatemala. Among the Mayan and Aztec civilizations in the Meso-America, the Ceiba species is considered as a sacred "World Tree". The Indian kapok tree, Bombax ceiba, is worshipped by the Hindu community in North India as a nakshatra tree and home of the female spirits Yakshi [1]. There is West African belief that the first human was born from the trunk of a baobab tree (Adansonia spp.) and these plants are regarded as the "Tree of Life". Many plants of the Bombacoideae are valued as ornamentals in various parts of the world because of their  As a consequence of changes in circumscription and status of Bombacoideae, has led to the inclusion of 22 genera comprised of 120 species under this subfamily mainly distributed in the tropical regions. The Angiosperm Phylogeny Group (APG) IV Classification listed 24 genera in this subfamily. However, the classification by Maarten et.al. listed 27 genera under Bombacoideae [9]. This classification includes genera like Camptostemon, Lagunaria, and Uladendron in the Bombacoideae sub family. Molecular phylogenetic analysis established on nuclear (ETS, ITS) and plastid genes (matK, trnL-trnF, trnS-trnG) revealed that there are three key lineages noticeable by the kapok clade, seed, or fruit traitsthe winged seed clade, and the spongy endocarp clade [4]. Such studies established the monophyly of the core Bombacoideae subfamily and the entire genera without Pachira. The monospecific Septotheca falls outside the core Bombacoideae in many studies [4,10]. Dotted lines specify the changes in the genus limitation and the genera, which is described after the previous action, and are specified by a symbol (*), while the citation marks represent the tribes which are not validly published. Reproduced with permission from Carvalho-Sobrinho et al. [4] (originally Figure 1).

Habitat, Distribution, and Characteristics of the Subfamily Bombacoideae
Bombacoideae occupies different habitats in various parts of the world (Figure 3) [11]. Adansonia digitata is confined to semi-arid, stony, hot, dry, and woodland areas, with low rainfall. This plant favors well-drained soils ranging from clays to sandy soils [12]. However, some other plants favor wet and humid habitats. For instance, Bombax ceiba favors humid lowland deciduous forest and is sometimes found near stream banks [13,14]. Species belonging to Spirotheca are epiphytic stranglers. Some species are part of man- The early distribution of this plant group can be ascertained from fossil records. There are various arguments for the distribution of Bombacoideae. Croizat (1952) favored the knowledge of an African entrance with Bombacoideae transferring northwards from Antarctica by Madagascar, across into Africa and through the East Indies to Australia [21]. However, the concept cannot be supported by floral evolution and geological shreds of evidence [22]. According to another view based on palyno-morphological characteristics exhibited by the members of this plant group, the subfamily is assumed to have a triphyletic origin-with southern Central America, East Africa, Madagascar, and Southeast Asia as centers of origin [3]. Fossil records of this subfamily mainly belonged to microfossils (classified as belonging to the pollen genus Bombacacidites) and some macrofossils [23]. This plant group occurred in the North Tethyan flora and reached tropical regions of South America through Central America during the transition phase between the Cretaceous and Tertiary periods. Then they moved to Central Africa in the Paleocene epoch. During the Pliocene and Pleistocene periods, this group extended its distribution to the Caribbean and Central America. When the tropical flora reduced along with the North Tethys during the Upper Paleogene, the Bombacoideae retreated to North India and reached South East Asia during the Miocene epoch. From there, they expanded to New Guinea and North Australia [20,23]. In the present era, the distribution of the extant species mainly falls in the tropical regions, particularly in Africa, America, and Australia. More than 80% of the species' richness of this subfamily lies in the Neotropical region [8,11].
Native regions of various species in this group fall within the tropical region of Africa, America, and Asia. From their native regions, many species have been introduced to other parts of the world. Adansonia digitata is amongst the most widely distributed ones covering Asia, Australia, Northern America, and some oceanic islands. Distribution of this plant in the Caribbean and parts of America is through human agencies, where people from West Africa were transported between the sixteenth and nineteenth centuries for sugarcane plantations in the New World countries. In the Indian subcontinent, Arab traders or medieval Muslim rulers who maintained African slave armies mainly introduced this species. However, genetic analyses conducted in Indian populations revealed that the introduction occurred through multiple phases [31]. Most of the species have neotropical distribution, with some species having native ranges in Asia. Bombax ceiba has wild distribution in South East Asia and India. The place of origin of some plants is uncertain. The origins of wild areas of Ceiba pentandra (L.) Gaertn. are uncertain but now it is distributed throughout tropical regions including Asia [32].

Characteristics
Plants of Bombacoideae are usually perennial tall trees usually with swollen tree trunks. Trees of wet forests are usually evergreen while those of dry forests are deciduous [33]. Tree trunks may contain parenchymatous water storage tissue or mucilage cells.
Pneumatophores are present in the Camptostemon, a mangrove genus [8]. Barks are usually thin, often green. Most of the plants of Bombacoideae are characterized by their large size gigantic flowers with brush types [8]. Plants in these groups have a terminal flower and three bracts that exhibit a "bicolor unit". The first, lowermost bracts remain sterile, however, other bracts subtend cymose partial inflorescences. Flowers are usually subtended by an involucre of bracts. Sepals are usually large and fused and petals are usually fused to the stamen tube [34]. The fruit capsule has a hairy endocarp. Leaves are usually peltately-palmate. Petioles are pulvinate, k connate with or without lobes. Monothecal anthers are present. These characteristics are assumed to have resulted from the splitting of whole stamens. Transitional forms are observed in some plants [8]. Anther walls have 5-7 cells across. Staminodes are usually absent. Pollen may be flattened, triangular in polar view. Seeds are usually large and usually more than two cm long.
Most of the members of this subfamily are trees, especially shrubs, with characteristic two to five carpels, fruit capsules, rarely indehiscent, endocarp usually pubescent, pollen usually without spines, seeds usually glabrous, and exceptionally spinulose [8]. Some plants have a ploidy level other than diploidy. The lowermost chromosome numbers in this group were witnessed in Bombax insigne (2n = 18) from India and Pachira macrocarpa (2x = 26) from China, while uppermost numbers were documented in Eriotheca species (6x = 276) in Brazil [35]. Distinguishing characteristucs of the genera in this subfamily is provided in Table 1. The status of genera under Bombacoideae might be subjected to change in future revisions. The single species Chiranthodendron pentadactylon can be crossed with Fremontodendron sp. [8] exhibiting compatible genotypes. Neobuchia paulinae is an imperfectly known species that may be included in Ceiba [8].
Furthermore, polar compounds identified in leaf extracts consisted of several classes of flavonoids and hydroxycinnamic acids. Leaves from Cameroon [89] exhibited a very similar profile compared to the leaves from Mali [50].
Linoleic acid (38.8%), palmitic acid (24.3%), and oleic acid (21.9%) were identified as the dominant fatty acids of C. pentandra seed oil from Malaysia [96]. Malvalic and sterculic acids were also identified. A lower percentage of linoleic acid was found in the seed oil of C. pentandra from India [97]. Saturated fatty acids and monounsaturated fatty acids were obtained from the seeds of P. aquatica by using the Soxhlet apparatus and n-hexane as solvent. Palmitic acid and oleic acid were the most abundant with percentages of 49.0 and Aquatidial ( Figure 4) was previously isolated from a chloroform extracts of P. aquatica roots together with the known compounds lupeol, triacontyl p-coumarate, and isohemigossypolone [72]. Aquatidial is a new bis-norsesquiterpene with an uncommon skeleton, putatively derived from isohemigossypolone. Two new naphthofuranones, 11hydroxy-2-O-methylhibiscolactone A and O-methylhibiscone D (Figure 4), have been extracted from the P. aquatica stems [48].
Linoleic acid (38.8%), palmitic acid (24.3%), and oleic acid (21.9%) were identified as the dominant fatty acids of C. pentandra seed oil from Malaysia [96]. Malvalic and sterculic acids were also identified. A lower percentage of linoleic acid was found in the seed oil of C. pentandra from India [97]. Saturated fatty acids and monounsaturated fatty acids were obtained from the seeds of P. aquatica by using the Soxhlet apparatus and n-hexane as solvent. Palmitic acid and oleic acid were the most abundant with percentages of 49.0 and 18.2%, respectively [98]. Linoleic acid (11.2%) is the only polyunsaturated fatty acid identified.

Details of the Extraction and Isolation Procedure of Major Compounds from Bombacoideae for Industrial Applications
Different bioactive constituents, mainly terpenes, flavonoids, alkaloids, steroids, and fatty acids, have been isolated from the Bombacoideae subfamily. The extraction technique is the first pivotal step to obtaining active phytochemicals from plants. The choice of extraction procedure would depend mainly on the advantages and disadvantages of the process, including yield, biological activity, environmental friendliness, and safety. The fruit pulp of A. digitata revealed the presence of iridoids and phenols by using 70% ethanol as solvent [88]. Proanthocyanidins were obtained as major constituents from the pericarp of A. digitata fruits [54] by using a hydroalcoholic solution (methanol/H 2 O 80:20 v/v). Maceration with 95% ethanol of B. malabarica root bark led to the isolation of several sesquiterpenes, triterpenes, phenols, and sterols [73]. Conversely, cadinene sesquiterpenes were extracted from the roots of B. malabaricum by using H 2 O/acetone (3:7 v/v) [74]. B. malabaricum flowers extracted by 70% (v/v) aq. ethanol is characterized by different lignans.
Until now, the most applied extraction technique to isolate phytochemicals from the Bombacoideae subfamily is maceration. Researchers are exploring other extraction procedures using less energy and less solvent while producing higher yields and that are more environmentally friendly. Some advanced methods (i.e., pressurized and accelerated fluid extraction, supercritical extraction) have demonstrated to be useful in mediating related extraction difficulties along with increased extraction yields. Two of the most commonly employed extraction techniques of flavonoids are microwave-(MAE) and ultrasound-assisted extraction (UAE). High extraction efficiency and less destruction of the active constituents are the many advantages of UAE [99][100][101]. Nevertheless, MAE is preferred over UAE because MAE has been shown to increase the mass transfusion through the solid matrix, faster mixing of the extraction solvent thus preserving the highest possible driving forces, and ensuring the highest quality and quantity of the extracted constituents. Indeed, several works have proven that MAE allows for great extraction yields, a reduction of the volumes of solvents used, and a reduction of the extraction times [99,100]. MAE has been applied to extract flavonoids, tanshinones, coumarins, and terpenes [101]. These characteristics along with the simplicity of operation would position MAE as a valuable and suitable technology for industries with the growing demand for increased productivity and efficiency. However, until now little progress has been described for the MAE application to Bombacoideae species. Surely, taking into account all the MAE features, in the future, it will be possible to optimize the process by exploiting the opportunity to apply this innovative extraction method to the study of species belonging to the Bombacoideae family.

Application in Food/Use as Food
From ancient periods until today, many plants of the Bombacoideae have been used as food in various corners of the world. Parts used may range from leaves, seeds, tuberous roots to stem, flowers, et cetera. There are various variations in the use of food according to genera and cultures associated. Native African populations commonly use fruits of Adansonia digitata as famine food to make sauces, decoctions, and refreshing beverages [102].
The leaves, seeds, and pulp of the fruit of this plant are all edible. Lim (2012) reported the use of young leaves, seeds, fruit pulp, and tuberous roots of Adansonia gregorii F. Muell as food. Along with Adansonia spp, Ceiba pentandra is another one of the plant foods common to West Africa. Leaves of this plant are cooked in the form of slurry sauce [103]. The utilization as food for this plant group is not restricted to Africa but observed in other parts of tropical countries. In Central and South America, flowers and tender leaves of Pachira aquatica, a wetland tree, are cooked and used as vegetables [15]. Young roots of Bombax ceiba are eaten raw or roasted in Cambodia. The cuipo tree (Cavanillesia platanifolia), growing in Central America, is used by the natives for getting water. To collect water, a piece of the root is cut and the bark is removed on one end after keeping the root horizontal. When the clean end of the root is lowered, the water drains out through the cut end [104].
The use and preparation of food from the members of Bombacoideae dates back to time immemorial. For instance, in South America, from the ancient pre-Colombian period [105], flowers of Quararibea funebris were used as an additive to chocolate drinks. Ancient Mayans used the sap from Pseudobombax ellipticum to make an intoxicating drink by fermentation. This drink was likely used in religious ceremonies such as sacrifice and self-mutilation [33]. The use of various members of Bombacoides as fruits, vegetables, and other forms are highlighted in Table 3.

Traditional and Economic Uses
Various members of Bombacoideae are used as fiber and other utilities and some are also used as ornamental plants. Adansonia digitata is a multipurpose plant with various economic and social values [106]. In African countries, Adansonia digitata is very popular and reported to have more than three hundred traditional uses [102]. Ceiba Mill. is now popular throughout the tropical regions for ornamental landscaping [114]. Many species of the genus Ceiba were sacred to the Mayan civilization as depicted in ancient ceramics because of their cultural importance [33].
Many Bombacoideae species are economically important. Some species are collected for their wood that is soft and can easily be carved into canoes and other useful products. One popular wood is balsa wood obtained from the Ochroma pyramidale [16] and other species were widely used for making dugout canoes in ancient South America. Ancient Peruvians are believed to have used legendary Kon-Tiki rafts made from balsa wood to navigate across the Pacific Ocean and settle in the Polynesian islands [115]. The silky cotton-like fluff (kapok) present in the seed pods of Ceiba pentandra is used for stuffing pillows, bedding, and soft toys in various parts [116]. Silk hair present in seeds of Bombax ceiba are used in India from time immemorial for stuffing cushions, mattresses, pillows, and making clothes [117]. Various traditional and economic uses of the members of this subfamily are summarized in Table 4.

Ethnopharmacology
In various tropical countries, plants of Bombacoideae are used in traditional medicine mainly for pharmacological properties like anti-inflammatory, astringent, antimicrobial, stimulant, antipyretic, analgesic, and diuretic [2]. For instance, various parts of Bombax ceiba such as the stem bark, flowers, fruits, seeds, leaves, and root of young plants, are traditionally used as remedy in South India [108]. Its main therapeutic applications include diabetes, urinogenital disorders, gastrointestinal and skin diseases, gynecological, and general debility [129]. Another important plant from this subfamily in the Indian ayurvedic system is Ceiba pentandra known as Sweta Salmali for its acrid, bitter, thermogenic, diuretic, and purgative properties. The known pharmacological activities of Ceiba pentandra include hepatoprotective, antidiabetic, antipyretic, laxative, and anti-inflammatory [130]. Adansonia digitata is one of the most studied species for its therapeutic properties against antipyretic, diarrhea, dysentery, and as a substitute for cinchona in traditional medicinal preparations [105]. Different species under Bombacoideae having reported ethnopharmacological uses are summarized in Table 5.

Pharmacological Potential of Bombacoideae
The different species, viz. Adansonia digitata, Bombax ceiba, B. malabaricum, and Ceiba pentandra of the Bombacoideae family [136,146], were reported for their various pharmacological potentials, which are summarized in the following section (Table 6; Figure 5).    [177] Bark extracts STZ-induced diabetic rats At 600 mg/kg dose the extract could significantly decrease elevated levels of blood glucose in diabetic rats.

MTX-induced nephrotoxic rats
At 400 mg/kg dose could inhibit methotrexate (MTX)-initiated apoptotic and inflammatory cascades [184] Hepatoprotective activity Adansonia digitata L. aqueous extract of fruit; methanolic extract of the fruit CCL 4 induced hepatotoxic rats; paracetamol-induced hepatotoxicity in rats Reduction in serum AST, ALT, ALP, bilirubin levels were observed in carbon tetrachloride (CCL 4 ) induced hepatotoxic rat. Level of ALT, AST, ALP, total bilirubin, and total protein measurements were normalized in paracetamol-induced hepatotoxic rats.
Bombax ceiba L. The methanolic root extract of Bombax ceiba could scavenge DPPH radicals, lipid peroxidation, and ascorbyl radicals with an EC 50 value of 87 µg/mL. The extract also inhibited lipid peroxidation in rat-liver microsome induced by ascorbyl and peroxynitrite radicals with IC 50 values of 141 µg/mL and 115 µg/mL, respectively [192]. In another study, the methanol root extract of B. ceiba scavenged DPPH radical with an EC 50 value of 15.07 µg. The extract also could reduce the Fe 3+ to Fe 2+ in a dose-dependent manner with the maximum activity at 500 µg. The study also demonstrated that the administration of 3 g root powder could raise the antioxidant status in the human volunteer. The antioxidant activity properties of the root extract are attributed to their high phenolic and tannin contents [152]. The aqueous soluble partition (AQSF) of the methanolic root extracts of B. ceiba scavenged DPPH radical with an IC 50 value of 3.33 µg/mL [153]. Further, the methanol and petroleum ether root extract of B. ceiba was reported to scavenge DPPH radical with IC 50 values of 144.77 and 214.83 µg/mL [155]. The methanolic stem bark extract of B. ceiba exhibited antiradical activity with EC 50 values of 18.78, 23.62, and 139.4 µg/mL for nitric oxide, DPPH, and reducing power activity assay, respectively [193]. Similarly, Hossain et al. [154] reported the antioxidant activity of methanolic root extract of B. ceiba by DPPH scavenging assay (IC 50 value of 58.6 µg/mL). Gandhare et al. [156] reported that aqueous and ethanolic extracts of the B. ceiba bark exhibited DPPH, ABTS, nitric oxide, and superoxide radical scavenging activity along with total antioxidant activity. Besides the extract also inhibited lipid peroxidation and reduced ferric ions. The IC 50 values of aqueous extracts of B. ceiba varied between 85.71 and 102.45 µg/mL, and for ethanolic extract, it varied between 85.48 and 103.4 µg/mL. Komati et al. [163] reported that aqueous methanol extract of B. ceiba calyx reduced the level of reactive oxygen species (ROS), NADPH oxidase (NOX), and thereby lowered the mitochondrial dysfunction in methylglyoxal induced protein glycation. Further, in HEK-293 cells, Mn and Cu/Zn-superoxide dismutase and glutathione reductase antioxidant enzymes levels were improved. The whole plant methanolic extract of B. ceiba scavenged DPPH radical with an IC 50 value of 68 µg/mL [158]. The petroleum ether (PE) of B. ceiba flowers exhibited DPPH and Fe-chelating activities with IC 50 values of 37.6 and 33.5 µg/mL and diethyl ether extracts (DE) exhibited betacarotene bleaching test with an IC 50 value of 58.3 µg/mL. The antioxidant properties of B. ceiba flower extracts are attributed to the presence of beta-sitosterol and some fatty acids [80]. Similarly, another study reported that aqueous flower extracts of B. ceiba could scavenge DPPH radicals with an IC 50 value of 50.21 µg/mL [159]. The aqueous flower extracts of B. ceiba exhibited antioxidant activities against DPPH, hydroxyl, hydrogen peroxide, and ferric ion reducing antioxidant power (FRAP) activity with IC 50 values of 1.70 mg/mL, 4.20 mg/mL, 3.51 mg/mL, and 2.15 mg/mL, respectively [160]. The hexane, benzene, chloroform, ethyl acetate, acetone, methanol, and ethanol extracts prepared from methanolic flower extract of B. ceiba exhibited DPPH scavenging activity [161]. The hexane, chloroform, and methanolic extracts prepared from dried powder extracts of B. ceiba flower exhibited antioxidant activity in terms of FRAP, DPPH, and reducing power assay [162].
Bombax malabaricum DC. The n-hexane and methanol flower extracts of B. malabaricum scavenged DPPH radicals over a concentration range of 0.55-0.0343 mg/mL and 0.5-0.0312 mg/mL, respectively. The maximum DPPH scavenging was observed in the range of 0.55-0.5 mg/mL for both extracts [49]. The antioxidant potential of flower extract was attributed to the presence of bioactive constituent, viz. apigenin, cosmetin, xanthomicrol, saponarin, vicenin 2, isovitexin, and linarin. Similarly, in another study, the aqueous, acetone, and ethanol flower extracts of B. malabaricum flowers showed DPPH radical-scavenging properties along with Oxygen radical absorbance capacity (ORAC), reducing power, and liposome peroxidation inhibition activities [151].
Ceiba pentandra L. The different stem bark extracts of C. pentandra such as decoction, maceration, and methanol scavenged DPPH radical with IC 50 values of 87.84, 54.77, and 6.15 µg/mL, respectively. The extracts also restrained the H 2 O 2 -induced hemolysis and lipid peroxidation [165]. The Soxhlet seed oil extracts at 100 mg/mL concentration of C. pentandra exhibited DPPH, and OH radical scavenging along with FRAP, reducing power activities by 47.65%, 39.69%, and 309 FRAP units, and 20.52 µg of ascorbic acid equivalent, respectively [193]. The in vitro antioxidant evaluation of C. pentandra ethanol leaf extract demonstrated that the extract could scavenge DPPH, nitric oxide, and hydroxyl radicals with IC 50 values of 27.4, 24.45, and 51.65 µg/mL, respectively. The Gas chromatographymass spectrometry (GC-MS) study revealed the presence of 9 compounds, amongst which, hexadecanoic acid was found to be the most prominent compound [167]. In another study, Fitria et al. [166] demonstrated that a compound vavain or 5, 3 -dihydroxy-7, 4 , 5trimethoxyisoflavone isolated from the ethyl acetate fraction of stem bark of C. pentandra could scavenge DPPH radical with IC 50 value of 81.66 µg/mL. However, the ethyl acetate extract of the aerial part of C. pentandra scavenged the DPPH radicals with an IC 50 value of 0.0716 mg/mL [184]. The aqueous and methanol stem bark extracts of C. pentandra inhib-

Anti-Inflammatory Activity
Adansonia digitata L. The methanol leaf extracts of A. digitata reduced iNOS and NF-kB expression in LPSstimulated RAW264.7, thereby showing its anti-inflammatory potential [181]. The extract could inhibit NO production with an IC 50 value of 28.6 µg/mL. Similarly, the Dimethyl sulfoxide (DMSO) fruit pulp and aqueous leaf extract of A. digitata inhibited expressions of proinflammatory cytokine IL-8 [182]. The leaf extract (70 µg/mL) exhibited better anti-inflammatory activity compared to pulp extract (247 µg/mL).
Bombax ceiba L. The petroleum ether, ethanol, and aqueous bark extracts of B. ceiba at 1000 µg/mL concentration exhibited anti-inflammatory potential by stabilizing the Human red blood cell (HRBC) membrane. Amongst the different solvent extracts, better anti-inflammatory activity is shown by ethanol extract followed by aqueous and petroleum ether extract [183].
Ceiba pentandra (L.) Gaertn The ethyl acetate extracts of aerial parts of C. pentandra upon oral administration at 400 mg/kg dose could inhibit methotrexate (MTX)-initiated apoptotic and inflammatory cascades. The extract could improve the architecture of histopathological changes observed in the renal tissue of MTX-induced nephrotoxic rats [184].

Antimicrobial Activity
Adansonia digitata L. The methanolic and ethanolic leaf and stem bark extracts of A. digitata inhibited the growth of S. aureus and E. coli at different concentrations, viz, 100, 200, 500, and 1000 mg/mL with a minimum bactericidal concentration (MIC) at 100 mg/mL [169].
Bombax malabaricum DC. The n-hexane and methanol extracts (at 100 µg/mL) of B. malabaricum demonstrated antimicrobial activities against Gram-positive (E. coli, Neisseria gonorrhoeae, P. aeruginosa), Gram-negative (S. aureus, B. subtilis, Streptococcus faecalis) bacteria and fungi (Aspergillus niger, A. flavus Candida albicans). Of the two extracts, the methanol extract showed better activity against all the studied bacterial strains and C. albicans. Further, only the methanol extract exhibited moderate activities against A. niger and A. flavus [49].

Anticancer and Cytotoxicity Activity
Adansonia digitata L. The seed and pulp extracts of A. digitata (at 10, 100, and 500 µg/mL) exhibited anticancer activity against MCF-7 (breast cancer cell), Hep-G2 (liver cancer cell), and COLO-205 (colon cancer cell) in a dose dependent manner [172]. The results of the MTT study revealed that the inhibition ranges between 22 [185].
Bombax ceiba L. The diethyl ether and light petroleum ether extracts of B. ceiba flowers exhibited antiproliferative activity against human renal adenocarcinoma cell (ACHN) with respective IC 50 values of 53.2 and 45.5 µg/mL. The antiproliferative properties were attributed to the presence of beta-sitosterol and some fatty acids in B. ceiba flowers [80]. The brine shrimp lethality bioassay revealed that the petroleum ether, dichloromethane, and methanol extracts of B. ceiba roots exhibited cytotoxic effect with LC 50 values of 22.58, 37.72, and 70.72 µg/mL, respectively [155].
Ceiba pentandra (L.) Gaertn The petroleum and acetone stem bark extracts of C. pentandra at 15 and 30 mg/kg doses could reduce tumor weight by >50% and tumor volume on the 30th day in Dalton's lymphoma ascites (DLA) model [173]. Similarly, both these extracts of C. pentandra exhibited cytotoxic effects against Ehrlich ascites carcinoma (EAC) cells as evaluated by trypan blue assay [173]. At 15 mg/kg doses, both the extracts showed improvement in mean survival time and decline in tumor induced increase in body weight. Further, the petroleum ether, benzene, chloroform, acetone, and ethanolic extract of this plant demonstrated cytotoxicity in a concentration dependent manner after 3 h of incubation with EAC cells with EC 50 values of 53.30, 70.58, 250.48, 67.30, and 56.11 µg/mL, respectively.

Hepatoprotective Activity
Adansonia digitata L. The aqueous fruit pulp extract of A. digitata showed hepatoprotective potential in carbon-tetrachloride (CCL 4 ) -induced hepatotoxic rat models as significant reductions in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatize (ALP), and bilirubin levels were observed in extract-treated hepatotoxic rats [186,187]. The liver protection potential could be attributed to the presence of triterpenoids, β-sitosterol, β-amyrin palmitate, and α-amyrin or without, and ursolic acid in the fruit pulp [188]. The methanolic fruit pulp extract of A. digitata exhibited hepatoprotective potential in paracetamol-induced hepatotoxic rat models. The disturbances in the liver function such as ALT, AST, ALP, total bilirubin, and total protein measurements of the hepatotoxic rats were normalized due to the administration of paracetamol [189].
Bombax ceiba L. The hepatoprotective property of aqueous [159] and methanolic [190] flower extracts of B. ceiba was studied in CCl 4 -induced hepatotoxic rats. Treatment with extracts decreased elevated levels of glutamate oxaloacetate transaminase (SGOT), glutamic pyruvic transaminase (SGPT), alkaline phosphatize (ALP), bilirubin, triglycerides, and total protein. Treatment with the extract further attenuated the damage caused to the liver as seen by histological studies. The young roots of B. ceiba exhibited hepatoprotective activities in alloxan induced diabetic mice. Administration of ethanolic root extracts at 400 mg/kg decreased the hepatotoxicity in diabetic mice by reducing the elevated levels of SGOT and SGPT [176].
Ceiba pentandra (L.) Gaertn The ethyl acetate fraction of methanolic stem bark extract of C. pentandra exhibited a hepatoprotective effect against paracetamol-induced hepatotoxic rats by reducing the serum enzyme levels of SGOT, SGPT, ALP, and total bilirubin content [191].
Bombax ceiba L. The dichloromethane, ethanol, and aqueous thalamus and flower extracts of B. ceiba were reported for their antidiabetic properties in terms of their capacity to inhibit alpha-amylase and alpha-glucosidase enzymes under in vitro condition. The corresponding IC 50 values for alpha-amylase inhibition activities for thalamus were 36.22 µg/mL (dichloromethane extract), 35.32 µg/mL (ethanolic extract), and 31.31 µg/mL (aqueous extract) and for flowers, 38.13 µg/mL (dichloromethane extract), 35.23 µg/mL (ethanolic extract), and 33.00 µg/mL (aqueous extract) [174]. The n-hexane fraction of sepals [175] and ethanolic leaf extracts [177] of B. ceiba exhibited antidiabetic activities in STZ-induced diabetic rats. The n-hexane fraction at 0.1 gm/kg bw, b.d. dose reduced the fasting blood sugar level and restored the levels of serum insulin, Hb, and glycated hemoglobin in diabetic rats. Histological studies of also showed marked improvement in diminution in the area of the islets of Langerhans of pancreases in diabetic rats treated with the plant extracts [175]. Similarly, the leaf extract of B. ceiba (at 70, 140, and 280 mg/kg doses) decreased the fasting blood glucose, glycosylated hemoglobin, and increased the oral glucose tolerance in the STZ-induced diabetic rats. The antidiabetic property may be attributed to the antioxidant activity and protecting pancreatic β-cells of the extract [177]. The young roots of B. ceiba exhibited antidiabetic activities in alloxan-induced diabetic mice. Administration of ethanolic root extracts at 400 mg/kg decreased blood glucose levels in diabetic mice as compared to untreated diabetic mice at different time points (0-24 h). [176]. However, at 600 mg/kg dose the extract could significantly decrease elevated levels of blood glucose in diabetic rats [178].
Ceiba pentandra (L.) Gaertn The aqueous stem bark extracts of C. pentandra exhibited antihyperglycemic, insulinsensitizing potential, and cardioprotective effects in dexamethasone-induced insulin-resistant rats. Extracts of both 75 or 150 mg/kg doses could decrease the level of glycemia [179]. The decoction extracts of stem bark of C. pentandra decreased glucose level by increasing glucose uptake in the liver and skeletal muscle cells by 56.57% and 94.19%, respectively. The extract also reduced the glucose release in liver cells by 33.94% in a hypoglycemic milieu [165]. The ethanolic bark extract of C. pentandra at 200 mg/kg dose exhibited antihyperglycemic activity in STZ-induced diabetic rats by decreasing the levels of blood glucose, total cholesterol, and triglycerides, preventing degeneration of liver and pancreas, and increasing serum insulin and liver glycogen content [180]. The aqueous stem bark extracts of C. pentandra inhibited alpha-amylase and glucosidase with IC 50 values of 6.15 and 76.61 µg/mL, respectively, whereas the methanol extract inhibited alpha-amylase and glucosidase with IC 50 values of 54.52 and 86.49 µg/mL, respectively [168].

Miscellaneous Activities
The petroleum ether and methanol extract from B. ceiba stem bark displayed increased osteogenic activity as demonstrated by Chauhan et al. [37] in UMR-106 cells and surgical ovariectomy models in female Wistar albino rats. It has been reported that the administration of the extracts for 28 days ameliorated the consequences of ovariectomy-induced bone porosity, restoring the normal architecture of bone in experimented rats. The in vitro osteogenic activity of the extracts could be attributed to the presence of lupeol, gallic acid, and β-sitosterol in B. ceiba.
Komati et al. [163] reported the antiglycation properties of aqueous methanolic calyx extract of B. ceiba in methylglyoxal-induced protein glycation and oxidative stress in HEK-293 cells. The extract could inhibit advanced glycation end products (AGEs) formation and restrained Receptor for advanced glycation end products (RAGE) up-regulation in HEK-293 cells.
The aqueous and crude ethanol fruit extracts of B. ceiba exhibited diuretic effects in rats. Both aqueous and ethanol extracts could increase the urine output in the rats. The aqueous extract increased the urinary Na+ and K+ levels demonstrating the diuretic effect of the extracts [194]. The ethanolic leaf, bark, and fruit extracts of A. digitata exhibited antipyretic activity in albino rats at 400 and 800 mg/kg doses [149].

Mechanism of Action of Extracts and Bioactive Compounds of the Plants' Species with Pharmacological Properties
The different plant species of Bombacoideae are well known for their medicinal properties and can act as a useful bio-resource for medicines, nutraceuticals, pharmaceuticals, and chemical analogs for synthetic drugs. Bombacoideae plant species contain several bioactive phytocompounds such as alkaloids, anthocyanins, coumarins, flavonoids, lignans and neolignans, sesquiterpenes, sesquiterpene lactones, sterols, tannins, triterpenes, et cetera, which may be responsible for their antimicrobial properties. The antimicrobial action of phytocompounds might be due to their capacity to disintegrate cytoplasmic membrane, destabilize proton motive force, electron flow, active transport, and coagulation of the cell content in microbes [195]. Silva and Fernandes [196] also reviewed the antimicrobial properties of plants and concluded that different chemical classes of phytochemicals including alkaloids, flavonoids, terpenoids, phenols, tannins, et cetera may be responsible for their antimicrobial potential.
The different bioactive phytocomponents could exhibit anti-inflammatory activities by down regulating of signaling pathways like NF-κB pathway. This is done by different mechanisms such as (a) inhibiting common mediators of inflammation like NO, iNOS, and pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, and IL-12p40; (b) inhibition of chemokines such as RANTES and MCP-1; (c) downregulating mediators of inflammation such as cycloxygenase-2 (COX-2), prostaglandins, and leukotrienes; (d) reducing the production of ROS and lipid peroxidation; and (e) upregulating enzymatic (superoxide dismutase, catalase, etc.) and non-enzymatic (glutathione, etc.) defense systems [199]. The different species of Bombacoideae such as A. digitata and C. pentandra could inhibit inhibition against proinflammatory cytokine IL-8 expression or by reducing iNOS and NF-kB expression [181,182], and the activity is attributed to the presence of different phytoconstituents, viz. quercitrin, cinchonains 1a and 1b, cis-clovamide, trans-clovamide, and glochidioboside [184]. The phytoconstituents of different plants could show antidiabetic activities by inhibiting carbohydrate metabolizing enzymes like amylase and glucosidase enzymes, or by stimulating insulin release or by increasing glucose uptake by cells or by decreasing insulin resistance [200]. Several studies have rightly pointed out that different Bombacoideae plants could exhibit antidiabetic activities by inhibiting α-amylase and α-glucosidase enzymes [148].

Conclusions
Plants are considered important natural resources as food supplements and in traditional and modern medicine in different regions of the world. Bioactive phytochemicals are valued candidates for the discovery of new drugs. Detailed reporting of plants with food value, and therapeutic and economic importance, of subfamily Bombacoideae, was undertaken in this review. Isolated phytochemicals of diversified classes of secondary metabolites are reported to possess numerous therapeutic properties against different ailments. The bioactive phytochemicals from plants of this subfamily will play important roles in the development of new drug leads with less toxicity and side effects.