Sesbania grandiflora (L.) Pers.: A review of its phytochemistry, molecular pharmacology, and clinical potential

2.1. Taxonomy, morphology, and global distribution

Sesbania grandiflora belongs to the Kingdom—Plantae, Subkingdom—Tracheobionta, Superdivision—Spermatophyta, Order—Magnoliales, Subclass—Rosidae, Family—Fabaceae (Leguminosae), Genus—Sesbania, Species—grandiflora (L.) Pers [5]. Sesbania grandiflora can grow up to 4–10 m. The root system is typically shallow but spreading. It is heavily nodulated with nitrogen-fixing bacteria, contributing to soil fertility [6]. The bark is naturally furrowed deeply and develops corky, thick, grayish, pink, or whitish plates. It is slightly bitter to taste. Leaves are alternate, pinnate, and compound, 15–40 cm long. They are narrower at the ends of the rachis than in the middle. Both surfaces of the leaflets can have dense, appressed purplish-brown glands and are appressed villous but glabrescent. Its leaves are pinnately compound, 15–40 cm long, bearing 20–60 pairs of oblongs, rounded leaflets. Leaves are at the tips of the branches and become bright yellow before they fall. Inflorescences are 4–7 cm-long pendulous racemes with 2–5 large pink, red, yellowish, or white flowers. Flowers are 5–10 cm long, curved, and approximately 3 cm wide when closed. The bell-shaped calyx is 2 cm long, faintly two-lobed with five shallow teeth. Fruit pods are long (20 to 60 cm), narrow (6 to 9 mm), hanging, flat, septate, with approximately 15–50 swollen margins bearing red-brown seeds. Petiole is 7–15 mm long, and the leaf’s midrib (rachis) is terete, densely appressed pubescent when young and glabrescent at maturity. Calyx is campanulate (bell-shaped), 15–29 mm long, with the basal part persistent in the fruit. The corolla consists of five white or red fleshy petals: a standard petal oblongs-obovate to broadly ovate, 50–75 mm long and 35–50 mm wide, reflexed at anthesis (at flowering); two curved wings 50–105 mm long and 20–30 mm wide; and two united curved inside petals. Seeds are ellipsoid to subreniform (almost kidney shaped), 5–6.5 mm long and 2.5–4 mm wide [7,8].

2.2. Role in ethnomedicine and regional cuisines

In many parts of Southeast Asia, S. grandiflora has traditionally been used as food and medicine. In particular, the flowers are consumed in Northern Thailand and Malaysia either fresh, boiled, or steamed. This traditional use confirms with scientific findings on plants nutritional value and biological activities. In the modern era, the bioactivity of S. grandiflora extends beyond its traditional uses. Its rich protein fraction and high amino acid profile make it a valuable herbal-based protein source for the growing market as a nutraceuticals. The bioactive phytomolecules in Sesbania grandiflora also present a new possibility for use in functional foods and nutraceuticals [9]. The leaves have remarkably multifunctional applications, used to treat conditions such as epilepsy, night blindness, and bronchitis, and topically used as a poultice for rheumatic swellings, sprains, and wounds. Leaves are diuretic and laxative, and the juices of leaves are also consumed as a remedy to treat diarrhea and dysentery. The flowers are used in traditional practices for headaches, colds, and various inflammatory conditions, with the juice applied for eye sinus and congestion diseases. The decoction of bark is used for the treatment of smallpox, diarrhea, colic, and fever, and is applied topically for relieving rheumatic pain and gout. The roots are applied externally to alleviate inflammation and rheumatic swelling [10].

2.3. Comprehensive nutritional profile

Sesbania grandiflora is a good source of plant protein because of its well-documented high protein content. As reported, it has a much higher crude protein content (25.24%) than other tree fodders and shrubs. Its high nutritional value as feedstuff is due to its high protein and lower crude fiber content of 8.43%. Sesbania grandiflora seed nutritional composition was even more remarkable [11]. Seeds have a crude protein content of 37.78%, a total carbohydrate content of 34.91%, and a total lipid content of 5.2%, as reported by research. This indicates that S. grandiflora seeds may be a good energy and protein source. Further analysis of the protein content of the seed showed that globulin: 4.24% S. grandiflora seeds may supply a balanced amino acid content, making them a high-quality protein source in animal and human nutrition [12].

Sesbania grandiflora is also a rich source of essential micronutrients besides macronutrients. Specifically, the leaves of S. grandiflora have a high concentration of vitamins and minerals. In one investigation, the leaves were seen to have the following contents: Vitamin C:145 mg/100 g, Calcium:666 mg/100 g. Notably, the high level of Vitamin C adds not only to the antioxidant activity but also to the nutritional value of the plant. With its high calcium content, S. grandiflora could also be a significant plant source of the essential mineral, which is important to provide healthy bones. The presence of other minerals, such as potassium and sodium, also supplements the nutrient quality of S. grandiflora. The presence of such electrolytes would then mean that S. grandiflora could play the function of fluid balance regulation and facilitate various physiological processes [8].

This robust nutritional profile not only justifies its role as an edible herb but also contributes to the overall health benefits attributed to it in the traditional medicine system.

3.1. An inventory of bioactive constituents

The pharmacological activities of S. grandiflora are mainly due to its rich composition of various bioactive phytochemical constituents. Among these constituents, alkaloids, flavonoids, tannins, saponins, and sterols are the important constituents that play an important role behind the biological activities [10]. That includes anti-cancer, anti-inflammatory, and anti-diabetic activities. It acts both as a traditional medicine and nutraceutical. A total of 69 metabolites were identified from S. grandiflora, out of which Sesbagrandiflorain A, Sesbagrandiflorain B, and Sesbagrandiflorain C are the main active profiles of this herb. This comprehensive metabolite profile highlights the plants potential as a source of various bioactive constituents.

• Benzofurans: Are a class of biologically active chemical compounds having a benzofuran structure and an aryl group. They have shown multiple health benefits, such as anti-hypertensive, estrogenic, anti-cancer, and antioxidant properties. From the stem bark of 4 Benzofuran have been discovered and published, namely Sesbagrandiflorain A, Sesbagrandiflorain B, Sesbagrandiflorain C, and 2-arylbenzofuran [11,12].
• Phenol: Four phenols, namely Antiarol, 3, 5-di-t-Butyl-phenol, Gallic acid, Chlorogenic acid, Neochlorogenic acid, have been reported [13].
• Fatty acid: A total of six fatty acids have been isolated and reported, namely, Erucic acid, Nonanoic acid, 6-Octadecenoic acid, Hexadecanoic acid, methyl ester, and Linolenic acid from the leaves and seeds [13].
• Flavonoid: Nine flavonoids have been isolated and reported, namely, Sativan, Quercetin, Myricetin, Kaempferol, Cyanidin, Leucocyanidin, Chrysin-dimethylether, Dendroinfundin A, and Rutin have been found in the aerial parts and seeds [1].
  • Flavonoid glycosides: A total of eight Flavonoid glycosides have been isolated and reported, namely, kaempferol-3–2G-rhamnosylrutinoside, Panasenoside, Isoquercitrin, Tricin 7-O-(600-(E)-Sinapoyl)-B-D glucopyranoside, Luteolin-7-O-B-Glucopyranoside, Keampferol-5-O-Arabinoside, Kaempferol-3-O-B-D-Glucopyranosyl-(1!2)-B-D-Galactopyranoside, and Astragalin from the leaves and twigs [1].
  • Isoflavonoids: Two isoflavonoids have been isolated and reported, namely, Isovestitol, and Medicarpin from the roots of S. grandiflora [14].
  • Terpenoids: Two terpenoids have been isolated and reported, namely, Vomifoliol, and (6S, 7E) 6, 9-dihydroxy-10-(20hydroxyethoxy) 4,7-megastigmadien-3-one, from the leaves and twigs of S. grandiflora [15].
  • Glycoside: Six glycosides have been isolated and reported, namely, 3-oxo-α-ionol β-D-glucoside, 11-O-b-D-glucopyranoside-abscisic alcohol, 3, 6’-di-O-feruloylsucrose, Choushenoside A, Scarbroside, and 7-megastigmadien-3-one-9-O-b-Dglucopyranoside from the leaves and twigs of S. grandiflora [16].
  • Sesquiterpene lactone: Three Sesquiterpene lactones have been isolated and reported, namely, 8b-isobutyryloxycumambranolide, Britanin, and Callitrin from the leaves and twigs of S. grandiflora [1].
  • Ester: Two esters have been isolated and reported, namely, Ethyl 3-hexyl ester and 4-Ethoxy ethyl benzoate, from the leaves of S. grandiflora [17].
  • Carboxylic acid: Two carboxylic acids have been isolated and reported, namely, Malonic acid and Benzoic acid from the leaves of S. grandiflora [18].
• Triterpene: Two triterpenes have been isolated and reported, namely, Lupane and Betulinic acid from the roots of S. grandiflora [19].

3.2. Characterization of key compounds: medicarpin, betulinic acid, and novel isolates

Among the richness of phytochemicals in S. grandiflora, several compounds have been explored for their potent and specific biological potential, making them subjects of deeper scientific interest.

• Medicarpin: This isoflavonoid has been mainly extracted from the roots of S. grandiflora, but it is a phytoalexin, that is, produced on pathogenic attack. Its pharmacological profile is strong. It has been shown to effectively exhibit anti-tubercular activity against Mycobacterium tuberculosis, having a minimum inhibitory concentration (MIC) of 50 μg/ml. More recently, it has been postulated using molecular docking that the anti-biofilm potential of medicarpin to inhibit the enzyme responsible for Pseudomonas aeruginosa, the production of which serves to regulate the formation of biofilm c-di-GMP phosphodiesterase. Medicarpin’s ability to cross the blood-brain barrier, postulated in in silico models, may also hold promise of neuroprotective applications, but this should be further explored [20].
• Betulinic acid: A famous pentacyclic compound, betulinic acid is also present in S. grandiflora roots. It is one of the most examined natural products with potential cancer therapy. It is famous for inducing apoptosis in many cancer cell lines, especially in melanoma, but largely with minimal toxicity to the normal ones. That its anti-TB activity is maximized, having an MIC of 100 μg/ml, only further reinforces its therapeutic potential. Nevertheless, its low aqueous solubility and bioavailability have been a serious obstacle to clinical development of betulinic acid, a task in which scientists are currently engaged through the development of more soluble derivatives [16,17].
• Sesbagrandiflorains A and B: These compounds are amongst the most structurally new and exciting findings of S. grandiflora. They are dimers of 2-arylbenzofuran obtained by isolation of the stem bark. Both were demonstrated to have anti-TB, the Sesbagrandiflorain B being highly active with an MIC of 12.5 μg/ml against M. tuberculosis. This is much more active than Sesbagrandiflorain A (MIC = 200 μg/ml), which was attributed to a free hydroxyl group at C-6 in compound B. This observation presents an excellent structure-activity relationship principle since this particular structural aspect was critical towards its elevated anti-TB activity and identifies the plant as a source of new chemical scaffolds in drug discovery efforts [21].

Table 1 below summarizes the essential phytochemicals isolated from S. grandiflora and their key reported bioactivities. Table 2 summarizes the Synergistic effects of phytochemical interactions of Sesbania grandiflora.

Table 1. Major phytochemicals of Sesbania grandiflora.

Note: All MIC/IC₅₀ values are expressed in μg/ml.

Table 2. Synergistic effects of phytochemical interactions of Sesbania grandiflora.

4.1. Anti-cancer properties: from cytotoxicity to signaling pathway modulation

Sesbania grandiflora, or hummingbird tree, has gained valuable interest due to its potential role in oncology. Researchers have studied how its extracts and isolated compounds suppress cancer cell growth through various mechanisms.

4.1.1. Induction of apoptosis via the intrinsic pathway

The primary mechanism by which S. grandiflora unveils its anti-cancer effects is the induction of apoptosis, or apoptotic cell death. Numerous studies have shown that its fractions and extracts can trigger this process in different cancer cell lines, including those of the breast (MCF-7), lung (A549), colon (SW-480), and leukemia (U937) [24]. The evidence clearly shows the activation of the apoptosis’s intrinsic, or mitochondrial, pathway. Apoptosis mechanisms that have been observed include:

• Mitochondrial disruption and cytochrome C release: Permeabilizing the mitochondrial outer membrane is the critical step in the intrinsic pathway. Active metabolites from S. grandiflora, such as the cyclic peptide sesbanimide obtained from the seeds and a protein fraction (SF2) from the flowers, can directly disrupt mitochondrial function. The key signal that commits the cell to apoptosis is the disruption, which leads to the release of cytochrome C from the mitochondria to the cytoplasm. Apoptosis was demonstrated in both human colon cancer cells and murine ascites cells [21].
• Activation of caspase cascade: The cytochrome C release triggers the formation of the apoptosome, which activates the cascade of cysteine proteases. Studies have shown that treatment with S. grandiflora active constituents leads to the activation of caspases, including caspase-9, caspase-3, and caspase-8. The SF2 protein fraction causes a 4.4-fold increase in caspase-3 enzymatic activity in Daltons Lymphoma Ascites cells [22].
• Cleavage of PARP: Activated caspase-3 cleaves the cellular substrates, leading to apoptosis. Its primary targets are the Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme. PARP cleavage is a recognized characteristic of apoptosis and apoptosis in cells treated with the SF2 protein fraction and methanolic leaf extracts, indicating induction of the apoptotic program [25]. Figure 1 illustrates the complex anti-cancer mechanisms of S. grandiflora through four different pathways [20–22].

Figure 1. A complex anti-cancer mechanism of Sesbania grandiflora through four different pathways. (A) Mitochondrial-Mediated MOMP driven Apoptosis in sesbanimide and SF2 protein, which promotes the release of cytochrome C, formation of apoptosome, and activation of caspase cascade that results in PARP cleavage to 85 kDa fragments; (B) NF-κB Pathway inhibition indicating the inactivation of nuclear translocation as well as cyclin D1 downregulation for cell cycle regulation; (C) PI3K/Akt/mTOR Modulation by oleic acid and palmitic acid influencing PTEN/PI3K/Akt signaling for the reprogramming of metabolism; and (D) Additional Mechanisms such as G1/S and G2/M cell cycle checkpoints, VEGF-mediated anti-angiogenic activities, and microtubule dynamics disruption (adapted from [7,21]). [Click here to view]

4.1.2. Modulation of key cancer signaling pathways

Beyond the direct induction of apoptosis, compounds from S. grandiflora have been shown to interfere with critical signaling pathways that control cancer cell proliferation, inflammation, and survival.

• NF-κB pathway: A 2014 study has demonstrated that a methanolic extract of S. grandiflora leaves significantly reduced the activation of the NF-kappa B in A549 cells from human lung cancer. This suppression decreases the levels of cyclin D1, a downstream/signal target of NF-κB essential to cell cycle progression between G1 and the S phase [1,21]. This finding suggests that the plant’s anti-cancer effect is mediated by suppressing this key pro-survival and pro-proliferative pathway, a mechanism shown by many plant-derived anti-cancer agents [21].
• PI3K/Akt/mTOR pathway: Another key signalling pathway that often becomes hyperactivated due to alterations in cancer cells is the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which facilitates cell growth, proliferation, and survival and suppresses apoptosis. Four studies have also started correlating the anti-cancer activity of S. grandiflora to this pathway. It is hypothesized that fatty acid components of the flowers and leaves of the plant that contain elements such as oleic acid and palmitic acid can inhibit tumour growth through interference with PTEN/Akt/mTOR and PI3K/Akt pathways. While this research is still in its early stages, it opens up a new avenue for understanding the plant’s complex anti-cancer mechanisms [21].

4.2.1. Inhibition of carbohydrate-digesting enzymes

An important strategy for managing type 2 diabetes is to reduce postprandial hyperglycemia by slowing down the hydrolysis of carbohydrates [26]. Sesbania grandiflora has unveiled significant potential in this area through the inhibition of two key enzymes in the small intestine:

• α-Amylase: This enzyme primarily breaks complex carbohydrates into smaller oligosaccharides.
• α-Glucosidase: This enzyme is in the intestinal brush border of the intestine, responsible for the final breakdown of oligosaccharides and disaccharides into monosaccharides that can be absorbed into the bloodstream.

Methanolic extracts also indicated up to 81% inhibition of alpha-amylase and an IC ₅₀ value of 50.95 μg/ml, comparable to the standard drug acarbose. Similarly, the novel nanoparticle formulation developed using plant materials has been reported to have a significant inhibitory effect on enzymes, α-amylase, and α-glucosidase. A study went further by performing bio-guided fractionation to identify the specific compounds responsible for this activity. The study isolated 14 primary metabolites and found, for the first time, that the terpenoids vomifoliol (IC₅₀ = 64.5 mM) and loliolide (IC₅₀ = 388.48 mM), along with the well-known flavonoid quercetin (IC₅₀ = 17.45 mM), were potent inhibitors of α-glucosidase [27].

4.2.2. Enhancement of insulin action and pancreatic function

• Improved insulin secretion and β-cell function: The flower extracts of S. grandiflora have been reported to have therapeutic effects in diabetic rats on the level of insulin and C-peptide. Moreover, the pancreatic islets have been partially preserved and restored in the pancreas of rats histopathologically. This also indicates that the extract is protective or even regenerative of the β-cells of the insulin-producing pancreatic islet injured in diabetes [27].
• Enhanced glucose utilization: The extracts have been demonstrated to replenish hepatic glycogen, indicating that the body can store excess glucose in the liver. This is allied with regulating the main carbohydrate metabolic enzymes associated with glycolysis and gluconeogenesis, thus enhancing the stability of glucose levels in the body’s environment [27].
• Inhibition of advanced glycation end-products (AGEs): Nanoparticle formulations derived from S. grandiflora have shown a significant ability to inhibit the formation of AGEs, an effect featured in bioactive compounds like hydroxymethoxybenzaldehyde and the inherent anti-oxidant properties of the nanoparticles themselves [28]. Figure 2 illustrates the anti-diabetics activity of S. grandiflora, emphasizing its roles in enhancing glucose uptake, improving insulin secretion and sensitivity, inhibiting carbohydrate digestion and absorption, and suppressing gluconeogenesis.

Figure 2. Schematic representation of the anti-diabetic mechanisms of Sesbania grandiflora, illustrating its multifaceted actions: (1) modulation of GLUT4 expression in skeletal muscle, myocardium, and adipose tissue to enhance glucose uptake; (2) stimulation of insulin secretion through pancreatic β-cell recovery and reduced expression of ER stress-related proteins (CHOP, Caspase-12, Caspase-3); (3) improvement of insulin resistance via PPARγ activation, lipid profile enhancement, and suppression of SREBP-1 mediated lipogenesis; (4) reduction of initial glucose uptake by inhibiting carbohydrate-hydrolyzing enzymes (α-glucosidase, disaccharidase) and glucose transporters (SGLT-1, GLUT2); and (5) decreased metabolism of glucose in organs and tissues through suppression of gluconeogenic enzymes. Together, these pathways contribute to lowering blood glucose levels and improving metabolic health (adapted from [8,41]). [Click here to view]