Ethnomedicinal Uses,Phytochemistry,Pharmacological Activities,and Toxicology of Trevesia Vis. (Araliaceae) with a Focus on Trevesia palmata : Review

Abstract

Trevesia Vis. species are small evergreen trees belonging to the family Araliaceae that occur naturally throughout Asia. The multiple parts of Trevesia species have been used in traditional medicinal systems in several countries for their potential therapeutic properties, including pain relief, inflammation, fevers, microbial infections, diabetes, cancer, edema, bone fractures, and arthritis. This work presents a fascinating exploration of previous studies on Trevesia species, especially T. palmata, delving into their phytochemical constituents, biological activities, and toxicology, inviting you to uncover their potential further. This paper database meticulously compiles valuable data gathered from all accessible literature between 1842 and 2024 through a wide range of resources, including Web of Science, Scopus, Google Scholar, PubMed, Science Direct, Springer, and other scientific databases, ensuring a comprehensive and reliable overview of the research on Trevesia species. Various bioactive phytochemicals, such as triterpenoid saponins, flavonoids, and phenolic compounds, have been found in multiple parts of these plants. Chemotaxonomic investigations have revealed that the genus Trevesia may be closely related to the genera Aralia, Acanthopanax, and Hedera. Pharmacological studies showed that extracts and phytocompounds from T. palmata exhibit various biological activities, such as antiproliferative, anticancer, antibacterial, antifungal, antiviral, antioxidant, anti-inflammatory, antidiabetic, analgesic, thrombolytic, and hepatoprotective activities. Moreover, numerous toxicological reports revealed the safety of the T. palmata plant. For the first time, this paper highlights the role of therapeutic effects and health benefits of Trevesia species in food and medicine while also providing an overview of the current study status and future prospects for Trevesia species, mainly T. palmata.

Keywords

ethnomedicine pharmacology phytochemistry secondary metabolites

Introduction

The Araliaceae family, commonly known as the Ginseng family, is a highly diversified family with various species having great medicinal and economic value,^1,2 such as the genus of Panax L., Aralia L., Hedera L.,^2‐4 etc The Araliaceae family includes approximately 46 genera and 1700 species.⁵ They are predominantly found in tropical and subtropical regions⁶; most genera are shrubs or woody plants with compound leaves that are typically palmately or pinnately divided. Among the genera within the Araliaceae family, the genus Trevesia Vis. is notable for its unusual pseudo-compound leaves in several species.⁷ This genus includes eight species (namely T. palmata (Roxb. ex Lindl.) Vis. (1842), T. sundaica Miq. (1856), T. beccarii Boerl. (1887), T. burckii Boerl. (1887), T. valida Craib (1930), T. arborea Merr. (1934), T. lateospina Jebb (1999), and T. vietnamensis J.Wen & P.K.Lôc (2007))⁸ of small, sparsely branched trees primarily distributed across China, South and Southeast Asia, including countries like Myanmar,⁹ Thailand,¹⁰ Laos,¹¹ Cambodia, Vietnam,¹² Malaysia,¹³ Indonesia, Nepal, India, Bhutan, and Bangladesh.^8,14

Trevesia species have long been used as food. The uniquely shaped leaves also make some species, like T. burckii and T. sundaica, popular as ornamental plants.¹⁴ Moreover, Trevesia species are widely used in traditional medicine across Laos,¹¹ Vietnam,¹⁵ China,¹⁶ Malaysia,¹⁷ Thailand, India, Bangladesh,¹⁸ and other countries. Different parts of these plants treat various conditions affecting the skin, bones, joints, digestion, and reproduction.^17,19 Notably, T. palmata is one of the evergreen trees used for medicine and ornamental purposes.²⁰ It is used in folk medicine to treat various ailments, such as fever, inflammation, edema, diabetes, rheumatism, bone fractures, colic, stomachache, high blood pressure, snake bites, health promotion, nutritional supplementation, etc^19,21‐31 Additionally, its flower buds and young shoots are used as a potherb³²; its fruit is used for fishing; the core of its trunk is used for making hats³³; and it is also cultivated as an ornamental plant.³⁴ These species’ many noteworthy ethnomedicinal qualities may be the foundation for future studies of one of its phytochemical and pharmacological aspects. Despite their traditional use for various ailments, research on the chemical composition and pharmacology of Trevesia species remains limited. Most studies have focused on identifying and isolating triterpenoid saponins.¹⁹ These compounds exhibit several pharmacological effects, including antiproliferative, antioxidant, cognitive enhancement, physical recovery, metabolic stimulation, and health promotion.^35,36

Trevesia species have not been comprehensively assessed despite their medical and economic benefits. This study aims to provide updated information on recent developments in its botanical chemistry, safety profiles, pharmacology, and economic importance, hoping to inspire further research and guide future studies on the benefits of Trevesia species. Moreover, the chemotaxonomic significance of the isolated compounds was also discussed.

Research Methodology

A thorough bibliographic study covering works published between 1842 and 2024 was carried out. Information about Trevesia species and their synonyms was gathered from several resources, including Web of Science, Scopus, Google Scholar, PubMed, Science Direct, and Springer. Several ethnobotanical textbooks and abstracts were also consulted. Keywords included the scientific name of the Trevesia species, synonym, ethnobotany, phytochemistry, pharmacology, and toxicity used in this study. Additionally, the online databases, including the Plants of the World Online (https://powo.science.kew.org/), the Flora of China (http://www.efloras.org/), the WorldCat (https://search.worldcat.org/), the Synonymic Checklist and Distribution of the World Flora (https://www.worldplants.de/), and the Catalogue of Life (https://www.catalogueoflife.org/), were used to identify the scientific names of Trevesia species and their synonyms. The chemical structures were compared based on PubChem (https://pubchem.ncbi.nlm.nih.gov/).

The survey results obtained about 60 articles relevant to the topic of the present study. Several publications in the introduction and discussion sections, particularly for chemotaxonomic investigations (46 articles), were also included to provide additional information unrelated to the search parameters.

Ethno-traditional Uses

Trevesia species, herbs rich in ethnomedicinal significance, hold a venerable position in folk medicine across diverse cultures and regions. Based on our investigations, Trevesia species, especially T. palmata, have traditionally been widely used in folk medicine as a therapeutic remedy in several countries, such as Vietnam, Laos, Thailand, India, Bangladesh, Indonesia, etc.

Accordingly, T. sundaica (“Daun pelindo”) shoots and leaves are consumed as vegetables.³⁷ T. sundaica is also used for rheumatism, as a general tonic,¹⁹ and to treat heartburn.³⁸ In traditional medicine, the leaves of T. burckii (“Tapak hantu”) are applied to small ulcers, general skin diseases, bone fractures, anti-rheumatism, and reduced fever.¹⁷ Moreover, decoction of root bark and leaves drunk as a tonic with aphrodisiac properties.¹⁷

In Traditional Vietnamese Medicine, T. palmata (also known as “Snowflake Tree, Snowflake Plants, or Snowflake Aralia” in English, “Du Du Rung”, “Thong Thao Gai”, “Thau Dau Nui”, “Nhat Phien”, “Nhat Phien Qua Tron”, “Thoi Hoang”, “Thoi Phong”, “La Tang”, “Mac Rau Dong” (Tay), “Co Tang” (Thai), or “Tam Thong Dang” (Dao) in Vietnamese) has been used for reducing heat, diuretics, the treatment of fever, inflammation, edema, rheumatism, diabetes diseases, and bone fractures, as well as health-promoting effects.^24,29,31 In India, it is used as a general tonic and for bone fractures.^19,23 T. palmata (“Kawhtebel”) is also used for stomachaches by the Mizo ethnic group in the Lunglei district, Mizoram²⁶; moreover, leaves and fruits of T. palmata are edible and are used for treating stomachache and high blood pressure, especially the Mizo's consume the leaf juice for treating dyspepsia.²⁵ In Laos, T. palmata (“Tang” or “Kreuale Tang”) is used for postpartum recovery first and second phases (perineal healing and retraction of the uterus), in addition to being an adjunctive therapy in the elimination of lochia, abdominal pain, physical recovery, and lactagogue effects by the Kry ethnic group.¹¹ In Bangladesh, root paste of T. palmata (“Bon papay”) is applied to the swollen and painful penis of children in Chittagong Hill Tracts; additionally, paste prepared from roots and fruits is applied to snake bites.²⁸ T. palmata is used for treating urinary tract problems in eastern Indonesia.³⁹ T. palmata is also used in Peninsular Malaysia to treat bone fractures and skin-related diseases.^21,22 In northern Thailand, flowers and seeds of “Kai Lang Du” have been used by the Pwo people in the form of decoction to supplement nourishment for the body.³⁰ Particularly, T. palmata is also used for food and ornamental purposes. For example, the flowers and buds (shoots) of T. palmata (“Mo Tang”) are used to cook many popular dishes in Hmong cuisine (Thailand).⁴⁰ The flower buds (∼0.5 kg) of T. palmata (“Kawhtebel”) are placed in a pressure cooker for 10 min; the water is poured out, and the remaining food is set aside. First, chopped onions, garlic, and coriander are stir-fried with tomatoes for 5 min, and finally, flower buds are added and mixed well, which is called “Kawhtebel kan” (Mizoram, North East India).^27,41 Particularly, T. palmata (“Hpaw-bu”) is used as food in the Palaung tribe of Kyaukme township (Myanmar) for its nutritional value, with an observed protein content of 40.47%, total carotenoid of 0.023%, and carbohydrate of 7.64% in its flowers and buds.⁴² Additionally, β-carotene and retinol contents in T. palmata flowers are 463.51 ± 245.267 and 38.63 (µg/100 g), respectively. Therefore, T. palmata is commonly used in many dishes by most Karen adults (at the Samoeng National Forest in northern Thailand).⁴³ However, lactating women and young children should not eat it because this species is very bitter and negatively affects the taste of breast milk, or if eaten directly by children (or indirectly via breast milk), it causes stomachache.⁴⁴ According to magico-religious belief in the eastern Himalayas of India, leaves of the T. palmata (“Tago Schein”) plant are used in rituals and religious ceremonies in which evil spirits do exist.⁴⁵

This species’ many noteworthy ethnomedicinal qualities may be the foundation for future studies of one of its phytochemical and pharmacological aspects. Table 1 briefly summarizes the ethnomedicinal properties and uses of Trevesia species.

Table 1.

Ethno-traditional Uses of Several Trevesia Species.

Country/ethnic group	Plant parts	Preparation	Traditional uses	Refs
Trevesia sundaica
Indonesia -Java -Pedawa (Bali)	Shoots; Leaves	Vegetable	Young shoots and leaves are used as a vegetable.	³⁷
	Shoots; Leaves	Decoction	Treatment of rheumatism: Used as a general tonic.	¹⁹
	Leaves	Decoction	Used to treat heartburn.	³⁸
Trevesia burckii
Malaysia	Leaves	Poultice/Paste; Decoction	Leaves are applied to small ulcers, general skin diseases, bone fractures, anti-rheumatism, and reduced fever.	¹⁷
Indonesia - The Talang Mamak tribe	Leaves; Root barks	Decoction	Used to drink as aphrodisiac tonic.	¹⁷
Trevesia palmata
Vietnam	Leaves	Paste	Crush leaves to bandage bones: treat rheumatism and bone fractures.	^24,29
	Medulla trunk	Decoction	Reducing heat and diuretics, treating fever, inflammation, edema, and health-promoting effects.	^24,29
	Leaves; Buds; Trunk; Stems	Paste; Decoction	Used for paralytic, galactopoietic, rheumatism, diabetes, hurt falls, and edema.	³¹
India - Mizoram	Aerial parts	Decoction	Used for general tonic and bone fractures.	^19,23
- The Mizo Ethnic Group	Leaves; Stalks; Roots	Juice	Taken for stomachache.	²⁶
- Garo Hills (Meghalaya)	Leaves; Fruits	Vegetable; Juice	The leaves and flowers are eaten as food and used to treat colic, stomachache, and high blood pressure. Leaf juice is especially effective in treating dyspepsia.	²⁵
- The ethnic groups of Mizoram, North East India	Flowers	Vegetable; Decoction	Used to eat as a vegetable. Used to treat fever.	⁴¹
- Arunachal Pradesh	Flower Buds	Vegetable; Cooked	Used as a vegetable. Used to treat diabetes.	^27,41
	Leaves	Vegetable; Cooked	Used as a vegetable.	⁴⁶
Laos- The Kry Ethnic Group	Stems; Roots	Roast- Decoction- Drink	The first and second phases of postpartum recovery include peritoneal healing, retraction of the uterus, expulsion of lochia, abdominal pain, physical recovery, and lactagogue.	¹¹
Bangladesh- Chittagong Hill Tracts	Roots	Paste	Applied to the swollen and painful penis of children.	²⁸
Bangladesh- Chittagong Hill Tracts	Roots; Fruits	Paste	Applied to snake bites.	²⁸
Indonesia	Bark	Decoction	Used for urinary tract problems.	³⁹
Malaysia	Leaves; Stalks; Roots		Treatment of bone fractures and skin-related diseases.	^21,22
Thailand- The Hmong Ethnic Group- Din Kao-Karen; Mae Tum-Karen- The Pwo people	Flowers; Buds/Shoots	Vegetable; Cooked	Cooked in many popular dishes.	⁴⁰
	Young Flowers; Young Shoots	Vegetable; Boiled; Cooked	Boiled or cooked in many dishes.	^43,44
	Flowers; Seeds	Decoction	Used for nutritional supplementation.	³⁰
China- Guizhou; Guangxi; Yunnan	Young Stems; Young Leaves	Vegetable; Boiled; Cooked	Boiled or cooked in many dishes.	⁴⁷
Myanmar- The Palaung tribe, Kyaukme township	Flowers; Buds/Shoots	Vegetable; Cooked	Used as vegetable.	⁴²

Phytochemical Compositions

Recently, studies have focused mainly on the chemical composition of two species, namely T. sundaica¹⁹ and T. palmata.^{23,29,48‐50} According to the literature survey, no studies have been conducted on other Trevesisa species. Thus, the literature survey highlighted the occurrence of different types of phytocompounds in parts of T. sundaica¹⁹ and T. palmata.^{23,29,48‐50} More recently, the interest of phytochemists has focused on isolating specific biologically active compounds of T. palmata and T. sundaica. Phytochemical constituents isolated from different parts, plant origin (related to geography, climate, soil, region, etc), and extraction and identification methods can also lead to various phytochemical compounds.^{19,23,29,48‐50} Currently, this work has gathered literature reporting on the phytochemical composition of T. palmata and T. sundaica. The investigation results show several types of phytochemicals, including triterpenoids,⁵¹ phenolics, flavonoids,^52,53 etc In addition, previous preliminary phytochemical studies have also demonstrated that phytoconstituents such as saponins, alkaloids, flavonoids, tannins, reducing sugars, amino acids, and proteins are present in the methanolic extract of T. palmata leaves.^28,54 The details of these chemical components are summarized and discussed in this study.

Triterpenoid Saponins

Oleanane-type Triterpenoid Saponins

In 1997, the dried leaves and flowers of T. sundaica (collected from Italy) were extracted successively with petroleum ether and methanol, and the obtained methanolic extract was divided into aqueous (H₂O) and butanol (n-BuOH) soluble fractions by liquid-liquid distribution.¹⁹ Further purification over Sephadex LH-20 column chromatography (CC) and thin layer chromatography (TLC) followed by droplet countercurrent chromatography (DCCC) (n-BuOH-EtOH-AcOH-H₂O (8:4:2:1)), were separated by reverse-phase high-performance liquid chromatography (RP-HPLC), resulted in the isolation of six new bisdesmosidic saponin compounds (ie, triterpene saponins), namely 3β-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosylolean-12-en-28-oic acid β-D-glucopyranosyl ester (1); 3β-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosylolean-12-en-28-oic acid β-D-glucopyranosyl ester (2); 3β-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosyl]hederagenin 28-O-β-D-glucopyranosyl ester (3); 3β-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosylhederagenin 28-O-β-D-glucopyranosyl ester (4); 3β-O-α-L-rhamnopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosylolean-12-en-28-oic acid β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl ester (5); and 3β-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→6)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranosyl-olean-12-en-28-oic acid β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl ester (6). Moreover, several known triterpenoid saponins were also isolated from T. sundaica aerial parts, namely 3β-O-β-D-galactopyranosyl-(1→3)-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranosylolean-12-en-28-oic acid (7); 3β-O-β-D-xylopyranosyl-(1→3)-β-D-glucopyranosyl-(1→3)-[β-D-xylopyranosyl-(1→2)]-α-L-arabinopyranosylolean-12-en-28-oic acid β-D-glucopyranosyl ester (8); 3β-O-β-D-glucopyranosyl-(1→3)-[β-D-xylopyranosyl-(1→2)]-β-D-galactopyranosyloleanolic acid 28-O-β-D-glucopyranosyl ester (9); 3β-O-β-D-glucopyranosyl-(1→2)-[β-D-galactopyranosyl-(1→3)]-β-D-glucopyranosyloleanolic acid (10).¹⁹ The chemical structures of these compounds were elucidated based on 1-D and 2-D NMR spectra and mass spectrometric (MS) analyses.¹⁹

In 2000, De Tommasi and colleagues²³ were isolated and identified eight triterpene saponin compounds from the aerial parts of T. palmata collected from Italy, named 3β-O-[β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]olean-12-ene-28-O-[β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl (1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (11); 3β-O-[β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]olean-12-ene 28-O-[α-L-rhamnopyranosyl (1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (12); 3β-O-[β-D-quinovopyranosyl-(1→2)-α-L-arabinopyranosyl]olean-12-ene 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (13); 3β-O-[β-D-quinovopyranosyl- (1→2)-α-L-arabinopyranosyl]hederagenin 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (14); 3β-O-[β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]echinocystic acid 28-O-[α-L-rhamnopyranosyl (1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (15); 3β-O-[β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]16α, 23 dihydroxyolean-12-ene 28-O-{-α-L-rhamnopyranosyl (1→4)-[β-D-quinovopyranosyl-(1→2)]-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl]}ester (16); hederasaponin B or eleutheroside M (17); and macranthoside A (18)).²³ In addition, based on the basic hydrolysis reaction of compounds 12-17 (reaction conditions: 0.5 M KOH (1.0 mL); 110 °C/ for 2 h; pH 7), the mixture was then extracted with n-BuOH; the organic phase was evaporated to dryness, dissolved in CD₃OD, and analyzed by NMR spectroscopy.²³ The hydrolysis of saponins 12-17 yields prosapogenins 12a (namely, 3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl olean-12-en-28-oic acid (19)); 13a (namely, 3-O-β-D-quinovopyranosyl-(1→2)-α-L-arabinopyranosyl olean-12-en-28-oic acid (20)); 14a (namely, hederagenin-3-O-β-D-quinovopyranosyl-(1→2)-α-L-arabinopyranoside (21)); 15a (namely, 3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl echinocistyc acid (22)); 16a (namely, caulophyllogenin-3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosidic (23)), and 17a (namely, 3-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl oleanolic acid (24)), respectively.²³

From the methanolic extract of T. palmata aerial parts collected in Vietnam, three oleanane-type triterpene glycosides, namely hederagenin-3-O-β-D-glucopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside (25), macranthoside A (18), and α-hederin (26) were identified.⁴⁸

Lupane and Ursane-types Triterpenoid Saponins

In 2018, Kim et al⁴⁸ conducted extensive research to determine the ursane-type triterpenoid saponins. As a result, ilekudinoside D (27) and 3-O-α-L-arabinopyranosyl asiatic acid (28) were isolated from the methanolic extract of T. palmata aerial parts.⁴⁸ The structure of compound (28) isolated from T. palmata has not been reported previously. Structurally, compound (28) differed from compound (27) only by the absence of the glucopyranosyl unit linked at C-28 of the aglycon.⁴⁸

In 2019, three new triterpene saponins, including two lupane-types (namely, trevepaloside A (29) and trevepaloside B (30)), and one ursane-type (namely, trevepaloside C (31)) were isolated from T. palmata leaves.⁴⁹ Their structures were determined by 1D and 2D NMR spectra and HR-ESI-MS analysis.⁴⁹

Acetylated Saponins

Recently, two new acetylated saponin compounds, including acetyltrevesiasaponins A (32) and B (33), were isolated from the methanolic extract of T. palmata leaves.²⁹ The analysis of HR-ESI-MS and NMR spectra elucidated their chemical structures.²⁹ Additionally, acetyltrevesiasaponin B (33) is also hydrolyzed by the alkaline hydrolysis method, and then the product is purified on reversed-phase C-18 column chromatography and eluted with one mixed solution of acetone and water (2/3, v/v) to obtain prosapogenin 29a (namely, macranthoside A (18)).²⁹

Flavonoid and Phenolic Compounds

The HPLC analysis has indicated the occurrence of six prominent peaks, including gallic acid (34), catechin (35), caffeic acid (36), rutin (37), quercetin (38), and naringenin (39), respectively.⁵⁰ In particular, caffeic acid (195.48 mg/g) and catechin (165.23 mg/g) were detected as the major constituents, followed by rutin (36.10 mg/g), gallic acid (30.88 mg/g), quercetin (11.35 mg/g), and naringenin (2.99 mg/g) as the other polyphenolic compounds from the ethyl acetate extract of T. palmata leaves.⁵⁰

Table 2 and Figures 1–5 summarize and present a list of thirty-three phytocompounds isolated from different parts of Trevesia species and their six hydrolyzed compounds.

Figure 1.

The Structures of Oleanane-type Triterpenoid Saponins from T. sundaica (Drawn from ChemDraw Professional 16.0).

Figure 2.

The Structures of Oleanane-type Triterpenoid Saponins (Compounds 11-26) and Acetylated Saponin (Compound 33) from T. palmata (Drawn from ChemDraw Professional 16.0).

Figure 3.

The Structures of Ursane-type Triterpenoid Saponins (Compounds 27, 28, 31), Lupane-type Triterpenoid Saponins (Compounds 29, 30), and Acetylated Saponin (Compound 32) from T. palmata (Drawn from ChemDraw Professional 16.0).

Figure 4.

The Structures of Flavonoids (Compounds 35, 37-39) and other Phenolics (Compounds 34, 36) from T. palmata (Drawn from ChemDraw Professional 16.0).

Figure 5.

The Alkaline Hydrolytic Procedure of Saponins (Compounds 12-17, 33) from T. palmata (Drawn from ChemDraw Professional 16.0).

Table 2.

Phytocompounds Isolated from Multiple Parts of T. palmata and T. sundaica.

Classification	Compounds	Parts/sources	Methods	References
Oleanane-type triterpenoid saponins	Compound (1)	T. sundaica leaves	CC, Sephadex LH-20 CC, DCCC	¹⁹
	Compound (2)	T. sundaica leaves	CC, Sephadex LH-20 CC, DCCC
	Compound (3)	T. sundaica flowers	CC, RP-HPLC
	Compound (4)	T. sundaica flowers	CC, RP-HPLC
	Compound (5)	T. sundaica leaves	CC, Sephadex LH-20 CC, DCCC
	Compound (6)	T. sundaica leaves
	Compound (7)	T. sundaica aerial parts
	Compound (8)
	Compound (9)
	Compound (10)
	Compound (11)	T. palmata aerial parts		²³
	Compound (12)
	Compound (13)
	Compound (14)		Sephadex LH-20 CC, DCCC
	Compound (15)		CC, Sephadex LH-20 CC, DCCC
	Compound (16)
	Compound (17)
	Compound (19)	Compound (12)	Alkaline hydrolysis
	Compound (20)	Compound (13)
	Compound (21)	Compound (14)
	Compound (22)	Compound (15)
	Compound (23)	Compound (16)
	Compound (24)	Compound (17)
	Compound (18)	T. palmata aerial parts	CC, Sephadex LH-20 CC, DCCC.	²³
		T. palmata aerial parts	CC, Diaion HP-20, Sephadex LH-20 CC	⁴⁸
		Compound (33)	Alkaline hydrolysis	²⁹
	Compound (25)	T. palmata aerial parts	CC, Diaion HP-20, Sephadex LH-20 CC	⁴⁸
	Compound (26)		CC, Sephadex LH-20 CC
Ursane-type triterpenoid saponins	Compound (27)		CC, Sephadex LH-20 CC, prep-HPLC
	Compound (28)		CC, Sephadex LH-20 CC, prep-HPLC
	Compound (29)	T. palmata leaves	Diaion HP-20, CC	⁴⁹
Lupane-type triterpenoid saponins	Compound (30)
Lupane-type triterpenoid saponins	Compound (31)
Acetylated saponins	Compound (32)			²⁹
Acetylated saponins	Compound (33)			²⁹
Flavonoids and other phenolics	Compound (34)		HPLC	⁵⁰
	Compound (35)
	Compound (36)
	Compound (37)
	Compound (38)
	Compound (39)

Chemotaxonomic Significance

In the present work, a total of thirty-nine phytocompounds, including twenty-six oleanane-type triterpenoid saponins (1-10 for T. sundaica and 11-26 for T. palmata), three ursane-type triterpenoid saponins (27, 28, 31), two lupane-type triterpenoid saponins (29, 30), two acetylated saponins (32, 33), four flavonoids (35, 37-39), and two phenolics (34, 36) were isolated from T. palmata. Among these, saponins could be considered as typical secondary metabolites of T. palmata and T. sundaica. Notably, various phytocompounds, specifically compounds (1-6) isolated from T. sundaica and compounds (11-16), (28-33) isolated from T. palmata, have been recorded as previously unreported novel secondary metabolites. It should be noted that compounds (28-33) have been first identified from the genus Trevesia.

To our knowledge, compounds (1-6) were only found in T. sundaica but have not been observed in other Trevesia species. Known compounds from T. sundaica, specifically compound (7) isolated from Schefflera divaricata (Araliaceae),⁵⁵ compounds (8-9) isolated from Aralia decaisneana (Syn., Heptapleurum subdivaricatum) (Araliaceae)⁵⁶ and compound (10) isolated from Ilex dumosa (Aquifoliaceae),⁵⁷ have also been reported previously. Compound (17) isolated from T. palmata was previously obtained from Hedera helix,⁵⁸ Acanthopanax senticosus (Syn., Eleutherococcus senticosus) (Araliaceae),^59,60 and Anemone flaccida (Syn., Anemonastrum flaccidum) (Ranunculaceae).⁶¹ This was the first recorded species of the genus Trevesia. Therefore, the biosynthetic processes may be similar in T. palmata and the above-mentioned plants. Moreover, compound (18) isolated from the Vietnamese T. palmata sample was observed in T. palmata from Italy. Compound (18) was also found in several other species, such as Aralia elata (Araliaceae),⁶² Cephalaria aytachii,⁶³ Lonicera japonica, L. hypoglauca, L. similes, L. confusa, L. macranthoides (Caprifoliaceae),⁶⁴ Chytranthus macrobotrys, Radlkofera calodendron (Sapindaceae).⁶⁵

Compound (26) was considered one of the most common triterpene glycosides from the genus Hedera, including H. canariensis, H. caucasigena, H. colchica, H. helix, H. nepalensis, H. pastuchovii, H. rhombea, H. scotica, and H. taurica,⁶⁶ which was also found in T. palmata. In previous studies, compound (27) is a major phytocompound of triterpenoid saponin derived from Ilex kudingcha⁶⁷ and I. asprella.⁶⁸

In the genus Trevesia, four flavonoids and two phenolics were only purified from T. palmata, being caffeic acid (36) and catechin (35) predominant, followed by rutin (37), gallic acid (34), quercetin (38), and naringenin (39). These compounds (34-39) have been reported for the first time from this plant. Compound (36) is one of the hydroxycinnamate and phenylpropanoid metabolites more widely distributed in the plant kingdom with diverse biological activities, such as antioxidant, antimicrobial, anti-aging, and cytotoxicity properties.⁶⁹ In the past, compound (36) has been found in several genera of the same family, such as Aralia (eg, A. nudicaulis⁷⁰ and A. spinosa⁷¹), and Schefflera (eg, S. leucantha),⁷² etc In contrast, compound (38) was previously reported from A. hiepina,⁷³ A. dasyphylla,⁷⁴ etc Likewise, compounds (34-38) have been discovered from several Hedera species (eg, H. helix, H. nepalensis, H. rhombea, and H. colchica)⁶⁶ and Aralia species (eg, A. elata).⁷⁵ Moreover, compounds (36, 38) were also isolated from Dendropanax dentiger (Araliaceae),⁷⁶ while compounds (36, 37) were the major phenolic compounds isolated from Acanthopanax senticosus (Araliaceae).⁷⁷ So far, the compound (39) was reported only in the genus Trevesia (eg, T. palmata),⁵⁰ Panax (eg, P. ginseng),⁷⁸ and Acanthopanax (eg, A. koreanum⁷⁹ and A. senticosus⁸⁰) representatives of the Araliaceae family.

Recent explorations of these phytocompounds have facilitated a broadened understanding of the phytochemical diversity of the genus Trevesia. They may act as potential chemotaxonomic biomarkers or fingerprints to differentiate T. sundaica and T. palmata from other species of the Araliaceae family. Chemotaxonomic investigations have revealed that the genus Trevesia may be closely related to the genera Aralia, Acanthopanax, and Hedera. As can be noticed, compounds (28-33) were first identified from the genus Trevesia. Therefore, it could be concluded that these metabolites are suitable for distinguishing T. palmata and other genera from the Araliaceae family, while compounds (1-6) were previously only obtained from T. sundaica. This phytochemical study has enriched the knowledge of the phytochemical diversity of the genus Trevesia, especially the T. palmata species.

Pharmacological Activities

So far, only reports on T. palmata have been investigated regarding pharmacological effects; therefore, this work discusses only T. palmata. Scientific studies worldwide have revealed several insights into the pharmacological effects of T. palmata. Crude extracts and pure phytocompounds from different parts of T. palmata have shown significant antiproliferative,²³ anti-cancer,^50,81 antioxidant,^28,50,52 anti-inflammatory,^{28,29,49,50,81} antidiabetic,⁵⁴ antimicrobial,^28,48 antiviral,⁸² and analgesic effects.⁵⁴ The pharmacological properties of Trevesia palmata could be correlated with the significant phytocomponents, which exhibit various pharmacological effects with numerous mechanism insights. This section highlights the pharmacological effects of the active phytocompounds in the T. palmata plant (Table 3).

Table 3.

Pharmacological Effects of Various Extracts and Isolated Compounds from T. palmata.

Extracts/ compounds	Models	Effects	Refs
Antiproliferative and anticancer effects
Compound (11)	In vitro: Antiproliferative effect.	J774 cell line: IC₅₀ = 0.18 μM; HEK-293 cell line: IC₅₀ = 0.17 μM	²³
Compound (12)		HEK-293 cell line: IC₅₀ = 0.52 μM; WEHI-164 cell line: IC₅₀ = 1.8 μM
Compound (13)		J774 cell line: IC₅₀ = 0.1 μM; HEK-293 cell line: IC₅₀ = 0.2 μM
Compound (14)		J774 cell line: IC₅₀ = 0.46 μM; WEHI-164 cell line: IC₅₀ = 1.9 μM
Compound (15)		J774 cell line: IC₅₀ = 0.11 μM; HEK-293 cell line: IC₅₀ = 0.15 μM; WEHI-164 cell line: IC₅₀ = 0.24 μM
Compound (16)		J774 cell line: IC₅₀ = 0.1 μM; HEK-293 cell line: IC₅₀ = 0.32 μM; WEHI-164 cell line: IC₅₀ = 0.26 μM
Compound (17)		J774 cell line: IC₅₀ = 0.06 μM; WEHI-164 cell line: IC₅₀ = 0.6 μM
Compound (22)		J774 cell line: IC₅₀ = 0.19 μM
Compound (23)		J774 cell line: IC₅₀ = 0.07 μM
6-MP (positive control)		J774 cell line: IC₅₀ = 0.003 μM; HEK-293 cell line: IC₅₀ = 0.007 μM; WEHI-164 cell line: IC₅₀ = 0.017 μM
Methanolic extract from leaves	In vitro: Anticancer effect.	% inhibition of A549-lung cancer: 64.51%% inhibition of MCF-7-breast cancer: 26.31%% inhibition of HL60-hematologic malignancy: 8.32%% inhibition of SNU-1-stomach cancer: 78.88%% inhibition of HT-1080-fibrosarcoma: 64.3%	⁸¹
Ethyl acetate extract from leaves	In vitro: Anticancer effect.	The rate of apoptotic cells in MG63 cancer cells:- At concentrations of 10 μg/mL: 27.68%- At concentrations of 25 μg/mL: 45.2%- At concentrations of 50 μg/mL: 47.45%	⁵⁰
Antioxidant effect (The leaf extracts)
70% Ethyl alcohol extract	In vitro	DPPH: EC₅₀ = 9.375 (µg); FRAP: 47.524 ± 0.043 (mg/g extract)TPC: 10.836 ± 0.019 mg/g extract	⁵²
Positive control:- BHT- Trolox	In vitro	- DPPH: BHT = 14.7579 (µg/mg extract)- FRAP: Trolox = 2.625 ± 0.033 (mg/g extract)	⁵²
Methanolic extract	In vitro	DPPH: IC₅₀ = 524.64 ± 25.01 (μg/mL)Reduced Mo-VI to Mo-V: 394.5 ± 7.8 (AAE/g extract)	²⁸
Positive control:- BHT- Trolox	In vitro	DPPH assay:- Ascorbic acid: 26.28 ± 4.36 μg/mL- BHT: 59.28 ± 2.02 μg/mL	²⁸
n-Hexane extract	In vitro	DPPH: IC₅₀ = 651.10 ± 12.43 (μg/mL)ABTS: 49.17 ± 3.06 (mM TE/g extract)	⁵⁰
Chloroform extract		DPPH: IC₅₀ = 58.09 ± 4.72 (μg/mL)ABTS: 91.50 ± 3.04 (mM TE/g extract)
Ethyl acetate extract		DPPH: IC₅₀ = 4.72 ± 0.81 (μg/mL)ABTS: 242.33 ± 6.81 (mM TE/g extract)
Methanolic extract		DPPH: IC₅₀ = 5.95 ± 0.16 (μg/mL)ABTS: 57.83 ± 3.33 (mM TE/g extract)
Aqueous extract		DPPH: IC₅₀ = 13.86 ± 2.54 (μg/mL)ABTS: 126.5 ± 9.85 (mM TE/g extract)
Positive control:- Rutin- BHT		- Rutin: DPPH: IC₅₀ = 8.95 ± 2.54 (μg/mL); ABTS: 74.32 ± 5.66 (mM TE/g extract)- BHT: DPPH: IC₅₀ = 14.54 ± 0.67 (μg/mL); ABTS: 52.78 ± 4.35 (mM TE/g extract)
Anti-inflammatory effect
Methanolic extract from leaves (At concentrations of 1000 µg/mL)	In vitro: Antiarthritic assay	% inhibition of protein denaturation (bovine serum albumin): 89.24 ± 0.6584%Standard diclofenac sodium: 96.77 ± 1.1404% (P < .01)	¹⁸
Methanolic extract from leaves (At concentrations: 250-1000 μg/mL)	In vitro: Human red blood cell membrane stability	IC₅₀ = 491.26 μg/mL (R² = 0.989)	²⁸
Compound (32)	In vitro: NO production in LPS-activated BV2 cells	IC₅₀ > 100 μM	²⁹
Compound (33)	In vitro: NO production in LPS-activated BV2 cells	IC₅₀ = 40.7 μM
Compound (18)	In vitro: Cytotoxicity effect against BV2 cells	At a concentration of 20 μM, 81.7% of dead cells
Methanolic extract from leaves	In vitro: NO production from Raw264.7 cells	% inhibition: 90.47%.	⁸¹
Compounds (29-31)	In vitro: NO production in LPS-activated BV2 cells	At a concentration of 100 μM:- Compound (29): % inhibition of 17.4 ± 1.8%- Compound (30): % inhibition of 33.1 ± 1.2%- Compound (31): % inhibition of 11.7 ± 2.2%	⁴⁹
Positive control: L-NMMA	In vitro: NO production in LPS-activated BV2 cells	At concentrations of 20 µM: % inhibition of 58.8 ± 1.5%	⁴⁹
The leaf extracts: n-Hexane extract	In vitro: Anti-inflammatory assay (membrane stabilization method); Anti-arthritic assay (inhibition of proteolysis method)	- % anti-inflammatory inhibition: 23.4 ± 2.96%- % arthritic inhibition: 8.20 ± 0.27%	⁵⁰
Chloroform extract		- % anti-inflammatory inhibition: 33.16 ± 1.77%- % arthritic inhibition: 17.90 ± 1.73%
Ethyl acetate extract		- % anti-inflammatory inhibition: 40.04 ± 3.62%- % arthritic inhibition: 32.40 ± 3.32%
Methanolic extract		- % anti-inflammatory inhibition: 46.43 ± 2.85%- % arthritic inhibition: 27.60 ± 1.42%
Aqueous extract		- % anti-inflammatory inhibition: 39.32 ± 2.16%- % arthritic inhibition: 29.30 ± 1.75%
Positive control: Diclofenac sodium		- % anti-inflammatory inhibition: 27.42 ± 4.82%- % arthritic inhibition: 24.15 ± 2.17%
Ethyl acetate extract from leaves (TPEA)	In vivo: (CFA)-induced rats.Leflunomide (STD): 10 mg/kgTPEA extract (TPLD: 250 mg/kg; TPHD: 500 mg/kg)	On the 42nd day, the paw diameter of rats (P < .01):- Group I (blank control): 3.93 ± 0.29 mm- Group II (CFA): 9.5 ± 0.098 mm- Group III (CFA + STD): 6.67 ± 0.48 mm- Group IV (CFA + TPLD): 6.97 ± 0.26 mm- Group V (CFA + TPHD): 6.15 ± 0.39 mmOn the 42nd day, the paw thickness of rats:- Group V (CFA + TPHD): 37.43% compared with Group I	⁵⁰
	In vivo: Biochemical parameters to evaluate anti-inflammation (CRP; RF)	On the 42nd day, the C-reactive protein (CRP) levels in rats:- Group I (blank control): 0.35 ± 0.07 mg/dL- Group II (CFA): 0.2 ± 0.01 mg/dL- Group III (CFA + STD): 0.16 ± 0.02 mg/dL- Group IV (CFA + TPLD): 0.22 ± 0.03 mg/dL- Group V (CFA + TPHD): 0.35 ± 0.01 mg/dLOn the 42nd day, the rheumatoid factor (RF) in rats:- Group I (blank control): 0.52 ± 0.08 IU/mL- Group II (CFA): 0.37 ± 0.07 IU/mL- Group III (CFA + STD): 0.41 ± 0.24 IU/mL- Group IV (CFA + TPLD): 0.20 ± 0.02 IU/mL- Group V (CFA + TPHD): 0.34 ± 0.1 IU/mL	⁵⁰
Antidiabetic effect
Methanolic extract from leaves	In vivo: In oral glucose tolerance research in Swiss albino mice	After 120 min, reducing blood glucose levels in rats:- Group I (blank control): 5.48 ± 0.34 mmol/L- Group II (glibenclamide, 10 mg/kg b.w., p.o.): 2.88 ± 0.19 mmol/L; % lowering of blood glucose level 47.4%- Group III (extract,50 mg/kg b.w., p.o.): 5.58 ± 0.32 mmol/L- Group IV (extract, 100 mg/kg b.w., p.o.): 4.50 ± 0.28 mmol/L; % lowering of blood glucose level: 17.9%- Group V (extract, 200 mg/kg b.w., p.o.): 3.94 ± 0.26 mmol/L; % lowering of blood glucose level 28.1%- Group VI (extract, 400 mg/kg b.w., p.o.): 2.88 ± 0.32 mmol/L; % lowering of blood glucose level 47.4%	⁵⁴
Analgesic effect
Methanolic extract from leaves	In vivo: In the acetic acid-induced pain model Swiss albino mice	The mean number of abdominal constriction in rats:- Group I (blank control, 10 mL mg/kg b.w.): 5.4 ± 0.24- Group II (aspirin, 200 mg/kg b.w.): 2.8 ± 0.37; % inhibition of 48.1%- Group III (aspirin, 400 mg/kg b.w.): 2.0 ± 0.32; % inhibition of 63.0%- Group III (extract, 50 mg/kg b.w.): 3.6 ± 0.40; % inhibition of 33.3%- Group IV (extract, 100 mg/kg b.w.): 3.2 ± 0.37; % inhibition of 40.7%- Group V (extract, 200 mg/kg b.w.): 2.8 ± 0.49; % inhibition of 48.1%- Group VI (extract, 400 mg/kg b.w.): 2.4 ± 0.51; % inhibition of 55.6%	⁵⁴
Antimicrobial effects
Methanolic extract from leaves	In vitro: Disc diffusion method	S. aureus and P. aeruginosa: IZ ≈ 8-10 mm	²⁸
Compounds (18, 25-28)	In vitro: Antifungal bioassay	- Compounds (18, 25-28): Alternaria porri, Colletotrichum coccodes, Fusarium oxysporum: IC₅₀ > 256 μg/mL- Compound (27): Botrytis cinerea, Magnaporthe oryzae, Phytophthora infestans: IC₅₀ > 256 μg/mL- Compound (18): Botrytis cinerea (IC₅₀= 24 ± 11 μg/mL), Magnaporthe oryzae (IC₅₀= 5 ± 1 μg/mL), Phytophthora infestans (IC₅₀= 205 ± 26 μg/mL)- Compound (25): Botrytis cinerea (IC₅₀= 34 ± 7 μg/mL), Magnaporthe oryzae (IC₅₀= 4 ± 0 μg/mL), Phytophthora infestans (IC₅₀= 136 ± 13 μg/mL)- Compound (26): Botrytis cinerea (IC₅₀= 44 ± 17 μg/mL), Magnaporthe oryzae (IC₅₀= 2 ± 0 μg/mL), Phytophthora infestans (IC₅₀= 81 ± 33 μg/mL)- Compound (28): Botrytis cinerea (IC₅₀= 35 ± 7 μg/mL), Magnaporthe oryzae (IC₅₀= 5 ± 2 μg/mL), Phytophthora infestans (IC₅₀= 128 ± 0 μg/mL)	⁴⁸
Compound (17)	In silico: Anti- SARS-CoV-2	- The hit of −11 kcal/mol- Interactions with residues Lys417, Leu452, Tyr489, Phe456, and Leu455- Exhibited affinity with a strong bond and hot residue with S-RBD.	⁸²
Thrombolytic effect
The leaf: Methanolic extract	In vitro: Thrombolytic activity via using the clot lysis	% of thrombolysis: 43.298 ± 0.8647%	¹⁸
Ethyl acetate fraction		% of thrombolysis: 44.293 ± 0.5069%
n-Hexane fraction		% of thrombolysis: 44.211 ± 0.7428%
Chloroform fraction		% of thrombolysis: 43.280 ± 0.8724%
Aqueous fraction		% of thrombolysis: 40.332 ± 0.2913%

Antiproliferative and Anticancer Activities

Cancer arises from uncontrolled cellular proliferation. Therefore, antiproliferative activities, cell cycle control, and apoptosis are pivotal in antitumor activity.⁸³ Extracts from T. palmata contain saponins and ethyl acetate, which provide anti-proliferative²³ and anti-osteosarcoma effects.⁵⁰ This suggests that T. palmata has potential anti-cancer properties.

Antiproliferative Activity

Although no document was found in the past decade that any part of T. palmata was used to treat cancer in folk medicine, the isolated phytocompounds from T. palmata aerial parts exhibited their antiproliferative activities in recent investigations. De Tommasi et al (2000)²³ showed triterpenoid saponins isolated from the methanolic extract of T. palmata aerial parts to be antiproliferative to murine monocyte-macrophage (J774), human epithelial kidney (HEK-293), and murine fibrosarcoma (WEHI-164) cell lines. All eight of the isolated saponins and their pro-sapogenins (ie, 15a (compound 22)-16a (compound 23), prepared by alkaline hydrolysis) had anti-proliferative activities against the three cell lines.²³ The IC₅₀ values (μM) ranged from 0.06 to 0.46 μM against J774 cells, 0.15 to 0.52 μM against HEK-293 cells, and 0.26 to 1.0 μM against WEHI-164 cell lines. Compounds (17) and (15) had the most potent antiproliferative activity against J774 and (HEK-293, WEHI-164) cell lines, respectively. Specifically, the IC₅₀ values of compounds (11), (13), (14), (15), (16), (17), (22), and (23) against J774 cell lines are 0.18, 0.1, 0.46, 0.11, 0.1, 0.06, 0.19, and 0.07 μM, respectively. The IC₅₀ values of compounds (11), (12), (13), (15), and (16) against HEK-293 cell lines are 0.17, 0.52, 0.2, 0.15, and 0.32 μM, respectively. Similarly, the IC₅₀ values of compounds (12), (14), (15), (16), and (17) against WEHI-164 cell lines are 1.8, 1.9, 0.24, 0.26, and 0.6 μM, respectively. However, these isolated compounds showed weaker anti-proliferative effects than the positive control (6-mercaptopurine) with IC₅₀ values (μM) for J774, HEK-293, and WEHI-164 cell lines being 0.003, 0.007, and 0.017 μM, respectively.²³

Regarding the triterpenoid saponins structural relationship and anti-proliferative effects (SAR), the results of the investigation showed that the role of the hydroxyl group at position C-16 and the esterified saccharide chain at position C-28 in triterpenoid saponins structure is vital in mediating antiproliferative activity. However, the saccharide chain at position C-3 does not appear to be essential for cytotoxicity.^23,51

Anticancer Activity

A recent study has explored the anti-osteosarcoma property of T. palmata leaves.⁵⁰ This study conducted in India demonstrated the potent anti-osteosarcoma effect of this plant. Flow cytometry analysis examined the cell proliferation and cell cycle arrest in MG63 cancer cells treated with T. palmata extract. The rate of apoptotic cells increased with an increase in treatment doses (10 μg/mL (27.68%), 25 μg/mL (45.2%), and 50 μg/mL (47.45%)) resulting from Annexin V binding. Moreover, at doses of 10, 25, and 50 μg/mL, the sample showed a significant increase in cell cycle arrest.⁵⁰

In normal cells, the cell cycle comprises G1-S-G2-M phases with an inactive or quiescent G₀ state.⁸⁴ These four stages are also present in cancer cells; however, the regulation of the different phases may be altered.⁸⁵ Apoptosis is a programmed and physiological form of cell death and is the primary mechanism of cell death in cancer therapies.^86,87 Compared to controls not treated with plant extracts, more cells accumulated in all cell cycle phases and a higher proportion of cells in the sub-G₀/G₁ phase. This indicates that the apoptotic population has increased. In parallel with the above phase, the G₂/M phase and S phase of the cell cycle decrease, indicating reduced DNA replication. Cancer development is also associated with cell cycle down-regulation in the G₁/S and G₂/M phases and biochemical abnormalities as reported in previous studies.^50,88 According to the study, cell cycle arrest is critical in preventing malignancies. Thus, the ethyl acetate extract from T. palmata leaves promotes apoptosis and anti-metastasis in MG63 cells.⁵⁰ In other words, T. palmata leaf extract induced apoptosis and inhibited invasion in MG63 cells, possibly through inhibition of the G₁/S and G₂/M checkpoints of the cell cycle (Figure 6).

Figure 6.

Schematic Diagram of T. Palmata Leaf Extract-induced cell Cycle Arrest in MG63 cells (Created by Tran Van Chen).

In an in vitro study by Changyoung et al (2019),⁸¹ the methanolic extract of T. palmata leaves (syn., T. sphaerocarpa) was shown to have anticancer activity against cell lines, including A549-lung cancer, MCF-7-breast cancer, HL60-hematologic malignancy, SNU-1-stomach cancer, and HT-1080-fibrosarcoma, with a percent inhibition of 64.51%, 26.31%, 8.32%, 78.88%, and 64.3%, respectively.⁸¹ These findings can be attributed to the secondary metabolite component within the plant extract.

Antioxidant Activity

Adverse conditions such as extreme temperatures, drought, and nutrient deficiency can lead to the accumulation of high concentrations of reactive oxygen species (ROS), resulting in oxidative stress. To combat this, cells have developed a complex antioxidant system comprising enzymatic and non-enzymatic elements. Among the non-enzymatic components, plant secondary metabolites—specifically phenolic compounds—play a crucial role in defending against oxidative stress. These compounds act as antioxidants and are associated with preventing cardiovascular diseases and cancer in humans.⁸⁹ Effectively extracting and accurately assessing antioxidants from medicinal plants are essential for identifying potential antioxidant sources. This process is vital for promoting their application in functional foods, pharmaceuticals, and food additives.⁹⁰ Therefore, studying the antioxidant activity of extracts from different plant species could help establish their value as sources of new antioxidant compounds.

Source natural plants used in traditional medicine have antioxidant activities through different mechanisms, including 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, ferric-reducing power (FRAP) assay, ABTS radical scavenging assay, superoxide anion scavenging assay, and hydroxyl radical scavenging assay.⁹¹ Based on the medicinal plants used in Northern Thailand as postpartum herbal bath recipes by the Mien (Yao) community, T. palmata was tested to determine the antioxidant effect.⁵² Panyaphu and colleagues evaluated the antioxidant potential of 70% ethyl alcohol extract of T. palmata. Scavenging activities on DPPH radical (EC₅₀) and ferric-reducing antioxidant power (mg/g extract) were found to be 9.375 (µg) and 47.524 ± 0.043 (mg/g extract), respectively, while BHT and Trolox equivalents were 14.7579 (µg/mg extract) and 2.625 ± 0.033 (mg/g extract). T. palmata extract showed the content of total phenolic compounds as expressed as gallic acid equivalents (10.836 ± 0.019 mg/g extract).⁵²

Another study showed that the methanolic extract obtained from the leaves of T. palmata demonstrated very weak DPPH radical scavenging capacity with IC₅₀ values of 524.64 ± 25.01 μg/mL compared to standards (ascorbic acid of 26.28 ± 4.36 μg/mL and BHT of 59.28 ± 2.02 μg/mL). However, this plant extract reduced molybdenum (Mo-VI) to molybdenum (Mo-V) with a capacity of 394.5 ± 7.8 (AAE/g extract). This result reveals that T. palmata extract showed good total antioxidant capacity, from which it can be inferred that the good total antioxidant capacity of the methanolic extract may be due to the presence of alkaloids and flavonoids.²⁸

Recently, the free radical scavenging properties of different extracts from T. palmata leaves were determined by DPPH and ABTS radical scavenging assays via a study by Manoharan et al (2023).⁵⁰ As a result, n-hexane, chloroform, ethyl acetate, methanol, and aqueous extracts derived from T. palmata leaves significantly scavenged DPPH and ABTS free radicals. The IC₅₀ values for the n-hexane, chloroform, ethyl acetate, methanol, and aqueous extracts were determined to be 651.10 ± 12.43, 58.09 ± 4.72, 4.72 ± 0.81, 5.95 ± 0.16, and 13.86 ± 2.54 µg/mL, respectively. The ability to scavenge ABTS free radicals of the n-hexane, chloroform, ethyl acetate, methanol, and aqueous extracts were 49.17 ± 3.06, 91.50 ± 3.04, 242.33 ± 6.81, 57.83 ± 3.33, and 126.5 ± 9.85 (mM TE/g extract), respectively. Rutin (IC₅₀ = 8.95 ± 2.54 µg/mL for DPPH quenching capacity and 74.32 ± 5.66 mM TE/g extract for ABTS scavenging capacity) and BHT (IC₅₀ = 14.54 ± 0.67 µg/mL for DPPH quenching capacity and 52.78 ± 4.35 mM TE/g extract for ABTS scavenging capacity) were used as control positives in this study.⁵⁰ Overall, polar and semipolar solvent-extracted T. palmata leaves were more likely to exhibit moderate to strong antioxidant activity at concentrations varying from 4.72 to 58.09 µg/mL than nonpolar extracts (IC₅₀ = 651.1 µg/mL).⁵⁰

Anti-inflammatory Activity

Inflammation is the immune system's response to harmful stimuli such as pathogens, damaged cells, toxic substances, or radiation, aiming to eliminate these threats and initiate the healing process.^92,93 The main mechanisms involved in immune regulation include phagocytosis and the release of cytokines. Activated macrophages play a role in delivering antigens, resisting infections, and controlling inflammations.⁹⁴ It is a vital defense mechanism for maintaining health.^92‐94 However, if acute inflammation is not adequately controlled, it can become chronic and contribute to various inflammatory diseases.^92,93 Moreover, chronic local inflammation is associated with tumor growth, promoting tumor initiation and progression at the primary site and facilitating tumor dissemination and metastasis.⁸⁷ Therefore, there is a need to investigate potential compounds and develop new therapeutic agents to treat and management of treating and manage inflammation.⁹⁵

The investigation of medicinal herbs with anti-inflammatory activities is essential. Depending on the various experimental models employed, the extracts of T. palmata leaves contained unique anti-inflammatory activities. In the previous study for an in vitro antiarthritic assay, the methanolic extract of T. palmata leaves (1000 µg/mL) showed a mean inhibition of protein denaturation (bovine serum albumin) of 89.24 ± 0.6584%, compared to standard diclofenac sodium (1000 µg/mL) of 96.77 ± 1.1404% (P < .01). This study revealed that the extract of T. palmata had significant antiarthritic activity.¹⁸

In a study by Thao and colleagues (2018),²⁹ new acetylated saponin compounds, namely acetyltrevesiasaponin A (32), acetyltrevesiasaponin B (33), and prosapogenin 33a (18), separated from the leaves of T. palmata, were evaluated for their effect on nitric oxide (NO) production in LPS-activated BV2 cells. As a result of this study, compound (32) did not affect NO production with an IC₅₀ > 100 μM. In contrast, compound (33) exhibited weak inhibitory activity with an IC₅₀ value of 40.7 μM. However, compound (18) showed a cytotoxicity effect against BV2 cells. In other words, compound (18) produced 81.7% of dead cells at a concentration of only 20 μM.²⁹

Changyoung and colleagues (2019)⁸¹ reported that the methanolic extract of T. palmata leaves (syn., T. sphaerocarpa) collected from Quang Tri (Vietnam) has remarkable anti-inflammatory effects, with a percentage inhibition of NO production from Raw264.7 cells of 90.47%.⁸¹ According to a study, three new triterpene saponins, namely trevepaloside A (29), trevepaloside B (30), and trevepaloside C (31) isolated from T. palmata leaves, were also assessed via the nitric oxide assay. At a concentration of 100 μM, compounds (29), (30), and (31) weakly inhibited NO production in LPS-activated BV2 cells with inhibitory rates of 17.4 ± 1.8%, 33.1 ± 1.2%, and 11.7 ± 2.2%, respectively. Compared to the positive control, NG-Monomethyl-L-Arginine (L-NMMA, 20 mM) revealed inhibiting activity at 58.8 ± 1.5%. Thus, all the trevepalosides (29-31) exhibited modest inhibitory activity on nitric oxide production.⁴⁹ In another assay, human red blood cell membrane stability was investigated to establish the mechanism of the anti-inflammatory effect of the methanolic extract from T. palmata leaves. The study results showed that T. palmata extract effectively inhibited heat-induced hemolysis at different concentrations (250-1000 μg/mL) of the tested sample, with an IC₅₀ value of 491.26 μg/mL (R² = 0.989).²⁸

In a recent study, Manoharan et al (2023)⁵⁰ investigated the in vitro anti-inflammatory assay by membrane stabilization method and the anti-arthritic assay by inhibiting proteolysis method from the T. palmata leaf extracts. The results demonstrated that the n-hexane, chloroform, ethyl acetate, methanol, and aqueous extracts derived from the leaves of T. palmata exhibited anti-inflammatory and anti-arthritic activities. The % anti-inflammatory inhibitions for the n-hexane, chloroform, ethyl acetate, methanol, and aqueous extracts were determined to be 23.4 ± 2.96%, 33.16 ± 1.77%, 40.04 ± 3.62%, 46.43 ± 2.85%, and 39.32 ± 2.16%, respectively. Thus, the highest anti-inflammatory capacity was found in the methanolic extract (46.43 ± 2.85%). Similarly, the % arthritic inhibition was highest for ethyl acetate extract (32.40 ± 3.32%), followed by aqueous (29.30 ± 1.75%), methanol (27.60 ± 1.42%), chloroform (17.90 ± 1.73%), and n-hexane (8.20 ± 0.27%) extracts. The diclofenac sodium standard exhibited anti-inflammatory and anti-arthritic activities of 27.42 ± 4.82% and 24.15 ± 2.17%, respectively.⁵⁰

The in vivo anti-inflammatory and anti-arthritic activities of the ethyl acetate extract from T. palmata leaves were determined in a previous study.⁵⁰ Five groups of animals (Groups I, II, III, IV, and V) were designed for the in vivo bioassay. Groups I (blank control), II (CFA), and III (CFA + STD) served as blank, negative, and positive controls, respectively. Groups IV (CFA + TPLD) and V (CFA + TPHD) received ethyl acetate extract at doses of 250 and 500 mg/kg body weight (p.o.), respectively. Regarding paw diameter measurement, Complete Freund's Adjuvant (CFA)-induced rats were utilized to evaluate the therapeutic properties of treatment with the ethyl acetate extract from T. palmata leaves. Compared with group II (CFA, 9.5 ± 0.098 mm on the 42nd day), the ethyl acetate extract reduced the mean diameter of the rat paw in the CFA-induced inflammation on the 28th, 35th, and 42nd days after treatment. The results showed that ethyl acetate leaf extract had a significant dose-dependent anti-inflammatory effect against CFA-induced inflammation. On the 42nd day, the extract suppressed paw diameter by 6.97 ± 0.26 and 6.15 ± 0.39 mm at dosages of 250 mg/kg (group IV) and 500 mg/kg (group V) (P < .05), respectively. The T. palmata high dose (group V) effectively reduced paw thickness by about 37.43% compared with group I, indicating reduced inflammation. Additionally, the pain test scoring was analyzed through extension and flexion scores, which showed a gradual increase in pain as the inflammation in joints increased. Groups treated with the standard (III) and sample (IV and V) showed decreased pain effects. On the contrary, the mobility and stance scores increased considerably in the standard (III) and sample-treated (IV and V) groups. Regarding biochemical parameters to evaluate anti-inflammation, on the 42nd day after the treatment, C-reactive protein (CRP) levels in rats decreased by 0.2 ± 0.01, 0.16 ± 0.02, and 0.22 ± 0.03 mg/dL for groups II, III, and IV when compared with the group I (0.35 ± 0.07 mg/dL). However, the study results showed no drastic change in CRP levels in group V (0.35 ± 0.01 mg/dL) and were similar to group I. Additionally, group I (0.52 ± 0.08 IU/mL) showed elevated rheumatoid factor (RF) compared to groups II (0.37 ± 0.07 IU/mL), III (0.41 ± 0.24 IU/mL), IV (0.20 ± 0.02 IU/mL), and V (0.34 ± 0.1 IU/mL).⁵⁰ Histopathologically, group V treated with TPHD had normal epidermis and dermis, reduced inflammation compared with epidermis infiltrated by inflammatory cells and signs of focal necrotic bone, and mild stromal edema in the CFA-treated group.⁵⁰ Thus, the anti-inflammatory and anti-arthritic capacities of T. palmata leaf extracts, which contain polyphenolic compounds such as gallic acid, catechin, caffeic acid, rutin, quercetin, and naringenin,⁵⁰ imply that it is a promising herbal remedy for pain and inflammation management.

Antidiabetic Activity

Diabetes mellitus, one of the most prevalent endocrine metabolic disorders, leads to significant morbidity and mortality due to its microvascular and macrovascular complications.⁹⁶ Hyperglycemia, the primary symptom of diabetes mellitus, generates reactive oxygen species, causing lipid peroxidation and membrane damage.⁹⁷ Due to insulin deficiency, individuals with diabetes have elevated blood glucose levels. Various plants are used as antidiabetic remedies due to their insulin-mimetic or secretagogue properties. The hypoglycemic effects of these plants are attributed to chemical compounds such as glycosides, alkaloids, terpenoids, flavonoids, and carotenoids.⁹⁸ Research has demonstrated significant antidiabetic activity in extracts of T. palmata.

In oral glucose tolerance research on T. palmata for tested mice with diabetes, the fasted Swiss albino mice were grouped into six groups, including group control (1.0% Tween 80 in water, 10 mL/kg body weight), group positive control (glibenclamide, 10 mg/kg body weight), and groups receiving leaf extract (at doses of 50, 100, 200, and 400 mg per kg body weight).⁵⁴ As a result of the study, the methanolic extract of T. palmata leaves showed a dose-dependent hypoglycemic effect on blood glucose levels in hyperglycemic mice following 120 min of glucose loading. At a dose of 50 mg/kg, T. palmata extract was observed not to reduce blood glucose levels compared to the control group, with blood glucose levels of 5.58 ± 0.32 and 5.48 ± 0.34 (mmol/L), respectively.⁵⁴ However, at doses of 100, 200, and 400 mg/kg body weight, this extract was found to reduce blood glucose levels by 4.50 ± 0.28 (mmol/L) (corresponding to 17.9% lowering of blood glucose level), 3.94 ± 0.26 (mmol/L) (corresponding to 28.1% lowering of blood glucose level), and 2.88 ± 0.32 (mmol/L) (corresponding to 47.4% lowering of blood glucose level), respectively (P < .05).⁵⁴ In particular, the T. palmata extract treatment group (400 mg/kg) had a hypoglycemic effect corresponding to the control standard drug glibenclamide (10 mg/kg) with a hypoglycemic level of 47.4% (P < .05).⁵⁴ With the assayed antihyperglycemic activity, the T. palmata extract showed a significant antidiabetic effect in the mice model.⁵⁴ However, the corresponding natural bioactive compounds with antidiabetic activity are still unknown for this species. Unambiguously, more investigations are requested concerning the antidiabetic effects of T. palmata.

Analgesic Activity

Despite advancements in pain management, conservative treatments often yield inadequate responses. Additionally, potent analgesics like opioids frequently usually come with drawbacks such as side effects and dependence. This underscores the critical importance of discovering safer alternatives capable of effectively addressing various painful conditions, particularly chronic pain.^99,100 Research has been conducted to evaluate the analgesic properties of T. palmata extracts, yielding significant results.

A study suggested that T. palmata's methanolic extract (50, 100, 200, and 400 mg/kg, p.o.) had a substantial analgesic effect and reduced the abdominal constrictions caused by acetic acid in a dose-dependent way.⁵⁴ Specifically, at doses of 50, 100, 200, and 400 mg/kg body weight, the extract plant exhibited inhibitory effects of 33.3, 40.7, 48.1, and 55.6%, respectively (P < .05). While a standard analgesic drug, aspirin (at doses of 200 and 400 mg/kg body weight), reduced the number of constrictions by 48.10 and 63.0%, respectively (P < .05). The findings indicate that the methanolic extract's potency is comparable to that of a 200 mg/kg dose of aspirin. According to this investigation, the extract derived from T. palmata leaves demonstrated notable inhibition of abdominal constrictions in tested Swiss albino mice.⁵⁴

Antimicrobial Activity

Infectious diseases caused by microorganisms such as bacteria, viruses, fungi, or parasites continue to be a primary health concern, placing significant strains on the economy and public well-being. With the rise of antimicrobial resistance against current drugs, there's an urgent need for new approaches to developing innovative antibiotics and related products to counteract this problem. Currently, attention is turning towards exploring biologically active compounds found in plant species commonly used in herbal medicine, as they offer potential as excellent sources of antibacterial and antifungal properties.^101,102

Antibacterial and Antifungal Activities

Limited studies have been carried out to date concerning the antibacterial and antifungal efficacies of T. palmata. Thus far, only two in vitro studies have evaluated T. palmata's antibacterial and antifungal activities. The in vitro result suggested that the methanolic extract exhibited antibacterial activity against gram-positive (S. aureus) and gram-negative (P. aeruginosa) bacteria, with a zone of inhibition of approximately 8-10 mm. However, this extract was observed not to inhibit E. coli and S. agalactiae bacteria.²⁸

Another study found that isolated compounds from T. palmata leaves are used to inhibit phytopathogenic fungi (Alternaria porri, Botrytis cinerea, Colletotrichum coccodes, Fusarium oxysporum, Magnaporthe oryzae, and Phytophthora infestans), showing various antifungal effects.⁴⁸ The results of the in vitro antifungal bioassay revealed that except for compound (27) (IC₅₀ > 256 μg/mL), the other phytocompounds, including compounds (25), (18), (26), and (28) exhibited strong antifungal activities against M. oryzae, B. cinerea, and P. infestans with IC₅₀ values ranging from 2-5 μg/mL, 24-44 μg/mL, and 81-205 μg/mL (P < .001), respectively. In the structure-activity relationship of compound (27), the esterification of a C-28 carboxyl group with β-D-glucose of this compound may reduce the antibacterial activity.⁴⁸ However, these phytocompounds showed weak antifungal activity against A. porri, C. coccodes, and F. oxysporum (IC₅₀ > 256 μg/mL).⁴⁸ These findings suggest the potential antifungal activity of T. palmata's phytocomponents.

Antiviral Activity

A coronavirus's (COV) ability to bind and enter its host cells depends on the spike protein receptor binding domain (S-RBD). Therefore, it has emerged as an attractive antiviral drug target. The study by Muhseen and colleagues (2020)⁸² aimed to target S-RBD causing severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2) S-RBD with novel bioactive compounds against Coronavirus disease 2019 (COVID-19) via an in silico computational approach.⁸² As a result of this study, the hit of compound (17) has energies of −11 kcal/mol.⁸² Compound (17) exhibited several hydrophobic interactions with residues Lys417, Leu452, Tyr489, Phe456, and Leu455 essential in binding with the human ACE2 receptor.⁸² Importantly, this study demonstrated a new type of terpene, namely hederasaponin B or eleutheroside M (17), as a potential candidate for anti-COVID-19 drugs. Compound (17) exhibited affinity with a strong bond with S-RBD and has a hot residue of S-RBD that inhibits it. The study by Muhseen and colleagues provided a strong foundation for developing new, cost-effective, and safe plant-based drugs against SARS-CoV-2.⁸²

Thrombolytic Activity

The blockage of blood flow caused by clot formation, known as thrombosis, is a severe health problem that can lead to tissue oxygen deprivation and damage, contributing to morbidity and mortality across various conditions and among different groups of patients. Thrombosis presents a significant challenge to blood circulation and health, emphasizing the importance of interventions like fibrinolytic drugs, whose role is vital in improving patient outcomes.¹⁰³ Therefore, actions are taken to investigate and develop new potential compounds to minimize the adverse effects of the available thrombolytic drugs. Studies on T. palmata have shown promising results in this regard.

Sayeed et al (2014)¹⁸ evaluated in vitro the thrombolytic activity of one crude extract (methanolic) and four fractionated extracts (n-hexane, chloroform, ethyl acetate, and aqueous) of T. palmata leaves from the Sitakunda area (Chittagong, Bangladesh) by using the clot lysis of the active extracts. The screening bioassay revealed that T. palmata ethyl acetate fractionated extract had the highest activity, followed by n-hexane, methanolic, chloroform, and aqueous extracts with thrombolytic percentages of 44.293 ± 0.5069%, 44.211 ± 0.7428%, 43.298 ± 0.8647%, 43.280 ± 0.8724%, and 40.332 ± 0.2913%, respectively (P < .01). Thus, the research results have demonstrated the significant thrombolytic effect of T. palmata leaf extract and fraction when compared to streptokinase (positive control, 71.668 ± 0.4661%) and made a difference compared to water (negative control, 5.54 ± 0.9555%) (P < .01).¹⁸ Further investigation is needed to identify the specific molecules that exert thrombolytic effects and comprehensively understand their accurate mechanism of action. This requires a comprehensive investigation using both in vitro and in vivo methods.

Safety Evidence

Components extracted from plants can interact with biological component elements, such as tissues, cells, proteins, and DNA, which can disrupt the host body's immune response and metabolism. Therefore, assessing the in vivo behavior of test animals will provide a basis for the beneficial and toxic effects of natural compounds or plant extracts. Moreover, predicting pharmacokinetic models to evaluate compounds or herbal medicines and their intended effects is essential.¹⁰⁴

In a brine shrimp lethality bioassay, the toxicity effect of the leaf methanolic extract of T. palmata against brine shrimp nauplii was studied. The mortality rate of brine shrimp nauplii increased with the concentration of the extracted sample, with an LC₅₀ value of 0.57 μg/mL.²⁸

In a study by Rahman and colleagues (2014),⁵⁴ the in vivo acute toxicological evaluation of methanolic extract from T. palmata leaves was investigated using a Swiss albino mice model. As a result of the study, the methanolic extract of T. palmata leaves administered orally to tested mice at 100-3000 mg/kg did not show signs of toxicity or changes in behavioral patterns, and mortality was not observed. The study concluded that there was no toxicity in mice, even at the highest dose tested.⁵⁴ This result was confirmed through a follow-up study by Victoria and colleagues (2019).¹⁰⁵ The study also determined that the methanolic extract of T. palmata leaves was safe and showed no toxic effects when administered at a dose of 2000 mg/kg body weight in healthy Wistar albino rats.¹⁰⁵ In a similar study, the leaf ethyl acetate extract of T. palmata administered by oral route to healthy male and female Wistar albino rats at doses of 500, 1000, and 2000 mg/kg induced no significant differences in body weight, no altered morphology, behavioral actions, and functions in animals, no mortality, and no signs of toxicity. This study also showed that the median lethal dose (LD₅₀) of ethyl acetate extract from T. palmata leaves was estimated to exceed 2000 mg/kg. Thus, used doses (maximum up to 2000 mg/kg) are considered safe for treatment without adverse toxic effects.⁵⁰ Although there have been reports of acute toxicity of T. palmata leaf extract, the results of studies have determined that the LD₅₀ ranges from 2000 to 3000 mg/kg. This result may be due to differences in testing conditions, test animals, and extraction solvents. Therefore, more research is needed to evaluate this plant's acute and chronic toxicity.

In 2019, Victoria and colleagues revealed that the methanolic extract of T. palamata leaves administrated orally to Wistar albino rats at 200 and 400 mg/kg showed a significant decrease in all the serum marker levels of serum transaminases (ALT, AST), serum alkaline phosphatase (ALP), and total bilirubin (TB), as well as a significant increase in total protein concentration (P < .001).¹⁰⁵ Moreover, there were significant decreases in cholesterol levels treated with 200 and 400 mg/kg T. palmata extract compared with the CCl₄-treated rats (P < .05). Hematologically, the results of this study showed that the mean red blood cell (RBC) and hemoglobin (Hb) concentrations increased significantly at 200 mg/kg and 400 mg/kg of administration (P < .05). At doses of 200 mg/kg and 400 mg/kg, the eosinophil count was considerably reduced (P < .05). However, neutrophils and lymphocytes did not show significant differences at any of the tested doses.¹⁰⁵ In the same in vivo study, Victoria et al¹⁰⁶ also demonstrated that the methanolic extract of T. palmata leaves has shown the ability to maintain the normal functions of the liver as a hepatoprotective solid effect of this plant.¹⁰⁶

According to the study of Manoharan and colleagues (2023),⁵⁰ oxidative stress was assessed in the liver of the ethyl acetate extract T. palmata-treated rats by evaluating the antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and non-enzymatic glutathione (GSH), on the 42nd day after the treatment. As a result of this study, it was observed that there were statistically significant differences in the enzymatic antioxidants for the T. palmata extract-treated groups compared with the usual standard control group (P < .001 and P < .01). Briefly, a significant effect of the antioxidant enzymes was observed at a dose of 500 mg/kg of the ethyl acetate extract from T. palmata leaves. In other words, TPHD had a profound ability to activate SOD (0.41 ± 0.01 U/mg protein), CAT (0.34 ± 0.02 μmol of H₂O₂ consumed/mg protein), GPx (0.30 ± 0.02 μM of glutathione oxidized/mg protein), and GSH (0.33 ± 0.05 μM/mg protein) enzymes, which prove its enhanced cellular antioxidant activity in a dose-dependent manner. In this study, parameters assessing kidney function, including urea, uric acid, and creatinine levels, were also observed to decrease in all the treatment groups compared to the usual standard control group, except for the creatinine increase in the CFA-induced group. Regarding red blood cells (RBC), white blood cells (WBC), and hemoglobin (Hb) analysis, there was no significant change in the hematological parameters; nevertheless, the erythrocyte sedimentation rate (ESR) increased in the CFA-induced (23 ± 8.7 mm/h), TPHD (13 ± 2.9 mm/h), and standard-treated (7.3 ± 0.88 mm/h) groups. Biochemical and hematological parameters are essential because they explain the biological activities of a plant extract or its products on blood and indicate the toxicity of plant-based samples in animals.⁵⁰

Isolated compounds from T. palmata should also be investigated for their toxicity effects, which is the basis for novel drug development or herbal remedies.

Figure 7 illustrates the biologically active compounds and typical pharmacological activities of T. palmata and T. sundaica.

Figure 7.

Diagram Illustrating the Bioactive Compounds and Representative Pharmacological Properties of T. palmata and T. sundaica (Created by Tran Van Chen).

Conclusions and Future Perspectives

Various parts of Trevesia species have been used in traditional medicine across different countries and cultures to treat health conditions such as fever, inflammation, and edema or consumed as vegetables. For the first time, our comprehensive review of the literature reveals that T. sundaica (1-10) and T. palmata (11-39) contain thirty-nine distinct non-volatile components, including saponins, flavonoids, and phenolics. Isolated compounds and extracts from various parts of T. palmata using multiple extraction and isolation methods have demonstrated promising pharmacological activities, such as antiproliferative, anticancer, antioxidant, anti-inflammatory, analgesic, antidiabetic, antimicrobial, and thrombolytic properties. The results of modern pharmacology have also explained the use of this plant in folk medicine to treat inflammation, fever, pain relief, and diuresis. Chemotaxonomic investigations have revealed that the genus Trevesia may be closely related to the genera Aralia, Acanthopanax, and Hedera.

Although many studies have been conducted on T. sundaica and T. palmata, the phytochemical profile is still limited. The evaluation of pharmacological effects using crude extracts and isolated compounds has not yet been widely performed in in vitro and in vivo models. Furthermore, the biological potential of small compounds has not yet been considered. Based on the results of this overview, prospects for the Trevesia plant are proposed as follows: Firstly, given its extensive history of use, it is imperative to conduct further research to explore its active components and therapeutic potential. Secondly, promoting its cultivation and utilization across various fields will enhance its value and applications. Thirdly, further toxicological, preclinical, and clinical evaluations, structure-activity relationship studies, and the synthesis of new derivatives should be performed. These findings indicate significant potential for developing new, cost-effective, safe plant-based drugs, highlighting the urgent need for continued, in-depth research and development. Finally, the sustainable propagation, cultivation, development, and management of the quality of these plants are also conducted to prevent food security issues in the future.

The detailed information about Trevesia plants, especially T. palmata, and its pharmacological effects provided in this review can lay the groundwork for using this plant in the future in the research and development of multiple drugs or functional foods.

Footnotes

Abbreviations

Statement of Human and Animal Rights

This review article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this review article and informed consent is not applicable.

ORCID iDs

Tran Van Chen

Nguyen Trong Nghia

Nguyen Thanh Triet

Nguyen Thi Thu Hien

Ethical Considerations

Ethical approval is not applicable for this review article.

Author Contributions/CRediT

TVC: Conceptualization, Methodology, Investigation, Formal analysis, Data curation, Supervision, Writing–Original draft preparation, Writing–Reviewing and Editing. NTN: Writing–Original draft. VTT: Writing–Original draft. TVTN: Writing–Reviewing and Editing. NTT: Reviewing and Editing. NTTH: Investigation, Data curation, Conceptualization.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Nuraliev

Oskolski

Sokoloff

, et al. Flowers of Araliaceae: structural diversity, developmental and evolutionary aspects. Pl Diversity Evol. 2010;128(1):247‐268. doi: https://doi.org/10.1127/1869-6155/2010/0128-0012

Kang

Giang

VNL

Park

, et al. Evolution of the Araliaceae family involved rapid diversification of the Asian Palmate group and Hydrocotyle specific mutational pressure. Sci Rep. 2023;13(1):22325. doi: https://doi.org/10.1038/s41598-023-49830-7

Choi

. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C.A. Meyer. Acta Pharmacol Sin. 2008;29(9):1109‐1118. doi: https://doi.org/10.1111/j.1745-7254.2008.00869.x

Zhang

Zhan

, et al. Chemical composition and biological activities of essential oil from roots of Aralia continentalis. Chem Nat Compd. 2020;56:548‐550. doi: https://doi.org/10.1007/s10600-020-03087-y

Araliaceae Juss. Plants of the World Online. Kew Science. https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:30001539-2. 2024. Accessed 20 November 2024.

Plunkett

Wen

Lowry

II . Infrafamilial classifications and characters in Araliaceae: insights from the phylogenetic analysis of nuclear (ITS) and plastid (trnL-trnF) sequence data. Plant Syst Evol. 2004;245:1‐39. doi: https://doi.org/10.1007/s00606-003-0101-3.

Jebb

. A revision of the genus Trevesia (Araliaceae). Glasra. 1998;3(2):85‐113.

Trevesia Vis. Plants of the World Online. Kew Science. https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:328821-2. 2024. Accessed 20 November 2024.

Himmelsbach

Tagle

MAG

Füldner

, et al. Food plants of captive elephants in the okkan reserved forest, Myanmar (Burma), Southeast Asia. Ecotropica. 2006;12:15‐26.

10.

Esser

Jeeb

. The Araliaceae of Thailand. Thai For Bull (Bot). 2009;37:1‐6.

11.

Lamxay

de Boer

Björk

. Traditions and plant use during pregnancy, childbirth and postpartum recovery by the Kry ethnic group in Lao PDR. J Ethnobiol Ethnomed. 2011;7(14):1‐16. doi: https://doi.org/10.1186/1746-4269-7-14

12.

Wen

Lôc

Hiep

, et al. An unusual new species of Trevesia from Vietnam and its implications on generic delimitation in Araliaceae. Taxon. 2007;56(4):1261‐1268. doi: https://doi.org/10.2307/25065918

13.

Ridley

. New and rare Malayan plants. Series XII. J Straits Branch Roy Asiat Soc. 1922;86:292‐311. http://www.jstor.org/stable/41561713

14.

Trevesia sundaica Miq. Plants Database. The National Gardening Association. https://garden.org/plants/view/328325/Trevesia-sundaica/. 2024. Accessed 20 November 2024.

15.

Thi Thanh Huong

Phu Hung

Niranjana Murthy

, et al. Medicinal Plants used by the Tay Ethnic Group, Thai Nguyen Province, Vietnam. IntechOpen; 2022. doi: https://doi.org/10.5772/intechopen.108771.

16.

Gao

Wei

Yang

, et al. Ethnomedicine study on traditional medicinal plants in the Wuliang mountains of Jingdong, Yunnan, China. J Ethnobiol Ethnomed. 2019;15(41):1‐20. doi: https://doi.org/10.1186/s13002-019-0316-1

17.

Salim

Low

ALM

Al-Mekhlafi

. Phytochemicals composition of medicinal plants from Kuala Keniam National Park. Malays J Chem. 2023;25(2):43‐51.

18.

Sayeed

Faruk

Chowdhury

, et al. Thrombolytic and anti-arthritic activities of methanolic extract of Trevesia palmata. J Sci Technol. 2014;5(9):119‐124. doi: https://doi.org/10.26265/e-jst.v9i5.807

19.

De Tommasi

Pizza

Bellino

, et al. Triterpenoid saponins from Trevesia sundaica. J Nat Prod. 1997;60(11):1070‐1074. doi: https://doi.org/10.1021/np970263f

20.

Van Khoa

Van Nang

Hao

NTB

. Study on gaseous formaldehyde removal capability of some native plant species in Vietnam. Pharm Res. 2013;4(1):1‐7.

21.

Burkill

Haniff

. Malay village medicine. The Gardens’ bulletin. Straits Settlements. 1930;6:165‐321.

22.

Burkill

. A Dictionary of the Economic Products of the Malay Peninsula, Vols. 1 and 2. Crown Agents; 1935.

23.

De Tommasi

Autore

Bellino

, et al. Antiproliferative triterpene saponins from Trevesia palmata. J Nat Prod. 2000;63(3):308‐314. doi: https://doi.org/10.1021/np990231n

24.

Loi

. Vietnamese Medicinal Plants and Herbs. Medical Publishing House; 2004:224‐225. (in Vietnamese).

25.

Lalfakzuala

Lalramnghinglova

Kayang

. Ethnobotanical usages of plants in Western Mizoram. Indian J Tradit Knowl. 2007;6(3):486‐493.

26.

Lalmuanpuii

Rosangkima

Lamin

. Ethno-medicinal practices among the Mizo ethnic group in Lunglei district, Mizoram. Sci Vis. 2013;13(1):2229‐6026.

27.

Lalmuanpuii

Zothanpuia Zodinpuii

, et al. Phenological observations of selected wild edible vegetables from tropical and subtropical forest of Mizoram, Northeast India. Vegetos. 2020;33:409‐419. doi: https://doi.org/10.1007/s42535-020-00123-8.

28.

Arifin

Sultana

Mukharjee

, et al. In vitro antioxidant, brine shrimp lethality and antibacterial activities of methanol extract of Trevesia palmata leaves. J Noakhali Sci Technol Univ. 2017;1(2):49‐54.

29.

Thao

LTT

Quyen

, et al. New acetylated saponins from the leaves of Trevesia palmata. Nat Prod Commun. 2018;13(4):404‐410. doi: https://doi.org/10.1177/1934578X1801300407

30.

Pongamornkul

Muangyen

Phookaphin

, et al. Ethnomedicinal Knowledge of Pwo People in Northern Thailand. Res Sq. 2020. doi: https://doi.org/10.21203/rs.3.rs-21537/v1

31.

Bach

. Uses of medicinal flowering plant species In Lang Son province, Vietnam. J Popul Ther Clin Pharmacol. 2023;30(2):176‐192. https://doi.org/10.47750/jptcp.2023.1083

32.

Cao

Zhou

, et al. Ethnobotanical study on wild edible plants used by three trans-boundary ethnic groups in Jiangcheng County, Pu’er, Southwest China. J Ethnobiol Ethnomed. 2020;16(66):1‐23. doi: https://doi.org/10.1186/s13002-020-00420-1

33.

Watt

. The Commercial Products of India. John Murray; 1908.

34.

Trevesia Visiani. Flora of China. http://www.efloras.org/florataxon.aspx?flora_id=2&taxon_id=133344. 2024. Accessed 20 November 2024.

35.

Juang

Liang

. Biological and pharmacological effects of synthetic saponins. Molecules. 2020;25(21):4974. doi: https://doi.org/10.3390/molecules25214974

36.

Sharma

Kaur

Kumar

, et al. Saponins: a concise review on food related aspects, applications and health implications. Food Chem Adv. 2023;2:100191. doi: https://doi.org/10.1016/j.focha.2023.100191

37.

Trevesia sundaica Miq. Mansfeld's World Database of Agricultural and Horticultural Crops. https://mansfeld.ipk-gatersleben.de/apex/f?p=185:46:22265588388866::NO::module,mf_use,source,akzanz,rehm,akzname,taxid:mf,botnam,0,Trevesia%20sundaica,26403. 2024. Accessed 20 November 2024.

38.

Sujarwo

Keim

Savo

, et al. Ethnobotanical study of Loloh: traditional herbal drinks from Bali (Indonesia). J Ethnopharmacol. 2015;169:34‐48. doi: https://doi.org/10.1016/j.jep.2015.03.079

39.

Nisa

Astana

PRW

Triyono

, et al. Ethnobotanical study of medicinal plants used for treating urinary tract problems in eastern Indonesia. IOP Conf Ser: Earth Environ Sci IOP Publishing. 2021;905(1):012119. doi: https://doi.org/10.1088/1755-1315/905/1/012119

40.

Nguanchoo

Prachaya

Swangpol

, et al. Food plants in Hmong cuisine in Northern Thailand. Thai J Bot. 2014;6:131‐145.

41.

Kumar

Chandel

Pandey

, et al. Usage of wild edible plants among upland indigenous communities of Northeastern states of India. In wild food plants for zero hunger and resilient agriculture. Singapore: Springer Nature Singapore. 2023;2023:125‐147. doi: https://doi.org/10.1007/978-981-19-6502-9_5.

42.

NyoTin

. Some edible wild and cultivated plants used as food for Palaung tribe in kyaukme township. Univ Res J. 2008;1(1):167‐182.

43.

Punchay

Inta

Tiansawat

, et al. Traditional knowledge of wild food plants of Thai Karen and Lawa (Thailand). Genet Resour Crop Evol Title. 2020;67:1277‐1299. doi: https://doi.org/10.1007/s10722-020-00910-x

44.

Johnson

Grivetti

. Gathering practices of Karen women: questionable contribution to beta-carotene intake. Int J Food Sci Nutr. 2002;53(6):489‐501. doi: https://doi.org/10.1080/09637480220164389

45.

Chaudhry

Murtem

. Biodiversity conservation through totem, taboo and magico-religious beliefs in the eastern Himalaya of India: an ethno botanical study. Interdiscip Environ Rev. 2016;17(3-4):261‐285.

46.

Angami

Gajurel

Rethy

, et al. Status and potential of wild edible plants of Arunachal Pradesh. Indian J Tradit Knowl. 2006;5(4):541‐550.

47.

Zhou

Ren

Chen

. Chinese edible botanicals: types, efficacy and safety. In: Hui

, ed., Handbook of Food Science, Technology, and Engineering, Vol. 2006(2). Taylor & Francis Group; 2006:98-1‐98-28.

48.

Kim

Han

Thi Ngo

, et al. Identification of novel compounds, oleanane-and ursane-type triterpene glycosides, from Trevesia palmata: their biocontrol activity against phytopathogenic fungi. Sci Rep. 2018;8(1):14522. doi: https://doi.org/10.1038/s41598-018-32956-4

49.

Yen

Doan

Lien

GTK

, et al. New lupane-type and ursane-type triterpene saponins from the leaves of Trevesia palmata. Nat Prod Res. 2021;35(19):3285‐3292. doi: https://doi.org/10.1080/14786419.2019.1696797

50.

Manoharan

Jagadeesan

Nataraj

, et al. Efficacy of Trevesia palmata (Roxb. ex Lindl.) Vis. extract on MG 63 cell lines and arthritis-induced animal models. J Ethnopharmacol. 2023;300:115742. doi: https://doi.org/10.1016/j.jep.2022.115742

51.

Sparg

Light

Van Staden

. Biological activities and distribution of plant saponins. J Ethnopharmacol. 2004;94(2-3):219‐243. doi: https://doi.org/10.1016/j.jep.2004.05.016

52.

Panyaphu

Sirisa-ard

Ubol

, et al. Phytochemical, antioxidant and antibacterial activities of medicinal plants used in Northern Thailand as postpartum herbal bath recipes by the Mien (Yao) community. Phytopharmacology. 2012;2(1):92‐105.

53.

Victoria

Tanget

Sailo

, et al. Investigation of pharmacognostic, physicochemical and phytochemical studies of Trevesia palmata. J Emerg Technol Innov Res. 2019;6(6):38‐43.

54.

Rahman

Nandi

Sultana

, et al. Phytochemical screening, antihyperglycemic and analgesic activity studies with methanol extract of Trevesia palmata leaves. World J Pharm Pharmaceut Sci. 2014;3(10):91‐101.

55.

Pizza

Bellino

Venturella

. Triterpenoid saponins from Schefflera divaricata. J Nat Prod. 1997;60(7):663‐668. doi: https://doi.org/10.1021/np9605807

56.

Miyase

Shiokawa

Zhang

, et al. Araliasaponins I–XI, triterpene saponins from the roots of Aralia decaisneana. Phytochem. 1996;41(5):1411‐1418. doi: https://doi.org/10.1016/0031-9422(95)00788-1

57.

Heinzmann

Schenkel

. Saponins from Ilex dumosa. J Nat Prod. 1995;58(9):1419‐1422. doi: https://doi.org/10.1021/np50123a012

58.

Song

Yeo

Hong

, et al. Antiviral activity of hederasaponin B from Hedera helix against enterovirus 71 subgenotypes C3 and C4a. Biomol Ther. 2014;22(1):41‐46. doi: https://doi.org/10.4062/biomolther.2013.108

59.

Yamauchi

Yoshimatsu

, et al. Memory enhancement by oral administration of extract of Eleutherococcus senticosus leaves and active compounds transferred in the brain. Nutrients. 2019;11(5):1142. doi: https://doi.org/10.3390/nu11051142

60.

Liang

Song

, et al. Structural characterization of the metabolites of orally ingested hederasaponin B, a natural saponin that is isolated from Acanthopanax senticosus leaves by liquid chromatography–mass spectrometry. J Pharm Biomed Anal. 2021;197:113929. doi: https://doi.org/10.1016/j.jpba.2021.113929

61.

Liu

Zhu

Feng

, et al. Crude triterpenoid saponins from Anemone flaccida (Di Wu) exert anti-arthritic effects on type II collagen-induced arthritis in rats. Chin Med. 2015;10(1):1‐9. doi: https://doi.org/10.1186/s13020-015-0052-y

62.

Saito

Sumita

Tamura

, et al. Saponins from the leaves of Aralia elata SEEM.: Araliaceae. Chem Pharm Bull. 1990;38(2):411‐414. doi: https://doi.org/10.1248/cpb.38.411

63.

Kayce

Kirmizigul

. Isolation and identification of a new saponin from Cephalaria aytachii. Nat Prod Res. 2017;31(1):50‐57. doi: https://doi.org/10.1080/14786419.2016.1212029

64.

Chai

, et al. Quality evaluation of Flos Lonicerae through a simultaneous determination of seven saponins by HPLC with ELSD. J Chromatogr A. 2005;1070(1-2):43‐48. doi: https://doi.org/10.1016/j.chroma.2005.02.031

65.

Petit

Mitaine-Offer

Fischer

, et al. Anti-phytopathogen terpenoid glycosides from the root bark of Chytranthus macrobotrys and Radlkofera calodendron. Phytochem. 2021;188:112797. doi: https://doi.org/10.1016/j.phytochem.2021.112797

66.

Osama

El Sherei

Al-Mahdy

, et al. Genus Hedera: a comprehensive review of its phytoconstituents, diverse pharmacological activities and medicinal properties. Egypt J Chem. 2023;66(10):203‐245. doi: https://doi.org/10.21608/ejchem.2023.176914.7236

67.

Nishimura

Miyase

Noguchi

. Triterpenoid saponins from Ilex kudincha. J Nat Prod. 1999;62(8):1128‐1133. doi: https://doi.org/10.1021/np990128y

68.

Wen

Guan

Huang

, et al. A new oleanane-type triterpenoid glycoside from roots of Ilex asprella. China Journal of Chinese Materia Medica. 2017;42(13):2503‐2509. doi: https://doi.org/10.19540/j.cnki.cjcmm.20170512.005

69.

Magnani

Isaac

VLB

Correa

, et al. Caffeic acid: a review of its potential use in medications and cosmetics. Anal Methods. 2014;6(10):3203‐3210. doi: https://doi.org/10.1039/C3AY41807C

70.

Lion

Pichette

Mihoub

, et al. Phenolic extract from Aralia nudicaulis L. rhizomes inhibits cellular oxidative stresses. Molecules. 2021;26(15):4458. doi: https://doi.org/10.3390/molecules26154458

71.

Kiełkiewicz

Obrębski

Śliwińska

, et al. Detailed qualitative and quantitative UHPLC-DAD-ESI-MS3 analysis of Aralia spinosa L.(Araliaceae) phytochemical profile to evaluate its potential as novel plant material for bioactive compounds acquisition using in vitro culture. Ind Crops Prod. 2024;219:119123. doi: https://doi.org/10.1016/j.indcrop.2024.119123

72.

Wang

Liang

Khan

, et al. Chemical constituents from Schefflera leucantha R.Vig. (Araliaceae). Biochem Syst Ecol. 2020;91:104076. doi: https://doi.org/10.1016/j.bse.2020.104076

73.

Thuan

NTD

Hien

NTT

Hao

, et al. Flavonoids from the leaves of Aralia hiepiana. Vietnam J Sci Technol. 2018;56(4A):259‐265. doi: https://doi.org/10.15625/2525-2518/56/4A/12882.

74.

Thu Hien

Dieu Thuan

Van Huyen

, et al. Flavonoids from the leaves of Aralia dasyphylla Miq.(Araliaceae). Vietnam J Chem. 2018;56(6):695‐699. doi: https://doi.org/10.1002/vjch.201800072

75.

Hua

Peng

, et al. Comparison of chemical composition in the buds of Aralia elata from different geographical origins of China. R Soc Open Sci. 2018;5:180676. doi: https://doi.org/10.1098/rsos.180676

76.

Zheng

. Antioxidant activity of phenolic compounds from Dendropanax dentiger (Harms) Merr. Asian J Chem. 2013;25(14):7809‐7812. https://doi.org/10.14233/ajchem.2013.14618

77.

Liu

Wang

, et al. Simultaneous quantification of five bioactive components of Acanthopanax senticosus and its extract by ultra performance liquid chromatography with electrospray ionization time-of-flight mass spectrometry. Molecules. 2012;17:7903‐7913. doi: https://doi.org/10.3390/molecules17077903

78.

Liu

Kim

, et al. Curcubinoyl flavonoids from wild ginseng adventitious root cultures. Sci Rep. 2021;11:12212. doi: https://doi.org/10.1038/s41598-021-91850-8

79.

Nan

Park

Nam

, et al. Effect of Acanthopanax koreanum Nakai (Araliaceae) on D-galactosamine and lipopolysaccharide-induced fulminant hepatitis. J Ethnopharmacol. 2004;92(1):71‐77. doi: https://doi.org/10.1016/j.jep.2004.02.007

80.

Kwon

Kim

, et al. Comprehensive profiling of phenolic compounds and triterpenoid saponins from Acanthopanax senticosus and their antioxidant, α-glucosidase inhibitory activities. Sci Rep. 2024;14:26330. doi: https://doi.org/10.1038/s41598-024-77574-5

81.

Changyoung

Bui

, et al. Assessment of bioactivity of some plant species in Bac Huong Hoa nature reserve and its neighbourhood in Quang Tri province. VNU Journal of Science: Natural Sciences and Technology. 2019;35(1):119‐126. doi: https://doi.org/10.25073/2588-1140/vnunst.4873

82.

Muhseen

Hameed

Al-Hasani

, et al. Promising terpenes as SARS-CoV-2 spike receptor-binding domain (RBD) attachment inhibitors to the human ACE2 receptor: integrated computational approach. J Mol Liq. 2020;320(PartB):114493. doi: https://doi.org/10.1016/j.molliq.2020.114493.

83.

Baba

Câtoi

. Comparative Oncology. Bucharest (RO): The Publishing House of the Romanian Academy; 2007. Chapter 3, Tumor Cell Morphology. https://www.ncbi.nlm.nih.gov/books/NBK9553/#.

84.

Matthews

Bertoli

de Bruin

. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23:74‐88. doi: https://doi.org/10.1038/s41580-021-00404-3

85.

Yano

Tazawa

Kagawa

, et al. FUCCI real-time cell-cycle imaging as a guide for designing improved cancer therapy: a review of innovative strategies to target quiescent chemo-resistant cancer cells. Cancers (Basel). 2020;12(9):2655. doi: https://doi.org/10.3390/cancers12092655

86.

Chen

Jin

Dai

, et al. Aloperine induces apoptosis and inhibits invasion in MG-63 and U2OS human osteosarcoma cells. Biomed Pharmacother. 2018;97:45‐52. doi: https://doi.org/10.1016/j.biopha.2017.09.066

87.

Zhang

Liu

Ding

, et al. Yanghe decoction inhibits inflammation-induced lung metastasis of colorectal cancer. J Ethnopharmacol. 2025;340(2025):119257. doi: https://doi.org/10.1016/j.jep.2024.119257

88.

Sun

MacFarlane

Zhuang

, et al. Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem. 1999;274(8):5053‐5060. doi: https://doi.org/10.1074/jbc.274.8.5053

89.

Chaves

Santiago

Alías

. Quantification of the antioxidant activity of plant extracts: analysis of sensitivity and hierarchization based on the method used. Antioxidants. 2020;9(1):76. doi: https://doi.org/10.3390/antiox9010076

90.

Meng

, et al. Natural antioxidants in foods and medicinal plants: extraction, assessment and resources. Int J Mol Sci. 2017;18(1):96. doi: https://doi.org/10.3390/ijms18010096

91.

Krishnaiah

Sarbatly

Nithyanandam

. A review of the antioxidant potential of medicinal plant species. Food Bioprod Process. 2011;89(3):217‐233. doi: https://doi.org/10.1016/j.fbp.2010.04.008

92.

Azab

Nassar

Azab

. Anti-inflammatory activity of natural products. Molecules. 2016;21(10):1321. doi: https://doi.org/10.3390/molecules21101321

93.

Chen

Deng

Cui

, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204‐7218. doi: https://doi.org/10.18632/oncotarget.23208

94.

Pei

Kuang

, et al. Preparation, characterization, bioactivity, and safety evaluation of PEI-modified PLGA nanoparticles loaded with polysaccharide from Cordyceps militaris. Adv Compos Hybrid Mater. 2025;8(1):93. doi: https://doi.org/10.1007/s42114-024-01135-7

95.

Nunes

CDR

Barreto Arantes

Menezes de Faria Pereira

, et al. Plants as sources of anti-inflammatory agents. Molecules. 2020;25(16):3726. doi: https://doi.org/10.3390/molecules25163726

96.

Aikaeli

Njim

Gissing

, et al. Prevalence of microvascular and macrovascular complications of diabetes in newly diagnosed type 2 diabetes in low-and-middle-income countries: a systematic review and meta-analysis. PLOS Glob Public Health. 2022;2(6):e0000599. doi: https://doi.org/10.1371/journal.pgph.0000599

97.

Fatima

Bhat

Nisar

, et al. The role of dietary antioxidants in type 2 diabetes and neurodegenerative disorders: an assessment of the benefit profile. Heliyon. 2023;9(1):e12698. doi: https://doi.org/10.1016/j.heliyon.2022.e12698

98.

Jacob

Narendhirakannan

. Role of medicinal plants in the management of diabetes mellitus: a review. 3 Biotech. 2019;9(4):1‐17. doi: https://doi.org/10.1007/s13205-018-1528-0

99.

Malhotra

Joshi

Dey

, et al. Recent trends in chronic pain medicine. Indian J Anaesth. 2023;67(1):123‐129. doi: https://doi.org/10.4103/ija.ija_31_23

100.

Queremel Milani

Davis

. Pain management medications. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK560692 .

101.

Prestinaci

Pezzotti

Pantosti

. Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health. 2015;109(7):309‐318. doi: https://doi.org/10.1179/2047773215Y.0000000030

102.

Hemeg

Moussa

Ibrahim

, et al. Antimicrobial effect of different herbal plant extracts against different microbial population. Saudi J Biol Sci. 2020;27(12):3221‐3227. doi: https://doi.org/10.1016/j.sjbs.2020.08.015

103.

Loscalzo

Fauci

Kasper

, et al., eds. Harrison's Principles of Internal Medicine, 21e. McGraw-Hill Education; 2022.

104.

Fischer

Chan

. Nanotoxicity: the growing need for in vivo study. Curr Opin Biotechnol. 2007;18(6):565‐571. doi: https://doi.org/10.1016/j.copbio.2007.11.008

105.

Victoria

Ripans

Sailo

. Effect of Trevesia palmata on some biochemical and haematological parameters. Int J Eng Sci Technol. 2019;4(3):610‐614.

106.

Victoria

Sailo

Shantabi

, et al. Histological evaluation of the hepatoprotective effect of Trevesia palmata on carbon tetrachloride-induced hepatotoxicity. J Emerg Technol Innov Res. 2019;6(6):132‐135.