A Review on Bioactive Phytochemical Constituents and Pharmacological Activities of <i>Aegiceras corniculatum</i>: A Pharmaceutically Important Mangrove Plant

Sarkar, Pritam; Ahnaf, Tasfiya Rufaidah; Rouf, Razina; Shilpi, Jamil Ahmad; Uddin, Shaikh Jamal

doi:https://doi.org/10.1155/2024/9992568

Journal of Chemistry

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Abstract Introduction Materials and Methods Discussion Conclusion Abbreviations Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2024 | Article ID 9992568 | https://doi.org/10.1155/2024/9992568

A Review on Bioactive Phytochemical Constituents and Pharmacological Activities of Aegiceras corniculatum: A Pharmaceutically Important Mangrove Plant

Pritam Sarkar,¹Tasfiya Rufaidah Ahnaf,¹Razina Rouf,²Jamil Ahmad Shilpi,¹and Shaikh Jamal Uddin¹

Academic Editor: Maciej Przybyłek

Received03 Aug 2023

Revised24 Nov 2023

Accepted20 Dec 2023

Published04 Jan 2024

Abstract

Aegiceras corniculatum, commonly referred to as Khalsi, is a member of the mangrove Myrsinaceae family. The various parts of this plant have been used in traditional medicinal systems for their potential therapeutic effects in conditions such as asthma, microbial infections, diabetes, pain relief, inflammation, cancer, and arthritis. A diverse array of bioactive phytochemicals such as flavonoids, benzoquinones, triterpenes, polyphenolic acids, stilbenes, tannins, and macrolides have been identified in different parts of this plant. The aim of this review was to summarize the bioactive phytoconstituents reported from this plant that are accountable for the observed different pharmacological effects of the plant and further elucidate the possible underlying mechanisms by which these chemicals exert their actions. The search was conducted on various widely used database platforms, including Google Scholar, Scopus, Web of Science, SciFinder, and PubMed. Articles published until July 2023 were extracted and all the information was sorted based on the inclusion and exclusion criteria. The data revealed that anti-inflammatory compounds from this plant suppress iNOS, myeloperoxidase, COX, LOX, and cytokines (like TNF-alpha, IL-1ß, LTB₄, IL-12, and IL-6) to reduce inflammation. 5-O-Butyl-embelin, 2-hydroxy-5-ethoxy-3-nonyl1, 4-benzoquinone, 5-O-methylembelin, 5-O-methyl-rapanone, s-saponin, and 5-O-ethylembelin are some phytochemicals of A. corniculatum with anticancer properties, although their mechanism is unclear. A. corniculatum has antibacterial, parasitic, and antifungal effects, but no antiviral effects were reported. The plant-isolated coumaric acid and fatty acids interact with bacterial DNA/RNA and limit protein formation, making them antibacterial. Gallocatechin, epicatechin, epigallocatechin-3-O-gallate, epigallocatechin, and other tannins, as well as flavonoids like kaempferol, quercetin, and isorhamnetin, are some of the compounds in A. corniculatum that may depolarize and change bacterial membranes, showing antibacterial effect. These phenolic chemicals also reduce oxidative stress and help treat cancer and other inflammatory diseases. The extract of this plant activates the κ-opioid receptor, causing central antinociception. Catechol components, such as epigallocatechin-3-O-gallate, protect against CNS illnesses including Parkinson’s disease and amnesia. Despite numerous studies demonstrating various pharmacological advantages of this plant and its constituents, the number of clinical trials conducted on humans remains significantly limited.

1. Introduction

Since ancient times, in pursuit of a cure for their illness, humans have sought to nature for drugs. The initial usage of medicinal plants was instinctual, similar to that of animals. Over time, it became clear why people were turning to different plants for the treatment of different illnesses; as a result, the practice of using medicinal plants to combat disease moved away from an empirical basis [1]. The global market for herbal medicines was assessed at a financial value of 170 billion United States dollars in the year 2022 and calculations indicate that this market is anticipated to expand to USD 600 billion by the year 2033, exhibiting a compound annual growth rate (CAGR) of 15% during the period spanning from 2023 to 2033 [2]. Natural product utilization in medicine is an important resource for pharmaceutical businesses worldwide that are working to find new therapies [3]. Approximately 6,500 plant species are believed to inhabit Bangladesh, and among them, over 500 species are recognized for their medicinal properties, with 250 routinely employed in the formulation of healthcare remedies. Yet, most of these plants are not being investigated chemically, pharmacologically, or toxicologically to find out what parts of them are useful [4].

Mangrove and mangrove associates have long been widely used as medicinal and nonmedicinal purposes throughout the world. There are reports of extracts from plants of mangrove origin to have proven activity against human, animal, and plant pathogens [5]. The diversity in activity of these plants could be due to the peculiar environment (high moisture, large tidal difference, high salinity, etc.) in which they exist, producing stressful conditions, which might change their morphology, physiognomy, and biosynthetic pathways to survive [5]. Bangladesh has the largest single block of Sundarbans mangrove forests in the world, which is a globally significant ecosystem rich in plant biodiversity [5]. However, the scientific information about the biological effects of these plants and active substances is scarce and poorly documented. Aegiceras corniculatum, a Myrsinaceae mangrove plant, is called Khalsi in Bengali and grows in India, China, Singapore, Australia, Papua New Guinea, and Singapore. Traditional medicine has used the plant’s fruits, leaves, and stem bark to treat asthma, arthritis, diabetes, inflammation, cancer, hepatic diseases, and many others [6]. In different portions of this plant such as leaves, bark, root, stem, and twig, researchers have identified a number of bioactive secondary metabolites. These metabolites include, but are not limited to, flavonoids, polyphenolic chemicals, terpenoids, tannins, alkaloids, and various glycosides [7–17]. These compounds may be accountable for the plant’s antimicrobial, antidiabetic, analgesic, anti-inflammatory, anticancer, and antiarthritis effects. As a part of our continuing search for new insight of Bangladeshi traditional medicinal plants, here we report the bioactive phytoconstituents and pharmacological potential of A. corniculatum as well as the possible mechanism of action behind the pharmacological effects.

2. Materials and Methods

2.1. Methodology for Conducting the Search

For the start of this review, a thorough literature search was undertaken on 11th March 2023. The search was conducted on various widely used database platforms, including Google Scholar, Scopus, Web of Science, SciFinder, and PubMed. The search terms employed were “Aegiceras corniculatum” along with “pharmacological use,” “folk medicinal uses,” “mechanism of action,” and “isolated compounds.”

2.2. The Process of Study Selection

This review encompassed various types of investigations. The research encompasses various methodologies, including (a) investigations conducted on animal models (in vivo), (b) studies conducted in a controlled laboratory environment (in vitro), (c) computational studies that use computer models and simulations, (d) investigations that examine the pharmacological effects of plant extract and various phytochemicals derived from A. corniculatum, (e) studies that provide information on the specific concentrations, doses, and routes of administration for the extract and its individual compounds, and (f) investigations that elucidate the underlying mechanisms of action of the isolated phytochemicals.

2.3. The Process of Extracting Information

The articles that were examined underwent a comprehensive evaluation process that considered various factors such as the surname of the first author, the year of publication, the specific substance being studied, the experimental framework employed, the observations made, the outcomes observed, the proposed mechanism of action, and the concentrations that were evaluated. The searches revealed 949 records, of which around 84 studies met the criteria and rest of others are excluded. This document presents an overview of the fundamental stages involved in conducting a data search, including the processes of data exclusion and inclusion, as well as other pertinent details.

3. Discussion

3.1. Chemical Constituents of A. corniculatum

Various studies have identified that A. corniculatum extract contains a spectrum of naturally occurring chemical constituents, including flavonoids (such as kaempferol, quercetin, and isorhamnetin), benzoquinones (such as embelin), triterpenes (including aegiceradienol, genin-A, protoprimulagenin, and aegicerin), polyphenolic acids (such as gallic acid, coumaric acid, and syringic acid), stilbenes (such as resveratrol), and other compounds which have been isolated and are believed to contribute to the diverse medicinal properties associated with different solvent extracts (Table 1) [27–29].

3.2. Pharmacological Effects of A. corniculatum

3.2.1. Antioxidative

An imbalance between ROS (like O₂•−, H₂O₂, •OH) generation and detoxification in cells and tissues causes oxidative stress which arises as by-products of metabolic processes in biological systems [30, 31]. A study found that extracts derived from A. corniculatum, namely, n-hexane, EtOAc, and MeOH (Table 2), demonstrated proficiency in efficiently neutralizing different free radicals (like O₂•−, H₂O₂, •OH) in more than one in vitro experimental tests [27]. The potential explanation for the antioxidant property of A. corniculatum leaves may be attributed to their comparatively higher total phenolic content [38]. A noteworthy correlation was observed between the total phenol content and the outcomes of various antioxidant assays, including the DPPH and ABTS radical scavenging assays, as well as the FRAP and phosphomolybdenum assays (Table 2) [32]. The key phenolic constituents (Figure 1) found in Aegiceras corniculatum are predominantly present in the ethyl acetate extract, include flavonoids such as kaempferol, flavonol compounds like quercetin and isorhamnetin, polyphenolic acidic compounds including gallic and syringic acid, and sterol compounds like resveratrol [27, 28, 33]. The antioxidant properties are also shown by the MeOH extract of the plant which could be related to phenols and tannins (such as gallocatechin, epicatechin, epigallocatechin-3-O-gallate, and epigallocatechin) present in it [25, 38]. So, it can be said that A. corniculatum plant extracts possess free radical scavenging abilities, which aligns with its traditional application as an antioxidative agent.

3.2.2. Anti-Inflammatory

Diseases including diabetes, cardiovascular disease, cancer, and asthma all are involved with inflammation in some way [39]. Inflammation is a sophisticated immunological response that causes the consecutive release of proinflammatory cytokines. Therefore, the mitigation of inflammation-associated ailments can be achieved by suppressing the excessive production of inflammatory mediators, particularly proinflammatory cytokines such as IL-1b, IL-6, and TNF-alpha [40]. Based on a recent study, it was observed that the administration of A. corniculatum extracts at dosages of 250 and 500 mg/kg resulted in a significant reduction in paw edema in Swiss albino mice [6]. By combining different in vivo and in vitro models (Tables 2 and 3), a study indicates that extracts obtained from A. corniculatum, specifically methanol and ethyl acetate extracts, exhibit notable inhibitory effects on the chronic inflammatory phase and these effects are observed through the suppression of mononuclear cell infiltration, fibroblast proliferation, collagen fiber production, and connective tissue formation, all of which contribute to the development of granuloma [45]. Carrageenan-induced pleurisy is a very common method used to test anti-inflammatory therapeutics [49]. Methanol and ethyl acetate extract of A. corniculatum protects against acute lung inflammation by lowering nitrate/nitrite concentrations and MPO enzyme levels and also decreases neutrophils and mononuclear infiltration at a higher dose (100 mg/kg) in a mice model of pleurisy [47] (Table 3). Different classes of phytochemicals are isolated from different parts of A. corniculatum (Table 4) which is the potential causative factor for the observed anti-inflammatory effect [51, 52]. In accordance with the outcomes of a research, it has been found that the ethyl acetate extract of plant demonstrates inhibitory effects on the production of eicosanoids like LTB₄ (IC₅₀: 0.86 ± 0.03 g/ml), 5-HHT (IC₅₀: 3.4 ± 0.04 μg/ml), and 12-HHT (IC₅₀: 0.08 ± 0.002 μg/ml), with only a minor effect on 12-HETE (IC₅₀: 8.0 ± 0.18 μg/ml), thus demonstrating that it has comparatively strong binding preference towards the 5-lipoxygenase and cyclooxygenase-1 in relation to the 12-lipoxygenase [43]. The ethyl acetate extract derived from plants contains a diverse range of triterpenes and phenolic compounds (like flavonoids), which have the potential to exhibit anti-inflammatory properties [14, 28, 32, 43]. Ethyl extract of this plant contains two triterpenoid saponins (3β, 16α, 20α)-3,16,28-trihydroxyolean-12-en-29-oic acid 3-{O-β-D-glucopyranosyl (1 ⟶ 2)-O-[β-D-glucopyranosyl (1 ⟶ 4)]-α-L-arabinopyranoside} and aegicoroside A (Figure 2) which show anti-inflammatory effect by inhibiting the production of TNF-α, IL-6, and IL-12 p40 [14]. The presence of flavonoids, specifically quercetin, kaempferol, and isorhamnetin (Figure 1), in the ethyl acetate extract may be associated with its dual anti-inflammatory effects. These flavonoids have the ability to inhibit both cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, which play a crucial role in the synthesis of various inflammatory mediators including cytokines, chemokines, and adhesion molecules [43, 53]. At a maximal oral dose of 50 mg/kg, methanol extract reduced paw swelling in a rat arthritic model by approximately 67%, but it had no effect on LTB₄-induced cell infiltration, further demonstrating its preference for the COX pathway [43, 45]. Triterpenes, phenols, and tannins previously reported in the methanol extract may be responsible for its anti-inflammatory properties [25, 38, 54]. Epicatechin, a tannin, is found in the methanol extract of the plant [25]. (−)-Epicatechin exhibits a greater negative binding affinity compared to CA, leading to the enhancement of various proteins such as HSP-30, HSP-70, HSP-90, interleukin-10, and FOXP3. Additionally, (−)-Epicatechin demonstrates the ability to inhibit interleukin-6, peptidoglycan, flagellin, and dectin in silico [55]. Also, a study reveals that epicatechin decreases iNOS, COX-2, NO, PGE₂, and proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) in LPS-stimulated RAW264.7 cells, making it a potent anti-inflammatory compound [56]. An investigation about n-hexane extract of the plant demonstrated a decrease in 12-HETE formation with an IC₅₀ value of 0.36 ± 0.12 μg/ml and simultaneously an increase in 12-HHT and also exhibited an antagonistic effect on the synthesis of 5-LOX metabolites, specifically LTB₄ and 5-HETE, in rat neutrophils, indicating a selectivity towards lipoxygenases pathway [43]. It is possible that the presence of benzoquinones is responsible for the selectivity of hexane extract towards lipoxygenases [16, 43, 57, 58]. Oxidative stress plays a significant role in the development of chronic inflammation [59]. Current research aimed to replicate the anti-inflammatory response to oxidative stress in an in vivo model of glucose oxidase-induced paw edema in mice revealed that extracts derived from A. corniculatum possess the ability to inhibit the production of proinflammatory mediators in the presence of oxidative stress, owing to their capacity to scavenge OH radicals [27]. Thus, it can be inferred that n-hexane, EtOAc, and MeOH extracts derived from the A. corniculatum possess anti-inflammatory properties that are exerted through various mechanisms of action (Figure 3). Hence, A. corniculatum, a species of mangrove plant, has been employed for numerous years in the management of various inflammatory and autoimmune conditions, such as coronary artery disease, rheumatoid arthritis, and allergies and asthma, and its utilization as a traditional remedy has garnered significant recognition.

(a)

(b)

3.2.3. Antiproliferative

Cancer indicates a significant global public health concern, exerting a considerable influence on nations across the spectrum of development. In the year 2018, there was a global estimation of approximately 18.1 million newly diagnosed cases of cancer and it is projected that by the year 2030, this figure will increase to reach approximately 23.6 million cases [60]. The significance of identifying medicinal plants with notable cytotoxic potential for the advancement of cancer therapies has experienced a notable increase in the past decade, and progress in this domain is currently expanding [61]. The methanolic extract obtained from A. corniculatum demonstrated pronounced cytotoxic effects on healthy, colon, and breast cancer cells, as evidenced by IC₅₀ values ranging from 0.02 to 0.66 mg·mL⁻¹. However, the cytotoxicity against gastric cancer cells was notably low [62]. Different classes of phytochemicals are isolated from different parts of A. corniculatum (Table 1) which may be responsible for anticancer or cytotoxic effect [51, 52]. 3-O-[α-L-Rhamnopyranosyl-(1 ⟶ 2)-α-L-rhamnopyranosyl-(1 ⟶ 2)-β-D-galactopyranosyl-(1⟶3)-β-D-glucopyranosyl-(1⟶2)-β-D-(6′-O-methyl)glucuronopyranosyl]-13β, 28-epoxy-3β, 16α-dihydroxy-olean and sakurasosaponin (Figure 2) are two triterpenoid saponins isolated from the EtOAc extract of A. corniculatum leaves showing apoptosis of B16F10 melanoma cells [14]. A study said that significant cytotoxic effects have been reported for sakurasosaponin and sakurasosaponin methyl ester (Table 4) against MCF7, A549, and HCT116 cell lines, with IC₅₀ values ranging from 2.89 ± 0.02 to 9.86 ± 0.21 μM [63]. A research suggested that sakurasosaponin shows antitumor effect through decreasing mitochondrial membrane potential, increasing cytochrome C release into the cytoplasm, and elevating caspase-3 activity that causes apoptosis [50]. Various benzoquinones are extracted from various parts of the plant, potentially contributing to its anticancer properties [16, 23, 64]. 2-Hydroxy-5-ethoxy-3-nonyl1, 4-benzoquinone, 5-O-butyl-embelin, 5-O-methylembelin, 5-O-methyl-rapanone, and 5-O-ethylembelin are some of the benzoquinone phytoconstituents (Figure 2) of A. corniculatum plant, and they show selective cytotoxicity against HL-60, HepG2, BGC-823, and A2780 cell lines [23]. The benzoquinone derivatives, namely, 5-O-ethylembelin and 5-O-methylembelin (Table 4), which have been extracted from A. corniculatum, have been found to induce cell cycle arrest in HL-60 cells specifically in the phase, and this effect is believed to be mediated through their interaction with microtubular proteins [16, 65]. However, the precise mechanism underlying this interaction remains to be elucidated.

Higher levels of reactive oxygen species (ROS) produced through persistent aerobic glycolysis, subsequent pyruvate oxidation in mitochondria, receptor and oncogene activation, and activation of growth factor-dependent pathways or oxidizing enzymes contribute to the induction of genetic instability [66]. Various studies have proposed that the protective effect of antioxidants against cancer is manifested through the inhibition of the generation of carcinogenic metabolites [67, 68]. Also, epigallocatechin-3-O-gallate inhibits DNA methyltransferase activity and controls histone acetylation, which increases apoptosis and also activates mitogen-activated protein kinases to boost anticancer action [69]. Therefore, A. corniculatum has anticancer benefits against various cancers through a variety of methods and may serve as a future source of anticancer drugs.

3.2.4. Analgesic

A study suggested that A. corniculatum’s ethanolic and water-soluble extracts (200 and 400 mg/kg, p.o.) had a substantial analgesic effect, increased latency in Eddy’s hot plate, and reduced the writhing caused by acetic acid in a dose-dependent way [70]. According to another investigation, the extract derived from A. corniculatum demonstrated notable inhibition of writhing impulse (Table 3). Specifically, at doses of 250 mg/kg and 500 mg/kg body weight, the extract exhibited inhibitory effects of 54.78% and 75.60%, respectively, and these findings indicate that the extract’s potency is comparable to that of a 25 mg/kg dose of diclofenac sodium [6]. The potential mechanism underlying the antinociceptive effect of methanol plant extract appears to involve the activation of the κ-opioid receptor. On the other hand, the n-hexane extract may exert its effects by acting as an opioid agonist on the peripheral opioid receptor, thereby counteracting withdrawal abstinence syndrome through the GABAB receptor. In contrast, the neurogenic analgesic action of the EtOAc extract was not found to be mediated by the opioidergic system. Instead, it is possible that the extract exerts its effect by inhibiting the biosynthesis of proinflammatory PGs [41]. Different investigations found that flavonoids, flavonols, benzoquinones, triterpenes, polyphenolic acids, stilbenes, and others are some naturally occurring chemical constituents isolated from plant extract and may be responsible for reducing both central and peripheral pain effect through different mechanisms [27–29, 71].

3.2.5. Antimicrobial

Several investigations have demonstrated that A. corniculatum possesses antimicrobial properties against different microorganisms (Table 2) [7, 20, 36, 55]. An antimicrobial refers to any substance that has the ability to eliminate microorganisms or inhibit their proliferation or development. There are primarily four types of antimicrobial drugs, including antibacterial, antifungal, antiviral, and antiparasitic drugs [72, 73]. An in vitro study found that A. corniculatum stems are used to inhibit adult earthworms (Pheretima posthuma) showing anthelmintic effect [36]. Also methanol extract of polyherbal mixture containing A. corniculatum and Chaetomorpha antennina demonstrated a suppressive effect of approximately 63.50 ± 0.408% on P. falciparum, a parasite that causes malaria, when tested at a concentration of 1.5 mg/ml [44]. The plant contains various benzoquinones (embelin), including 2,5-didehydroxy-6-methylembelin, embelin, 5-O-ethylembelin, and 5-O-methylembelin (Table 4). These have exhibited antimalarial activity in laboratory tests against both chloroquine-sensitive (3D7) and resistant (K1) strains of the malaria parasite [24]. Benzoquinones are the most cytotoxic substances presumably because of their higher electrophilicity and autooxidation potential [74]. These findings suggest potential antimalarial activity of A. corniculatum’s phytoconstituents.

Methanol extract derived from A. corniculatum exhibits in vitro inhibitory effects on the growth of Fusobacterium nucleatum, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans in the disk diffusion method, and the observed effect can be attributable to the existence of (−)epicatechin and coumaric acid within the extract [55]. There is a possibility that coumaric acid can bind to the phosphate anion present in the DNA double helix. Moreover, it can potentially insert itself into the groove of the DNA double helix, and these interactions have the potential to affect the production of proteins and the growth of bacteria [75]. A recent study has demonstrated that the EtOAc fraction exhibited the most potent antituberculosis activity, with a minimum inhibitory concentration (MIC) of 6.25 μg/ml, with the highest total phenolic content and antioxidant activity. A clear correlation was observed between the amounts of phenolic content and the effectiveness of the antituberculosis activity [28]. Different extracts of A. corniculatum contain phenolic compounds (Figure 1) such as polyphenolic acid (like gallic acid and coumaric acid); tannins (such as gallocatechin, epicatechin, epigallocatechin-3-O-gallate, and epigallocatechin); and flavonoids (like kaempferol, quercetin, and isorhamnetin) which may be responsible for antimicrobial activity [11, 25, 38, 43, 55, 76]. The existing literature suggests that the inhibition of pathogenic bacteria by phenolic compounds is attributed to the depolarization and alteration of membrane fluidity [77]. Moreover, the fatty acids derived from the pneumatophore of A. corniculatum exhibited significant efficacy against GNB Klebsiella pneumoniae and a medium efficacy against GPB Staphylococcus aureus. The results suggest that the ability of the fatty acid fractions to kill bacteria depended on the presence of long-chain unsaturated fatty acids [20]. Possible mechanisms by which antibacterial fatty acids exert their effects include the potential to hinder DNA/RNA replication, impede cell wall formation, disrupt the integrity of the cytoplasmic membrane, and interfere with metabolic pathways [78]. Macrolides such as isocorniculatolide A; 11-O-methylisocorniculatolide A; 11-O-methylcorniculatolide A; 12-hydroxy-11-O-methylcorniculatolide A; and corniculatolide A are isolated from A. corniculatum which may show antibacterial activity through their ability to bind the bacterial 50S ribosomal subunit causing the inhibition of bacterial production of protein [12, 79]. These findings point to the possibility of antibacterial action on the part of the phytoconstituents found in A. corniculatum. Two compounds, called as Acornine 1 and Acornine 2 (Table 4), were extracted from A. corniculatum, and both of them demonstrated growth inhibitory activity against the fungus T. clypeatus [7]. Both of the Acornines are triterpenoid saponins, which have been found to possess the ability to disrupt the structural integrity of the cell membrane, resulting in the release of cellular contents and afterwards inhibition of fungal growth [7]. Therefore, it is obvious that this plant is effective against a wide spectrum of microorganisms through different mechanisms.

3.2.6. Effect on CNS Diseases

Phenolic compounds capable of traversing the blood-brain barrier have been observed to elicit beneficial health outcomes within the brain [80]. As different extracts of A. corniculatum contain phenolic compounds, it may have effect on CNS [11, 25, 43, 81, 82]. Tolcapone and entacapone are inhibitors of COMT, a novel category of pharmaceuticals employed in the therapeutic management of Parkinson’s disease, both of which are catechol analogues [83]. Epigallocatechin-3-O-gallate (Figure 1), a catechol analogue that is derived from A. corniculatum, exhibits strong inhibitory effects on human catechol-O-methyltransferase (COMT), potentially impeding the progression of Parkinson’s disease [25, 84]. A study also shows that strong antioxidant activities in A. corniculatum have been shown to improve cognitive performance in both adult and elderly rats and can be used to treat amnesia [48]. Furthermore, it has been reported that the methanol plant extract elicits a central antinociceptive effect by activating the κ-opioid receptor [41]. Only a few studies have been carried out on the central nervous system (CNS) to explore the neuropharmacological impacts of this specific plant. Further research is required to investigate the neuropharmacological activity of this plant and elucidate its mechanism of action.

3.2.7. Antidiabetic Effect

According to a research study, it was discovered that the ACEt extract derived from the leaves of A. corniculatum exhibits antidiabetic properties in male albino rats. This effect is achieved by enhancing the activity of hexokinase (Table 3) while simultaneously reducing the activities of glucose 6-phosphatase and fructose-1,6-bisphosphatase [42]. Alpha-glucosidase inhibitors reduce postprandial blood glucose and insulin by inhibiting small intestine carbohydrate absorption in diabetic patients [85]. The results of an in vitro study demonstrated that the ethyl acetate portion and water portion extracts derived from the leaves of A. corniculatum exhibited inhibitory effects on the alpha-glucosidase enzyme. The IC₅₀ values for the ethyl acetate portion and water portion were determined to be 40.59 µg/mL and 60.79 µg/mL, respectively [37]. Further research is warranted to identify the specific molecules underlying the antidiabetic effect and to comprehensively understand the precise mechanism of action, and this necessitates a comprehensive investigation utilizing both in vivo and in vitro approaches.

4. Conclusion

The primary sources for the development of medical drugs are active ingredients derived from medicinal plants. Different classes of compounds, including flavonoids, benzoquinones, tannins, triterpenes, polyphenolic acids, stilbenes, and macrolides, are present in A. corniculatum that are responsible for a wide range of pharmacological effects. Quercetin, (3β, 16α, 20α)-3,16,28-trihydroxyolean-12-en-29-oic acid 3-{O-β-D-glucopyranosyl (1 ⟶ 2)-O-[β-D-glucopyranosyl (1 ⟶ 4)]-α-L-arabinopyranoside}, isorhamnetin, aegicoroside A, kaempferol, and (−)-epicatechin are some of the chemicals isolated from this plant that may be responsible for anti-inflammatory activity. The compounds present in this plant exhibit inhibitory effects on iNOS, myeloperoxidase, COX, and LOX enzymes and additionally reduce the production of various cytokines including TNF-α, IL-1ß, IL-6, and LTB4, resulting in an anti-inflammatory response. A specific substance called S-saponin, derived from this plant, has been identified to induce cell death through mitochondrial-mediated pathways in both androgen-dependent and castration-resistant cells, by modulating androgen receptor (AR) mechanisms. Also, 2-hydroxy-5-ethoxy-3-nonyl1, 4-benzoquinone, 5-O-butyl-embelin, 3-O-[α-L-rhamnopyranosyl-(1 ⟶ 2)-α-L-rhamnopyranosyl-(1 ⟶ 2)-β-D-galactopyranosyl-(1 ⟶ 3)-β-D-glucopyranosyl-(1 ⟶ 2)-β-D-(6′-O-methyl)glucuronopyranosyl]-13β, 28-epoxy-3β, 16α-dihydroxy-olean, 5-O-methylembelin, 5-O-methyl-rapanone, and 5-O-ethylembelin are some of the other phytochemicals of A. corniculatum showing anticancer effect, but their exact mechanism is still unknown. Multiple studies have revealed that A. corniculatum exhibits antimicrobial properties against a variety of microorganisms, including both types of bacteria, parasites, and fungi. However, no evidence of antiviral effects has been observed. Different in vitro and in vivo studies found that different extracts of A. corniculatum are used to inhibit adult earthworms (Pheretima posthuma) showing anthelmintic effect and inhibit P. falciparum showing an antimalarial effect. Plant-isolated coumaric acid and fatty acids have the capacity to interact with bacterial DNA/RNA and to inhibit protein production through a variety of mechanisms and can show antimicrobial effect. Macrolides from A. corniculatum may inhibit bacterial protein production by binding the bacterial 50S ribosomal subunit. Gallocatechin, epicatechin, epigallocatechin-3-O-gallate, epigallocatechin, and other tannins, as well as flavonoids like kaempferol, quercetin, and isorhamnetin, constitute some of the phenolic compounds found in A. corniculatum that may be responsible for antibacterial activity by depolarizing and changing the fluidity of bacterial membranes. These phenolic compounds are also responsible for acting as antioxidants by reducing oxidative stress which will assist to diminish a variety of inflammatory disorders (such as asthma and arthritis), cancer, and various other ailments. Two triterpenoid saponins, Acornine 1 and Acornine 2, were isolated from A. corniculatum, and both exhibited growth inhibitory action against T. clypeatus. One possible explanation for this is the capacity of the triterpenoid saponin to limit fungal development by compromising the structure of the cell membrane. Evidence has been discovered supporting the idea that this particular plant possesses a central antinociceptive effect through the activation of the κ-opioid receptor. In addition, the neuroprotective properties of this plant against several central nervous system (CNS) disorders like Parkinson’s disease and amnesia could potentially be ascribed to the existence of catechol compounds, including epigallocatechin-3-O-gallate. In addition, certain scholars have also discovered the plant’s potential antidiabetic properties through the inhibition of the alpha-glucosidase enzyme. However, additional investigation is necessary to determine the exact neuropharmacological and antidiabetic effects. In summary, A. corniculatum exhibits a diverse range of pharmacological properties, including antibacterial, antioxidant, anticancer, anti-inflammatory, antidiabetic, analgesic, and neuroprotective effects. This finding provides evidence for the utilization of this botanical species as a traditional remedy.

Abbreviations

COX:	Cyclooxygenase
IL-6:	Interleukin-6
TNF-α:	Tumor necrosis factor-α
ROS:	Reactive oxygen species
PG:	Prostaglandin
TXA2:	Thromboxane A2
LTB4:	Leukotriene B4
LOX:	Lipoxygenase
HPETE:	Hydroperoxyeicosatetraenoic acid
MPO:	Myeloperoxidase
Bcl-2:	B-cell lymphoma 2
DPPH:	2,2-Diphenyl-1-picrylhydrazyl
TBARS:	Thiobarbituric acid reactive substances
MIC:	Minimal inhibitory concentration
PLA:	Polylactic acid
iNOS:	Nitric oxide synthase
ICAM-1:	Intercellular adhesion molecule 1
PMNs:	Polymorphonuclear neutrophils
FOXP3:	Forkhead box protein 3
12-HHT:	12-Hydroxyheptadecatrienoic acid
EtOAc:	Ethyl acetate
MeOH:	Methanol
ACEt:	Acetic acid
GNB:	Gram-negative bacteria
GPB:	Gram-positive bacteria
Compound 1:	3-O-[α-L-Rhamnopyranosyl-(1 ⟶ 2)-α-L-rhamnopyranosyl-(1 ⟶ 2)-β-D-galactopyranosyl-(1 ⟶ 3)-β-D-glucopyranosyl-(1 ⟶ 2)-β-D-(6′-O-methyl)glucuronopyranosyl]-13β, 28-epoxy-3β, 16α-dihydroxy-olean
Compound 18:	(3β, 16α, 20α)-3,16,28-Trihydroxyolean-12-en-29-oic acid 3-{O-β-D-glucopyranosyl (1 ⟶ 2)-O-[β-D-glucopyranosyl (1 ⟶ 4)]-α-L-arabinopyranoside}
COMT:	Catechol-O-methyltransferase
IC:	Inhibitory concentration
GABAB receptors:	G-Protein coupled receptors
DPP-IV:	Dipeptidyl peptidase-4.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

PS and TRA accumulated the literature and systematically analyzed the data. PS and RR drafted and revised the manuscript. JAS and SJU supervised the project and provided helpful comments and revisions.

Acknowledgments

The authors are grateful to Research and Innovation Centre, Khulna University, and Pharmacy Discipline, Khulna University, for providing financial (grant no Khubi/Gacell-04/2000-147) and laboratory support to conduct this project.

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