A Comprehensive Insight into the Phytochemical, Pharmacological Potential, and Traditional Medicinal Uses of Albizia lebbeck (L.) Benth.

Background Albizialebbeck is a deciduous tree having tremendous medicinal utilities, for example, respiratory, skin, gastrointestinal, oral disorders, eye, urinary, genital, anorectal, inflammatory, and neurological disorders, and venereal diseases. Several studies have been undertaken on the medicinal and traditional values of A. lebbeck. Objective The detailed information about its medicinal uses and pharmacological implications is highly scattered and distributed in different data sources. Hence, the study was conducted to supply an inclusive review of its ethnomedicinal uses, phytochemicals, and the available pharmacological attributes supporting its efficiency in traditional medicine. Method Literature surveys were conducted on this medicinal plant via search engines like Google Scholar, PubMed, and Science Direct, and obtained information up to December 2020 has been assessed and analyzed for this study. Results Systematic investigation revealed that A. lebbeck consists of various phytochemicals, including major alkaloids, flavonoids, saponins, and terpenoids. Its crude extract, fraction, and bioactive compounds exhibited potent adulticidal, antiallergic, anticancer, anticonvulsant, antidiabetic, antidiarrheal, anti-inflammatory, antimicrobial, antinociceptive, antioxidant, antiparasitic, antipyretic, antivenom, estrogenic, neuroprotective, nootropic, ovicidal, and wound healing activities. Conclusions This study proposes that A. lebbeck remains a rich source of phytochemicals with various biological activities which possess outstanding therapeutic benefits to humanity across the world. However, studies are required to estimate the potential side effects. Moreover, mechanistic physiognomies of the isolated compounds with known bioactivities are quite limited; thus, forthcoming research needs to focus on the mechanisms of these active phytochemicals to facilitate their potential enrolling for drug discovery.


Introduction
Medicinal plants and their derived natural products have long served as the primary healthcare requirements of millions of populations for centuries. Among these medicinal plants, many plants have been scientifically documented and validated for their exceptional medicinal efficacy. e genus Albizia comprises 150 taxonomically accepted species, which are widely distributed in Asia, Africa, and Australia, as well as tropical and subtropical America [1]. Albizia lebbeck mainly grows in the Indian subcontinent and Myanmar (Burma) and is also widely while it is also entitled in many other languages throughout the world, for example, Acacia amarilla, cabellos deángel, and lengua de mujer in Spanish; Bois noir and Viellefille in Franz; Darash in Urdu; Karuvagei and Vagei in Tamil; Khago and Ka se in ai. In Burmese, it is spelled Kokko; Lebbek, siris tree, and woman's tongue tree in English; Mara in Sinhalese; Sarin and Shrin in Punjabi; Siris, SIrish, and Sirisha in Bengali; Siris and Sirisha in Hindi; Sultanaulasjar in Arabic; and Tekik in Javanese [2,9].
is species contains a huge number of phytochemicals, out of which several phytochemicals have excellent medicinal properties and also showed tremendous pharmacological activities. ere are a couple of compounds that have been exposed to pharmacological examinations and deficiently summed up with dispersed and scant data accessible on traditional uses. Additionally, there has been a lack of information that relates the pharmacological attributes of this plant to its ethnomedicinal applications. Likewise, patented formulations and safety profiles have been inadequately explored.
Even though many studies have been published on the biological activity of A. lebbeck extracts and their phytoconstituents [23][24][25], none of the reviews has been published with comprehensive information on pharmacological activities and elaborative insights of countrywise medicinal uses as well as different medicinal systemwise therapeutic potential. is prompted us to write this study, which covers botanical description, taxonomy, geographic distribution, medicinal usage, phytochemistry, and pharmacological qualities of A. lebbeck. e obtained information on phytochemicals, therapeutic uses, and pharmacological credits would optimistically assist the scientific community in planning safe tests that incorporate bioactive mixtures.

Materials and Methods
For this paper, an inclusive literature search was conducted up to January 2021. To identify appropriate statistics on the botanical description, traditional medicinal uses, phytochemistry, and pharmacological activities of A. lebbeck, information was retrieved from various resources, including Google Scholar, Science Direct, PubMed, and literature books. e keywords used for the database were "Albizia lebbeck," "Medicinal Uses," "Traditional Uses," "Botany," "Chemical Constituents," "Pharmacology," and "Biological Activities" with Boolean operators. Database that was unsuccessful in meeting the inclusion and quality criteria required in traditional uses, phytochemistry, and pharmacological attributes was excluded. e scientific name of the plant was authenticated by different databases like "the plant list" and "plants of the world online" (http:// www.plantsoftheworldonline.org/; http://www.theplantlist. org/).

Botanical Description
Albizia lebbeck grows as a deciduous tree with a length up to 18 m and a straight bole. Its bark is brownish-gray in color. e leaves of the plant are bipinnate, which are alternately arranged on the smooth, green twigs. e leaves turn a deep yellow color before falling during the dry season. e inflorescence is of corymb type with 30-40 flowers. Flowers are dimorphic, puberulent, and fragrant white to greenishyellow in color. Calyx and Corolla are funnel-shaped; their pod is pale, flat, and straw-colored and remains on trees after a long-time of ripening. Seeds are brown, ellipsoidal (4)(5)(6)(7)(8)(9)(10)(11)(12) ca. 10 × 6-7 mm, and their pleurogram is parallel to margins of the seed [2]. e picture of A. lebbeck plant and its different parts is shown in Figure 2.
e stem bark paste is applied on ulcer and flower decoction and leaves for gargling to cure weak and spongy gums and chronic pharyngitis by the Meena tribe [8]. e Zulu tribes from Africa use bark and roots in the treatment of scabies, inflamed eyes, piles, and bronchitis [11]. In Tibetan traditional medicine, it is recommended in the treatment of kapha, pitta, poisoning, erysipelas, and ulcer [34]. In Taiwan, it is used as an anthelmintic, diuretic, stimulant, and tonic [35]. e people of Tamil Nadu use plants to fix bone fractures. e tribal communities in Himachal Pradesh and Kashmir use plants to relieve inflammation [28]. It is commonly called Shirish, Koroi, and Parrot tree in Bangladesh and has been used by the local people in the treatment of ophthalmia. Additionally, its barks and seeds are used as astringent and are given in piles, diarrhea, toothache, and gum problems. Further, bark and leaf decoctions are recommended against bronchial asthma and other allergic disorders [36]. Moreover, saponins of A. lebbeck have been reported to be used in Alzheimer's and Parkinson's disease treatment [37]. e ethnomedicinal uses, including data from various countries and medicinal practices of A. lebbeck, are given in Table 2.

Phytochemistry
Phytochemical studies of A. lebbeck have exposed the presence of various chemical constituents, including alkaloids, phenols, flavonoids, saponins, phytosterols, and terpenes [14]. Besides, seeds are good source of protein 2.272%, lipids 0.27%, fatty acid (linolenic acid, oleic acid, palmitic acid, and steric acid), tetradecane, hexadecane, phytol, nonadecane, eicosane, vitamin E, stigmastadiene, and octadecane [21,45]. Complex triterpenoid saponin, that is   [46]. Other than that, leaves contain essential oil in which 2-pentylfuran (16.4%), (E)-geranyl acetone (15.46%), (E)-α-ionone (15.45%), and 3-Octanone (11.61%) are abundantly found [11]. e present review suggests that the majority of phytochemicals contained in A. lebbeck should be explored and isolated from its bark and seeds, and additionally, other parts should be investigated too in the wake of the maximum utility of this plant to mankind. e bark contains albiziasaponins (A-E) and lebbeckoside C, which possesses anticancer activity [9,38]. Lebbeckosides A-B isolated from root showed an inhibitory effect on high-grade human brain tumor cells [31]. However, the seed contains lebbeckalysin (hemolysin), which possesses potent antitumor and antimicrobial effects [47]. Flavonoids (geraldone, luteolin, and isookanin) were     Piles and diarrhea [5] Evidence-Based Complementary and Alternative Medicine isolated from the bark having the capability of inhibiting the α-glucosidase and α-amylase activity [17]. Among reported chemical compounds, 45 bioactive molecules have been discussed in the pharmacological section. ese studies suggested that most of the phytochemicals have been isolated from bark and seeds, and other parts are still needed to be explored. Plenty of molecular structures of various phytochemicals are procured from PubChem, and their detailed information is given in Table 3 and Figure 5.

Pharmacological Activities
Several pharmacological studies showed that extracts/fraction/compounds of leaves, bark, and flower of Albizia lebbeck (L.) Benth exhibited significant antiallergic activity, anticancer, anticonvulsant, antidiabetic, anti-inflammatory, antimicrobial, antinociceptive, antioxidant, antiparasitic, antivenom, neuroprotective, nootropic, antipyretic, antidiarrheal, ovicidal, adulticidal activity estrogenic, and wound healing activities. e foremost pharmacological attributes, extract/fraction/compound extracted from different parts of the plant, investigational doses, experimental models, and their results have been given in Figure 6, and pharmacological activities are also described as follows.
6.1. Antiallergic Activity. Ethanolic extract (200 mg/200-250 gm b. w., p.o.) of A. lebbeck stem bark exhibited excellent antiallergic activity in toluene-2,4-diisocyanate-(TDI-) sensitized allergy model Brown Norway rats and HeLa cells expressing endogenous H1R with a significant decrease in the numbers of sneezing, nasal rubbing, and mRNA expression which have been found to elevate TDI-induced H1R and HDC, although the least doses of extract (0.1 to 10 μg/ml) also reduced PMA-or histamine-induced upregulation of H1R mRNA in HeLa cells [48]. Besides, catechin present in the ethanolic extract from A. lebbeck bark showed potent activity by modulating histamine release and cytokine expression. In vitro, chloroform, methanol, and water extracts of leaf and bark showed a significant mast cell stabilizing effect with 19.71-59.69% against compound 48/80 [15,51].

Anticancer Activity. Bark and leaves of A. lebbeck
showed a potent anticancer effect from diverse cell lines. A saponin-rich fraction from the bark of A. lebbeck exerted antiproliferative activity via MTT assay in human breast cancer cell line MCF-7 by inhibiting the growth with IC 50 1 µg/ml and inducing apoptosis at 10 µg/ml by promoting activation of caspases 3 and 8. Furthermore, in shell-less chick embryo culture assay, there was a significant (p < 0.05) reduction in the number of extremities, nodes, junctions, and total branches length between 0 and 3 hr and 0-6 hr of drug exposure (0.1, 0.5, and 1 μg/ml) and elevation of chromosomal aberration observed [40]. In another study, lebbeckosides A and B isolated from the root showed significant cytotoxic activity against U-87 MG, TG1 high-grade human brain tumors cells with IC 50 3.46, 1.36, and 2.10, 2.24 μM, respectively [31]. e isolated compounds lebbeckosides A and B are responsible for initiating apoptosis in the cancerous cell by the activation of caspase 8 ( Figure 7). Apart, crude methanol extract from leaves exerted a cytotoxic effect on hepatocarcinoma (HepG2) cancer cell line with IC 50 24.03 μg/ml [52]. In another study, gold nanoparticles isolated from aqueous leaf extract of A. lebbeck showed cytotoxicity against HCT-116 colon cancer cells with IC 50   ROS production, decreased ΔΨm, apoptotic morphological changes by AO/EtBr, and altering pro-and antiapoptotic protein expressions [53].

Anticonvulsant Activity.
e methanolic fraction of chloroform soluble part of the ethanolic extract of A. lebbeck (20, 40, or 100 mg/kg i.p.) exhibited remarkable anticonvulsant activity against pentylenetetrazole-induced convulsions and maximum electroshock in mice by delaying the onset of spasms and clonic convulsions. Fraction also delayed the latency to stage 4 significantly in lithium-pilocarpine-induced seizures. Moreover, in electrical kindling, fractions decreased the behavioral score. However, the fraction showed no protective effect against strychnine-induced convulsions [54]. Furthermore, 200 and 400 mg/kg (p.o.) ethanolic extract of A. lebbeck leaves demonstrated a considerable anticonvulsant effect by reducing the duration of hind limb extensor in the MES model and delaying the onset of convulsions in the PTZ mode [55]. Evidence-Based Complementary and Alternative Medicine

Antidiabetic Activity.
e bark of A. lebbeck demonstrated noteworthy antidiabetic activity. e methanol extract (200, 350, and 620 mg/kg) exhibited antihyperglycemic activity against streptozotocin-nicotinamide stimulated type II diabetes mellitus rats by significantly decreasing the level of serum glucose, creatinine, urea, cholesterol, triglycerides, LDL-cholesterol, and VLDL-cholesterol and increasing HDL levels as compared to diabetic control [16]. A study was conducted to evaluate in vitro antidiabetic activity of geraldone, isookanin, and luteolin isolated from methanolic extract of A. lebbeck bark, which showed potent inhibition against α-glucosidase and α-amylase (73.14 to 93.98%). e mechanistic approach of geraldone, isookanin, and luteolin has been graphically represented in Figure 7. In another study, it was demonstrated that methanol/dichloromethane extract of A. lebbeck bark possesses antidiabetic activity in streptozotocin-induced diabetic rats via significant reduction of blood glucose, BUN, SCr, GSP, TC, TG, LDL-c, and VLDL-c and increases plasma insulin level, hepatic enzymes, SOD, CAT, GSH, and HDL-c levels [17,18].
6.5. Anti-Inflammatory Activity. Administration of leaf essential oil (100, 200, and 400 mg/kg) caused significant inhibition of carrageenan-induced edema [11]. Leaves aqueous and ethanolic extract showed anti-inflammatory effect at 200 mg/kg with percentage inhibition of 39.36% and 42.55% in carrageenan-induced paw edema and also reduced granuloma formation with 38.55% and 42.33%, respectively [49]. In another study, petroleum ether and ethanol extracts (400 mg/kg) exhibited maximum inhibition of carrageenaninduced inflammation with percentage inhibition of 48.6% and 59.57%; dextran-induced group 45.99% and 52.93%; cotton pellet-induced models 34.46% and 53.57%, and Freund's adjuvant-induced animal group 64.97% and 68.57%, respectively [28], while bark petroleum ether: ethyl acetate: methanol extract (1 : 1 : 1) significantly (p < 0.001) reduces carrageenan-induced rat hind paw edema at 400 mg/kg with 36.68% [56]. Moreover, n-hexane, dichloromethane, ethyl acetate, and n-butanol fraction from flowers reduce inflammation in carrageenan-induced paw edema. Among tested fractions, the most potent activity was shown at 1 g/kg by dichloromethane (71.6%) followed by ethyl acetate (60.3%) [        Evidence-Based Complementary and Alternative Medicine administered orally to evaluate analgesic activity by eddy's hot plate and tail-flick test. In the hot plate method, a significant elevation was observed in the mean basal reaction time, and an elevation in the latency time was found in the tail-flick method [26]. In another study, among n-hexane, dichloromethane, ethyl acetate, and n-butanol fraction from flower, only dichloromethane fraction (1 g/kg) significantly increases in pain threshold in the hot plate test [37]. Bark petroleum ether: ethyl acetate: methanol extract (1 : 1 : 1) showed a significant reduction in the number of writhes by 52.4% and significant elongation of tail flicking time with 61.48% at 400 mg/kg [56].

Antioxidant Activity.
Increased production of reactive oxygen species is a cause of most human diseases, including cardiovascular disease and cancer. Cells enable upregulation of antioxidant defenses and other protective systems against mild oxidative stress, although severe stress can harm the integrity of DNA, proteins, and lipids and lead to cell death by apoptotic or necrotic mechanisms [59]. erefore, the antioxidant effect of A. lebbeck is evaluated. Geraldone, isookanin, and luteolin isolated from the bark of the plant are tested for DPPH-free radical scavenging assay, where geraldone showed the best activity (IC 50 21.5 μM) [17]. ese isolated compounds are able to neutralize the free radicals, including RNS and ROS, by activating antioxidant enzymes (Figure 7). Zinc oxide nanoparticles from the stem bark exhibited the most potent antioxidant effect against hydrogen peroxide-free radical with IC 50 48.5 μg/ml [57]. Petroleum ether, ethyl acetate, and methanol barks extracts of A. lebbeck were evaluated for DPPH-free radical scavenging activity, where ethyl acetate (81.13%) and methanol extract (78.23%) showed high radical scavenging activity, followed by petroleum ether (74.82%) at 100 μg/ml [58]. Additionally, leaves crude methanol extract showed DPPH and ABTS radical scavenging activity with IC 50 34.22 and 108.7 μg/ml, respectively [52].  Extract significantly decreased the level of serum GLU, creatinine, urea, triglycerides, cholesterol, lowdensity lipoprotein-cholesterol, and very low-density lipoprotein-cholesterol and increased high-density lipoprotein levels [16] Geraldone, isookanin, and luteolin Bark Acarbose 10 mg/ml In vitro α-glucosidase and α-amylase inhibitory assay All three compounds significantly inhibit the α-glucosidase and α-amylase enzymes [17] Methanol/ dichloromethane extract Stem bark 100-400 mg/kg Glibenclamide 1 mg/kg In vivo streptozotocin-induced diabetic rats using male albino Wistar rats Significant reduction of blood glucose, BUN, SCr, GSP, TC, TG, LDL-c, and VLDL-c and increasing plasma insulin level, hepatic enzymes, SOD, CAT, GSH, and HDL-c [18] 5 Antidiarrheal activity Aqueous methanol extract Seed 2.5-5 mg/kg i.p.
Loperamide 1 mg/kg i.p. In vivo castor oil-induced diarrhea using albino rats and mice Extract significantly inhibited the cathartic effect of castor oil in a dose-dependent manner [63] Evidence-Based Complementary and Alternative Medicine 13  14 Evidence-Based Complementary and Alternative Medicine 6.11. Neuroprotective Activity. e symptoms of Alzheimer's disease include deterioration of memory, judgment, and decision-making power which reduces impairment in the orientation of physical surroundings and language [61]. It was observed that seed hydromethanolic extract (100-300 mg/kg orally) reduced biochemical oxidative stress and improved functional outcomes of behavioral studies by improving memory and cognition functions via inhibiting anticholinesterase, thereby preserving acetylcholine concentration [21]. e second most common neurodegenerative disease is Parkinson's disease which causes parkinsonism that occurs due to the loss of neurons in the substantia nigra and elsewhere in association with the presence of ubiquitinated protein deposits in the cytoplasm of neurons and thread-like proteinaceous inclusions within neurites [61]. e anti-Parkinson activity was evaluated by performing behavioral and biochemical oxidative stress assay in Wistar albino rats. It was observed that the plant extract can be able to ameliorate motor function and prevent biochemical damage in brain cells [12].

Nootropic Activity.
e n-butanol fraction (10 and 25 mg/kg) from dried leaves of A. lebbeck exhibited excellent nootropic activity in mice by using the elevated plus maze and passive shock avoidance paradigm. On both doses, the inflexion ratio (IR) was increased significantly, while IR was found to decrease at the utmost dose (50 mg/kg) after 24 h after exposure as well as on day 9 in the passive avoidance test. Moreover, the fraction (10, 25, and 50 mg/kg) dosedependently reduced the lithium-induced head twitches and at 50 mg/kg significantly potentiated and prolonged the haloperidol-induced catalepsy [20].
6.13. Miscellaneous Activity. Ovicidal and adulticidal activities were studied against Culex quinquefasciatus, Aedes aegypti, and Anopheles stephensi from hexane, benzene, chloroform, ethyl acetate, and methanol extracts; among tested extracts, methanolic extract obtained from the leaf and seed showed absolute mortality at 200, 250, 150, and 300, 375, and 225 ppm against Ae. aegypti, C. quinquefasciatus, and An. stephensi, respectively. Methanol leaf extract showed the highest adulticidal activity against An. stephensi with LC 50 65.12 ppm [62]. n-Hexane, dichloromethane, ethyl acetate, and n-butanol fraction from flower were evaluated for antipyretic activity. e most potent effect was shown by dichloromethane followed by ethyl acetate at 1 g/kg with a reduction of 8°C and 5°C, respectively [37]. Aqueous methanol extract from seed (5 mg/kg i.p.) almost entirely inhibits the castor oil-induced diarrhea [63]. e pharmacological profile of various parts of A. lebbeck is shown in Table 4.

Conclusion
Albizia lebbeck is an Ayurvedic plant and has been widely utilized in the treatment of anorectal, eye, gastrointestinal, genital, inflammatory, neurological disorders, oral disorders, respiratory, skin, urinary disorders, and venereal diseases across the world. Different parts of the plant have been used, but bark appears to be the most often used plant part in the employment of traditional medicine. However, in support of its therapeutic uses, more scientific clinical trials extensively are necessary. e phytochemical studies revealed an abundance of saponins with other chemicals, for example, flavonoids, phenols, and glycosides. A. lebbeck has been studied for many pharmacological activities against allergy, cancer, convulsant, diabetes, inflammation, parasitic infestation, snake venom, nootropic, pyrexia, diarrhea, and so on, and there remains still a scarcity of information on the mechanism of action. Additionally, it is worth noting that even though A. lebbeck has been used in the treatment of various ailments, it is an ingredient in several Ayurvedic formulations; nonetheless, studies are required to evaluate the possible toxicities or adverse effects. In forthcoming research, studies should target the discovery of the chemical compounds responsible for the therapeutic action, which comprise the mechanisms of action.

Conflicts of Interest
e authors declare no conflicts of interest with regard to the submitted work.