Fphar 15 1322083

TYPE Review
PUBLISHED 21 March 2024

DOI 10.3389/fphar.2024.1322083
A comprehensive review of
OPEN ACCESS ethnomedicinal approaches,
EDITED BY
Irina Ielciu,
University of Medicine and Pharmacy Iuliu
phytochemical analysis, and
Hatieganu, Romania
REVIEWED BY
pharmacological potential of
Francis-Alfred Unuagbe Attah,
University of Ilorin, Nigeria
Smith B. Babiaka,
Vitex trifolia L.
University of Tuebingen, Germany
*CORRESPONDENCE Javad Mottaghipisheh 1†, Marzie Kamali 2†,

Mohammad Hashem Hashempur,
[email protected]
Amir Hossein Doustimotlagh 3,4,
Aida Iraji, Mohammad Hossein Nowroozzadeh 5, Fatemeh Rasekh 6,
[email protected]
†
Mohammad Hashem Hashempur 1* and Aida Iraji 7*
These authors have contributed equally to this
work and share first authorship 1
Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine,
School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, 2Molecular Medicine Research
RECEIVED 15 October 2023
Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran,
ACCEPTED 27 February 2024 3
Department of Clinical Biochemistry, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj,
PUBLISHED 21 March 2024
Iran, 4Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran,
5
CITATION Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University
Mottaghipisheh J, Kamali M, Doustimotlagh AH, of Medical Sciences, Shiraz, Iran, 6Department of Biology, Payame Noor University (PNU), Tehran, Iran,
7
Nowroozzadeh MH, Rasekh F, Hashempur MH Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
and Iraji A (2024), A comprehensive review of
ethnomedicinal approaches, phytochemical
analysis, and pharmacological potential of Vitex
trifolia L..
Front. Pharmacol. 15:1322083. Plants, renowned for their rich reservoir of metabolites, play a pivotal role in
doi: 10.3389/fphar.2024.1322083 addressing health-related issues. The Verbenaceae family stands out, showcasing
COPYRIGHT immense potential in preventing and treating chronic diseases. Vitex trifolia L. (V.
© 2024 Mottaghipisheh, Kamali, trifolia), a shrub with a rich history in traditional medicine, particularly in Eastern
Doustimotlagh, Nowroozzadeh, Rasekh,
Hashempur and Iraji. This is an open-access Asia, has garnered attention for its diverse therapeutic applications. This
article distributed under the terms of the comprehensive review aims to bridge traditional knowledge and
Creative Commons Attribution License (CC BY). contemporary insights by investigating ethnopharmacology, phytochemistry,
The use, distribution or reproduction in other
forums is permitted, provided the original and pharmacological effects of V. trifolia. The keyword “V. trifolia” and its
author(s) and the copyright owner(s) are synonyms were searched within the main scientific databases including
credited and that the original publication in this PubMed, Web of Science, ScienceDirect, Google Scholar, and Baidu Scholar
journal is cited, in accordance with accepted
academic practice. No use, distribution or (from 1974 to 2022, last search: 21.10.2023). Phytochemical analyses reveal a
reproduction is permitted which does not spectrum of secondary metabolites in V. trifolia, including terpenoids, flavonoids,
comply with these terms. lignans, phytosterols, anthraquinones, and fatty acids. Notably, terpenoids and
flavonoids emerge as the main bioactive metabolites. Pharmacological studies
validate its therapeutic potential, demonstrating significant antioxidant, anti-
inflammatory, hepatoprotective, anticancer, anti-amnesic, antimicrobial,
antiviral, anti-malaria, antispasmodic activities, and reported insecticidal
effects. Despite existing literature exploring pharmacological attributes and
secondary metabolites of related species, a conspicuous gap exists,
specifically focusing on the pharmacological activities and novel methods of
Abbreviations: V. trifolia L., V. trifolia; GGPP, Geranylgeranyl pyrophosphate; EOs, Essential oils; TPC,
Total phenolic content; TFC, Total flavonoid content; SGPT, Glutamate pyruvate transaminase; SGOT,
Glutamate oxaloacetate transaminase; ALP, Alkaline phosphatase; NO, Nitric oxide; LPS,
Lipopolysaccharide; IL, Interleukin; TNF-α, Tumor necrosis factor; ZnO NPs, Zinc oxide
nanoparticles; MCV, M. contagiosum virus; HSV, Herpes simplex virus; PGE2, Prostaglandin E2;
ERK1/2, Extracellular signal-regulated kinase 1/2; LT50, Lethal time to cause 50% mortality; MTT
assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay.
Frontiers in Pharmacology 01 frontiersin.org

Mottaghipisheh et al. 10.3389/fphar.2024.1322083
purification of pure metabolites from V. trifolia. This review aimed to fill this gap by
delving into traditional medicinal applications, exploring secondary metabolites
comprehensively, and providing an in-depth analysis of pharmacological effects of
pure metabolites. Combining traditional uses with contemporary pharmacological
insights, this article sought to serve as a crucial reference for future research and
practical application of V. trifolia. This approach contributes substantially to
understanding the plant, fostering scientific inquiry, and facilitating its broader
application in healthcare.
KEYWORDS
Vitex trifolia L., secondary metabolites, ethnomedicine, phytochemistry, bioactivities
1 Introduction plant parts and extracts utilized, also different separation

methodologies could indeed assist futuristic investigations of
Plants play a crucial role in health-related problems due to their this species.
rich reservoir of bioactive metabolites. These natural metabolites The current study is an attempt to fill this gap by investigating
found in various plant species, such as those belonging to the the traditional medicine applications of V. trifolia, along with an in-
Verbenaceae family, have shown immense potential in preventing depth analysis of its secondary metabolites through an updated
and treating chronic diseases, offering a promising opportunity for literature search strategy, where existing information on
therapeutic interventions (Hashempur et al., 2018; Alyasin et al., chromatographic steps and the plant parts/extracts employed
2020; Conti et al., 2021). Verbenaceae is one of the largest families of which led to the isolation and identification of its precious
the plant kingdom, consisting of trees, shrubs, lianas, and herbs. secondary metabolites are described in detail.
Verbenaceae comprise of 34 genera and around 1,200 species. Vitex Moreover, it explores the pharmacological effects of the individual
is known as one of the largest genera in the family, possessing pure metabolites isolated from V. trifolia a crucial aspect that has thus
270 species mainly distributed in tropical areas, with a few in far been overlooked in the existing literature. Hence, this article aimed
subtropical regions (Rani and Sharma, 2013; Yao et al., 2016). to serve as a vital reference for future research endeavours and the
Vitex trifolia L. (V. trifolia) is a shrub or shrubby tree that may practical utilization of V. trifolia Through a comprehensive exploration
grow up to 6 m in height. It is found in some regions of Asia, China, of both the traditional uses and contemporary pharmacological insights,
India, Indonesia, Sri Lanka, Singapore, and Australia. This plant has this review is an attempt to contribute substantially to understanding V.
a rich history in traditional medicine for its effectiveness in treating trifolia and pave the way for further scientific inquiry and application of
asthma and respiratory disorders. It has been reported that most this intriguing plant species.
plant parts such as the fruit, leaf, root, flower, and stem
demonstrated medicinal values; however, its fruit is the most
studied and used part (Zaki et al., 2022). Different types of 2 Methodology
secondary metabolites including terpenoids (mainly labdane-type
diterpenes), flavonoids, lignans, phytosterols, anthraquinones, and In this study, a comprehensive literature search was done
fatty acids have been reported in V. trifolia; whereas terpenoids and focusing on V. trifolia across various online databases and
flavonoids have been identified as the main bioactive compounds relevant books. The search employed the term ‘Vitex trifolia’ and
(Yan et al., 2023). Pharmacological studies have further validated its its synonyms ‘Vitex agnus-castus var. trifolia (L.) Kurz, Vitex indica
therapeutic potential by demonstrating significant antioxidant, anti- Mill., Vitex integerrima Mill., Vitex trifolia var. trifoliolata Schauer,
inflammatory, hepatoprotective, anticancer, anti-amnesic, and Vitex variifolia Salisb.’, (confirmed by http://www.
antimicrobial, antiviral, anti-malaria, and antispasmodic activities. plantsoftheworldonline.org), while targeted prominent databases
Additionally, some studies have reported its insecticidal effects including PubMed, Web of Science, ScienceDirect, and Google
(Tandon et al., 2008). These findings highlight the diverse Scholar. Baidu Scholar were also included in the search with a
beneficial properties associated with V. trifolia and support its specified time frame from 1974 to 2022 (the last search was
use in traditional medicine for various health conditions. conducted on 21.10.2023). The search yielded 889, 283, 1,263,
In recent years, the medicinal potential of V. trifolia has 1,023, and 147 articles in each database, respectively. After this
garnered significant attention, particularly within traditional refinement process, a total of 164 articles emerged as pertinent to the
medicine. A series of review papers have explored various aspects scope of this review. This judicious selection ensures that the
of this plant species with emphasis on its pharmacological properties information is comprehensive and focused, contributing to the
(Chan et al., 2016; Kamal et al., 2022; Yan et al., 2023). The most literature review robustness.
recent review explores the pharmacological attributes and secondary
metabolites of V. trifolia L. and V. rotundifolia L. f., providing
insights into their properties. However, despite the existing body of 3 Traditional uses of V. trifolia
literature, there remains a conspicuous gap in the current discourse,
particularly the phytochemical aspects of V. trifolia, as an invaluable Various ethnopharmacological studies have demonstrated
natural agent, where complementary information regarding the promising medicinal applications for different plants (Mosavat

et al., 2015; Ayeni et al., 2022; Das et al., 2022). V. trifolia, commonly based on their main classifications (Figures 1–7); however, more
known as the chaste tree or five-leaved chaste tree, has gained details including plant parts used and chromatographic techniques
recognition as a botanical drug, particularly in Eastern Asia. applied are listed in Supplementary Table S1.
Throughout the years, ethnomedicinal investigations have
documented the diverse therapeutic applications of this plant
(Blois, 1958; Ban et al., 2020). 5 Biosynthesis of terpenoids, flavonoids
The traditional use of the fruit can be traced back to ancient and iridoids
times, with its earliest recorded mention appearing in Shen
Nong’s Classic of Materia Medica of China. This historical Since the main Vitex trifolia compounds identified as
text was commended for its medicinal properties and terpenoids, flavonoids, and iridoids, thus this section allocates to
addressed as a remedy for various afflictions. Among its briefly overview the natural biosynthesis pathways of these
benefits, it was believed that it alleviated conditions like cold compounds. Terpenoids are derived from the mevalonate (MVA)
and heat between the tendons and bones, addressed dampness pathway, exhibiting activity within the cytosol, or alternatively from
impediment, enhanced vision by brightening the eyes, the plasticidal 2-C-methyl-D-erythriol 4-phosphate (MEP)
strengthened the teeth, unblocked the “nine orifices” (body pathway. The MEP pathway predominantly serves as the source
openings), and even eliminated taeniasis, a condition caused of hemi-, mono-, di-, and triterpenoids, whereas the MVA pathway
by tapeworm infection. This valuable fruit has a significant is primarily responsible for the synthesis of sesqui- and triterpenoids
place in traditional medicine, connecting its potent healing (Cheng et al., 2007; Maffei et al., 2011) (Figure 8A).
qualities to improve human health (Wu et al., 2009a). Iridoids represent a vast category of monoterpenoids, distinguished
Furthermore, it has been credited with promoting hair growth. by their skeletal structure consisting of a cyclopentane ring fused with a
Tonga, known for its rich traditional practices, utilized the plant six-membered ring containing an oxygen atom, commonly known as
for its remarkable healing properties. Specifically, they harnessed the iridane skeleton. Typically, these compounds have been identified in
its powers to treat oral infections and inflammations (Limousin plants in conjunction with sugar molecules, rendering their glycosides
and Bessières, 2006). and allowing for their classification (Villasenor, 2007). The iridoid
In Unani medicine, the plant is known as Sambhalu and has system is derived from geraniol through a unique folding process,
been employed to reduce libido (Suchitra and Cheriyan, 2018). In distinct from the folding observed in monoterpenoids. There are over
Papua New Guinea, the indigenous population utilizes the stem of V. thousand different known natural iridoids, with structural variations
trifolia L. to treat dysentery. The leaves of V. trifolia, called primarily arising from hydroxylations, esterifications, and changes in
Jalanirgundi in traditional Ayurvedic medicine, are commonly stereochemistry (Figure 8B) (Dewick, 2002).
prepared as a decoction or used topically as a poultice. They Flavonoids originate from the phenylpropanoid metabolic pathway
have been employed to alleviate joint pain, inflammation, and and possess a fundamental composition consisting of a C15 benzene
rheumatism (Kirtikar and Kirtikar, 1980; Thenmozhi et al., ring structure of C6-C3-C6. In recent years, substantial research has
2015). In New Caledonia, Rotuma, and the Solomon Islands, been conducted to uncover the intricate mechanisms underlying the
heated leaves are commonly used to alleviate severe headaches by biosynthesis of flavonoids in plants (Liu et al., 2021). The entry of
rubbing them on the forehead or consuming them as an infusion (de p-coumaroyl-CoA into the flavonoid biosynthesis pathway signifies the
Kok, 2007). The fruits of V. trifolia, commonly called Manjingzi in start of the synthesis of specific flavonoids, which begins with the
the Chinese Pharmacopoeia, have a long-standing history in formation of chalcone (Nabavi et al., 2020). Chalcone serves as the
traditional Chinese medicine. They are known for their wind- initial crucial product in the metabolic pathway of flavonoids, offering a
heat-dispersing properties, making them valuable in treating fundamental framework for subsequent synthesis of flavonoids (Zhou
various ailments such as headaches, migraines, and et al., 2009). Flavanones have the potential to generate numerous
ophthalmodynia. The traditional use of Manjingzi highlights its iterations based on this fundamental framework, such as flavones,
effectiveness in addressing conditions associated with wind heat, flavonols, anthocyanidins, and catechins (Figure 9) (Mottaghipisheh
providing relief, and promoting overall wellbeing. Besides, the et al., 2021).
flowers of V. trifolia have demonstrated usefulness in treating
fever (Talreja and Tiwari, 2020).
5.1 Terpenoids
4 Phytochemistry 5.1.1 Monoterpenoids and sesquiterpenoids
Most of the V. trifolia monoterpenoids are iridoids and their
So far, over 180 metabolites have been identified from different corresponding glycosides (metabolites 1–10). Besides the iridoids,
parts of V. trifolia. Investigation of the chemical profile has led to the an acyclic monoterpenoid vitexoid (15) has been isolated from the
isolation of terpenoids (monoterpenes, sesquiterpenes, diterpenes, fruits and is a characteristic metabolite of V. trifolia (Djimabi et al.,
triterpenes, and phytosterols), ecdysteroids, flavonoids, lignans, 2021). Only two aromadendrane-type sesquiterpenoids (16 and 17)
phenylpropanoids, anthraquinone, fatty acids, along with were found in the fruits (Gu et al., 2007).
xanthones isolated from the endophytic fungi of the fruit (Peng
et al., 2021). Among them, the diterpenes special labdane-type are 5.1.2 Diterpenoids
the most significant metabolites in this species. In the following The V. trifolia fruits and leaves can be considered as a rich source
sections, the isolated/identified phytochemicals have been classified of cyclic diterpenes, predominantly containing monocyclic, bicyclic

FIGURE 1
Chemical structure of monoterpenoids and sesquiterpenoids isolated from V. trifolia.
(labdane, halimane, clerodane), and tricyclic (abietane) skeletons. Halimane diterpenoids (71–81), known as rearranged labdanes,
Noteworthy, all these chemical types were separated from semi- have further been isolated from this species. According to
polar fractions or semi-polar soluble extracts (acetone, ethyl acetate) diterpenoids classification by Roncero and his co-workers, most
utilizing various chromatographic techniques. Labdane diterpenoids V. trifolia halimane diterpenoids belong to halim-1 (10)-enes
(18–70) with fifty-three derivatives have been characterized as the (71–73) and halim-5 (10)-enes (74–80) groups, described as the
highest abundance among other phytochemicals. Except for two largest structures of halimanes (Roncero et al., 2018). The leaves of
glycosylated diterpenoids (69 and 70), the remaining metabolites of V. trifolia also synthesized three clerodane diterpenoids, named as
the genus have been identified in aglycosylated form. Recently, vitexfolin B (82), vitextrifloxide I (83), and dysoxydensin G (84)
phytochemical investigation on the ethanol extract of the fruits of (Luo et al., 2017c).
V. trifolia yielded four new labdane diterpenoids vitetrolins A-D Abietanes diterpenoids (85–89) have been isolated from the
(47–48, 20 and 54) (Djimabi et al., 2022). fruit’s extracts or non/semi-polar fractions (Ono et al., 2000; Li et al.,
A labdane diterpenoid alkaloid, 9α-hydroxy-13 (14)-labden- 2020b; Djimabi et al., 2021). From this plant, aromatic five abietanes,
16,15-amide 68, with an α,β-unsaturated-γ-lactam moiety, was known as the most abundant naturally occurring abietanes,
isolated from V. trifolia leaves (Luo et al., 2017c). Further including abietatrien-3β-ol (86), ferruginol (87), 3β-
investigation on the isolation of V. trifolia labdane diterpenoid acetoxyabieta-8,11,13-triene-12-ol (88), and vitexifolin C (89)
alkaloids led to identification of a cyano-substituted pyrrole cyclic have been isolated (Gonzalez, 2015).
system (64–67) from the ethanolic extract of the leaf. The precursors Djimabi et al. identified helipterol (90), possessing a monocyclic
of geranylgeranyl pyrophosphate (GGPP), ammonia, and an amino scaffold, from the fruit alcoholic extract V. trifolia, as the only
acid may contribute to the biosynthesis of these remarkable natural source which is so far reported (Djimabi et al., 2021).
metabolites (Luo et al., 2017b). Moreover, viterotulin D (37), vitetrifolin H (79), 15,16-epoxy-9-

FIGURE 2
(Continued).
hydroxylabda-13 (16),14-diene (29), and 3β-acetoxyabieta-8,11,13- successfully identified three triterpenoid saponins (97–99) derived
trien-12-ol (88) were screened out to be the specific secondary from the leaves (Mohamed et al., 2013).
metabolites (Wu et al., 2009b). The various class of structures is Within the various Vitex species, ecdysteroids are of great
shown in Figure 2. attention due to their distinctive characteristics advantageous in
chemotaxonomy (Sena Filho et al., 2008). Noteworthy
5.1.3 Triterpenoids and phytosterols ecdysteroids, such as ecdysone (compound 120), 20-
In Vitex trifolia, the most abundant subclasses of triterpenoids hydroxyecdysone (compound 121), 20-hydroxyecdysone 2,3-
identified are oleanane, ursane, and lupane, with 92 to 110 monoacetonide (compound 122), turkesterone (compound
representative compounds (Figure 3). Additionally, one 123), and polypodine B (compound 124), have been identified
metabolite with a taraxerane skeleton (compound 111) has been in the leaves of this plant (Thoa et al., 2018). Additionally, this
isolated, further enriching the chemical profile of this species (Yong- species is known to contain several sterol
Sheng Chen et al., 2010; Djimabi et al., 2021). Given the abundance derivatives—specifically phytosterols (compounds 112–118)
of triterpenoids in their free form in V. trifolia, Mohamed et al. have and an ergostanoid (compound 119)—which have been

FIGURE 2
(Continued).
reported to contribute to the phytochemical diversity of the plant from the seeds (Guan et al., 2010). These isolated compounds have
(Huang et al., 2013; Ban et al., 2018; Li et al., 2020b). been observed to exist either as free-standing molecules or in
glucosidic form, often conjugated mainly with glucose units, as
seen in structures 126, 128–131, and 136–137. Furthermore, a
5.2 Flavonoids distinct glucoside, the neohesperidoside moiety, has been
discovered in a conjugated form as quercetin 7-O-
Figure 4 presents a detailed representation of the varied neohesperidoside (compound 134), within the ethyl acetate
flavonoid subclasses identified within V. trifolia, including extract of the plant (Mohamed et al., 2013). This array of
flavones (entities 125–132), flavonols (entities 133–142), and flavonoid derivations not only highlights the chemical complexity
flavanones (entities 143–144). Among these, a particular focus of V. trifolia but also signifies the potential of the plant as a resource
has been noted on methoxylated flavones, specifically for multifaceted bioactive compounds.
compounds 132 and 135–141. These compounds are
characterized by having between two to five methoxyl groups
and have been detected primarily within polar extracts or 5.3 Lignans, phenylpropanoids
fractions derived from the fruits and leaves of the plant (Lee and xanthones
et al., 2013; Li et al., 2020a).
Further studies have resulted in the isolation of specific Matairesinol 4′-O-β-D-glucopyranoside 145 was a new lignan
methoxylated flavones, including vitexicarpin (compound 135), isolated from leaves by Ban and his co-workers (Ban et al., 2018).
artemetin (compound 138), and chrysoplenol D (compound 140) The metabolite 153 dimer structure of dihydro-benzofuran

FIGURE 2
(Continued). Chemical structure of diterpenoids isolated from V. trifolia.
neolignan was separated from the fruit butanol extract (Gu et al., obtained from stems and leaves (Figure 6) (Quan-Yu Liu
2008). Recently, six new xanthone dimers (161–166) and seven et al., 2014).
known analogues (167–173) have been reported of ethyl acetate The investigation focused on the impact of four distinct
extract of Diaporthe goulteri L17, vitex fungi, phenylpropanoid, and drying methods on the antioxidant properties of V. trifolia:
xanthone metabolites of this species are represented in Figure 5 microwave-drying, oven-drying, sun-drying, and freeze-drying.
(Peng et al., 2021). The findings indicated that the non-thermal method—freeze-
drying—and microwave-drying better preserved the antioxidant
properties of the leaves compared to oven-drying and sun-drying,
5.4 Miscellaneous which both resulted in decreased antioxidant properties. In terms
of total phenolic content (TPC) and total flavonoid content
Only isolated anthraquinone, physcion 174, was produced (TFC), V. trifolia leaves retained TPC and TFC values of
through the polyketide pathway (Chemical metabolites from 4,664 ± 109 GAE/100 g and 637 ± 10 mg QE/100 g,
fruits of V. trifolia). Benzoic acid and derivatization (175–182) respectively. These values significantly surpass those of mature
instance vanillin 181 were isolated from different plant parts plants, which showed TPC of 3,229 ± 36 GAE/100 g and TFC of
(Djimabi et al., 2021). Furthermore, saturated, and unsaturated 87.0 ± 0.5 mg QE/100 g) (Chong and Lim, 2012; Chandrasekaran
long-chain fatty acids (185–187) and alcohol (188) were et al., 2019).

FIGURE 3
(Continued).
5.5 Essential oils climate, topography, and soil composition), as well as age and
genetic type of the plants (Barra, 2009).
Extensive analyses have been performed on essential oils (EOs) Overall, V. trifolia is particularly rich in monoterpene
from various parts of the V. trifolia species, including seeds, leaves, hydrocarbons, ranging from 4.04% to 44.57%, and oxygenated
aerial components, and flowers. Notably, an Indian research group monoterpenes between 6.13% and 31.26%. Metabolites such as
achieved the highest yield of EOs from leaves at 5% utilizing steam cis-ocimene (199) at 44.57%, α-pinene (191) ranging from 4.04%
distillation. Figure 7 illustrates the chemical structures of the major to 23.87%, sabinene (193) from 9.44% to 39.14%, 1,8-cineole (197)
metabolites found within these EOs. β-caryophyllene (202), a at 6.13%–31.26%, and terpinyl acetate (198) between 9.6% and
volatile sesquiterpene commonplace across numerous Vitex 13.48% are among the key chemical constituents
species, has been consistently identified in V. trifolia, as characterizing these oils.
referenced in nine previous studies, commanding a majority
presence in five of these—specifically within the EOs derived
from leaves and flowers (Suksamrarn et al., 1991; Musa et al., 6 Biological activities of V. trifolia
2022). This metabolite has a defensive role in many plants,
released in both direct and indirect defence mechanisms against 6.1 Bioactivities of the extracts
insect and pathogens (Barreto et al., 2021). Moreover, 1,8-cineole
(197) features prominently in V. trifolia essential oils. Variations in 6.1.1 Antioxidant activity
the yields and the makeup of EOs metabolites, as presented in Furthermore, an examination of the antioxidant activities of
Supplementary Table S2, are attributable to such factors as the ethanol extracts from two Vitex species, V. negundo L., and V.
harvest timing, environmental conditions (including altitude, trifolia after 30 min exposure to DPPH, revealed that V. negundo

FIGURE 3
(Continued). Chemical structure of triterpenoids and phytosterols isolated from V. trifolia.
had greater antioxidant activity ranging from 62.6% to 94.22% with hepatoprotective effects of the tested metabolite were found to be
an IC50 value between 23.5–208.3 μg/mL. In comparison, V. trifolia comparable to those of the standard drug, silymarin, administered at
exhibited a slightly lesser range of antioxidant activity from 60.87% a dosage of 100 mg/kg b. w. with 7 days exposure. This similarity is
to 89.99% with an IC50 value ranging from 40.0 to 226.7 μg/mL. evident from the significant reduction in the serum levels of key liver
Given the total phenolic and flavonoid content, V. negundo showed enzymes, namely, glutamate pyruvate transaminase (SGPT) (342 U/
higher levels with 89.71 mg GAE/g dry weight of the extract and l in the control group vs. 88 U/l in the treatment group), glutamate
63.11 mg QE/g dry weight of the extract, respectively, whereas V. oxaloacetate transaminase (SGOT) (358 U/l in the control group vs.
trifolia had 77.20 mg GAE/g phenolics and 57.41 mg QE/g 136 U/l in the treatment group), and alkaline phosphatase (ALP)
flavonoids by dry weight of the extract in the in vitro study (416 U/l in the control group vs. 180 U/l in the treatment group).
(Saklani et al., 2017). Additionally, there is a decrease in the levels of total bilirubin
Additionally, V. trifolia demonstrated an IC50 value of 64.5 μg/ (1.2 mg/dL in the control group vs. 0.8 mg/dL in the treatment
mL in DPPH scavenging activity. This result supports the use of V. group) and gamma-glutamyl transpeptidase (GGTP) (251 U/l in the
trifolia as a traditional remedy for ciguatera fish poisoning, control group vs. 136 U/l in the treatment group), further
endorsing its therapeutic efficacy (Kumar-Roiné et al., 2009). confirming the hepatoprotective activity of the metabolite
(Anandan et al., 2009). This reduction in enzyme levels
6.1.2 Hepatoprotective activity underscores the therapeutic value of the treatment in maintaining
In an in vivo study the ethanolic extract of V. trifolia flowers at the liver health.
200 mg/kg b. w. dose exhibited significant hepatoprotective activity In an in vivo study, the acute toxicity assessments of ethanol and
against CCl4-induced hepatic injury in rats after 7 days treatment, aqueous leaf extracts of V. trifolia revealed LD50 values of 200 mg/kg
demonstrating remarkable hepatoprotective potential. The observed b. w., p. o. and 300 mg/kg b. w., p. o., respectively. Subsequently,

FIGURE 4
Chemical structure of flavonoids isolated from V. trifolia.
doses of 20 mg/kg b. w., p. o. and 30 mg/kg, b. w., p. o. of these 6.1.3 Antispasmodic activity
extracts were selected to evaluate their hepatotoxic activity. The In an in vivo study the assessment of viteosin-A (34) and
study demonstrated that both extracts, administered for 14 days, vitexicarpin (135), the primary active metabolites present in the
significantly reduced the total bilirubin levels. In the context of CCl4- n-hexane extract of V. trifolia, demonstrated that only vitexicarpin
induced hepatic toxicity (control group), the total bilirubin levels exhibited activity in the tracheospasmolytic bioassay. Notably, this
were 2.50 ± 0.04 mg/dL in the CCl4 group compared to 0.63 ± activity was observed at a minimum dose of 1.3 × 10−5 M, for 30 min,
0.01 and 0.93 ± 0.01 in the CCl4 + ethanol extract and CCl4 + utilizing sensitized guinea pig trachea stimulated by ovalbumin. The
aqueous extract groups, respectively. Furthermore, the serum findings suggest that vitexicarpin could potentially hinder the effects
marker enzymes showed a decrease in CCl4-induced hepatic of histamine released from sensitized mast cells by stabilizing the
toxicity, as indicated by the ALT levels decreasing from membrane function of the mast cells (Alam et al., 2002).
1,322.33 IU/L in the CCl4 group to 106.43 IU/L and 124.17 IU/L
in the CCl4 + ethanol extract and CCl4 + aqueous extract groups, 6.1.4 Anti-inflammatory activity
respectively. Similarly, ALP levels reduced from 442.10 IU/L in the In an in vivo study, the anti-inflammatory properties of the
CCl4 group to 202.47 IU/L and 236.91 IU/L in the CCl4 + ethanol hydroalcoholic extract of V. trifolia were investigated in rats at doses
extract and CCl4 + aqueous extract groups, respectively. of 100 mg/kg b. w. and 200 mg/kg b. w. The study demonstrated that
Concomitantly, there was an increase in the total protein levels the higher dose exhibited an inhibitory effect, as evidenced in the
in the animal subjects experiencing CCl4-induced hepatic toxicity, paw volume of 0.37 mL ± 0.01 after 5 h, compared to the control
with values of 5.93 ± 0.01 g% in the CCl4 group compared to 8.24 ± group treated with indomethacin, which had a paw volume of
0.03 and 8.05 ± 0.03 g% in the CCl4 + ethanol extract and CCl4 + 0.16 mL ± 0.01. The percentage inhibition of inflammation and
aqueous extract groups, respectively. These findings suggest the edema formation at the end of 5 h was 72.23%, while indomethacin
potential hepatoprotective effects of the ethanol and aqueous leaf demonstrated a higher percentage inhibition of 90.46%. The mean
extracts of V. trifolia, as they alleviate CCl4-induced hepatic toxicity values for total leucocyte count in the group treated with the
by modulating key biochemical markers (Manjunatha and hydroalcoholic extract were 9,333 ± 448 cells/cm3, whereas
Vidya, 2008). animals treated with indomethacin showed a count of 11,717 ±

FIGURE 5
(Continued).
444 cells/cm3. In the group treated with 200 mg/kg b. w., the 264.7 cells that were exposed to 10 μg/mL of lipopolysaccharide
percentage of polymorphonucleocytes and lymphocyte count was (LPS) for 24 h (Kumar-Roiné et al., 2009).
23.33% and 73.67%, respectively, while the indomethacin-treated The anti-inflammatory properties of leaf extracts from V. trifolia
group showed a count of 23.83% and 70.50%, respectively. were investigated through animal studies. The results revealed that
Furthermore, the groups treated with the hydroalcoholic extract the extract, administered at 200 mg/kg b. w., exhibited dose-
exhibited reduced levels of macrophages, mast cells, and other dependent anti-inflammatory effects. At this dosage, both
inflammatory mediators compared to the control group, aqueous and ethanolic extracts showed a significant activity (p <
indicating its potential to mitigate inflammation (Ankalikar and 0.0001) against the acute inflammatory response, demonstrating
Viswanathswamy, 2017). reductions of 46.91% and 60.49%, respectively. Although these
Of the 28 aqueous extracts of plants examined in an in vitro values were less than that of the reference standard (70.27%) on
study, V. trifolia demonstrated a notable ability to inhibit NO xylene-induced ear edema, the ethanolic extract inhibited edema
production without inducing toxicity. Specifically, at a notably at the 3rd hour (43%) in carrageenan-induced paw edema
concentration of 0.25 g/L of the tested extract, aqueous extracts compared to other treated groups. This effect was consistent in both
of V. trifolia exhibited significant NO inhibitory effects in RAW carrageenan-induced rat paw edema and xylene-induced ear edema

FIGURE 5
(Continued). Chemical structure of lignans, phenylpropanoids and xanthones isolated from V. trifolia.
in mice, underscoring the potential of V. trifolia as an effective anti- extracts prepared by maceration in ethanol and ultrasonication in
inflammatory agent (Kulkarni, 2011). dichloromethane exhibited the highest activity (60%–80% compared
An aqueous extract of V. trifolia leaf at a concentration of to untreated macrophages) in inhibiting IL-1β and TNF-α
2,500 μg/mL exhibited an inhibitory activity on the synthesis of production in human U937 macrophages after 6 h incubation.
interleukin (IL)-1, IL-6, IL-10, and iNOS mRNA with a mild effect These findings suggest that these specific extraction methods and
on tumor necrosis factor (TNF)-α. These findings indicate that the solvents effectively extract bioactive metabolites from V. trifolia
extract has the potential to modulate the expression of these leaves with potent anti-inflammatory properties in macrophages
inflammatory mediators, suggesting its anti-inflammatory (Wee et al., 2020).
properties (Matsui et al., 2009). Furthermore, in an in vitro
study, it was found that the aqueous leaf extract of V. trifolia at a 6.1.5 Anticancer activity and toxicity data
concentration of 5,000 mg/mL and 8 h incubation time displayed a Screening of five samples, namely, Alpinia galanga (L.) Willd.
notable inhibitory effect on the expression of multiple inflammatory (Zingiberaceae), Piper cubeba L. f. (Piperaceae), and Santalum
genes induced by LPS in RAW 264.7 cells. This inhibitory effect was album L. (Santalaceae), along with V. trifolia. at a concentration
confirmed by a significant decrease in COX-2, CCL-3, and CXCL-10 of 25 μg/mL and incubated for 24 h, revealed a significant inhibitory
mRNA production (between 3 and 4-fold compared to the control activity against the T47D breast cancer cell line, with inhibition
group). Moreover, the extract exhibited inhibitory activity on LPS- percentages of 96.4%, 87.6%, 82.6%, and 88.7%, respectively.
induced p50 mRNA synthesis, further supporting its anti- Epirubicin and doxorubicin were used as positive control, and
inflammatory properties (Matsui et al., 2012). DMSO for negative control (Dai et al., 2018). The cytotoxic
The effect of V. trifolia leaf extracts, obtained through different activities of the V. trifolia aerial parts were evaluated in an in
extraction methods, on cytokine production, such as IL-1β and vivo study using three different extracts: methanol, ethyl acetate,
TNF-α in human U937 macrophages, was examined in an in vitro and chloroform. The brine shrimp bioassay method was employed
study. Among various extraction techniques tested (Soxhlet, for this purpose. The results indicated that the methanolic extract
ultrasonication, and maceration) and using different solvents, the exhibited the highest cytotoxic activity, with an LC50 value of

FIGURE 6
Chemical structure of Miscellaneous metabolites isolated from V. trifolia.
FIGURE 7
Chemical structures of the major secondary metabolites from V. trifolia essential oil.

FIGURE 8
Biosynthesis pathways of terpenoids (A) and iridoids (B).
140 mg/mL. The ethyl acetate extract showed slightly lower The synergistic anticarcinogenic effects of ethanolic extracts
cytotoxicity, with an LC50 value of 165 mg/mL. Lastly, the from V. trifolia L. and Triticum aestivum L. (Poaceae) were
chloroform extract displayed the least cytotoxicity among the investigated in an in vitro study. Both extracts demonstrated
three, with an LC50 value of 180 mg/mL, compared with anti-degranulation properties individually, and their combination
potassium dichromate as the positive control (El-Kousy et al., 2012). synergistically enhanced the anticarcinogenic potential. This was
The cytotoxicity of different extracts from V. trifolia was observed through their ability to inhibit 3,8-diamino-5-ethyl-6-
assessed on brine shrimp and Hep-G2 cell lines. The tested phenylphenanthridinium bromide-induced liver microsomal
extracts included the crude hot aqueous-methanol extract, degranulation. Additionally, these extracts exhibited inhibitory
chloroform-methanol extract, ethyl acetate methanol extract, and effects on cell proliferation in HCT116 and A549 cell lines. These
the residue from the methanol extract. Notably, the residue from the findings highlight the potential of V. trifolia and T. aestivum extracts
methanol extract exhibited the highest cytotoxic activity, showing an as synergistic agents in cancer prevention and treatment
IC50 value of 6 μg/mL against Hep-G2 cells. The crude hot aqueous- (Mathankumar et al., 2015).
methanol extract, chloroform-methanol extract, and ethyl acetate Another in vitro study investigated the impact of gamma
methanol extract demonstrated IC50 values of 10.7 μg/mL, 20.8 μg/ irradiation treatment at a dose of 7.5 kGy (source: 60Co) on the
mL, and 65.8 μg/mL, respectively, in comparison to the positive dried coarse powder of legundi leaves, focusing on its potential as an
control. These findings indicate varying degrees of cytotoxicity anticancer agent and its chromatogram profile. The IC50 values of
against Hep-G2 cells for different V. trifolia extracts, with the legundi leaf extract against MCF cancer cells after 72 h of incubation
residue from the methanol extract displaying the most potent increased from 8.2 μg/mL to 12.1 μg/mL after exposure to the
activity. Interestingly, the same trend was observed in the brine irradiation dose of 7.5 kGy. Similarly, for HeLa cells, the IC50
shrimp assay (El-Sayed et al., 2011). value increased from 7.6 μg/mL to 16.9 μg/mL, and for K-562
In an in vitro study, the dichloromethane extracts of V. trifolia cells, it increased from 19.7 μg/mL to 22.4 μg/mL (Winarno
leaf demonstrated significant toxicity against various cancer cell et al., 2020).
lines, including SQC-1 UISO, OVCAR-5, HCT-15 COLADCAR,
and KB with ED50 of 2.2 mg/mL, 2.9 mg/mL, 1 mg/mL, and 1.9 mg/ 6.1.6 Anti-amnesic activity
mL, after 72 h incubation respectively. These findings highlight the In the passive avoidance and T-maze models, a high dose
potential of V. trifolia leaf extracts as a source of metabolites with (20 mg/kg, b. w.) of aqueous V. trifolia leaf extract demonstrated
cytotoxic activity against different cancer cell lines (Hernandez a significant (p < 0.01) anti-amnesic activity. The extract led to a
et al., 1999). notably shorter escape latency time (12s) compared to the control

FIGURE 9
Biosynthesis of flavonoid.
group (29s) and showed a maximum percentage of time spent in the that Vitex trifolia exhibited the highest larvicidal activity against C.
probe quadrant by 60.75%. This result was nearly twice as high as quinquefasciatus larvae, with the most effective results. This was also
that of the control group, indicating improved memory retention observed in the investigation of the larvicidal activity of fatty acid
compared to both the control and other treatment groups methyl ester extracts, where V. trifolia demonstrated the highest
(Mohanbabu et al., 2015). larvicidal activity among the species tested. Furthermore, a
comparative study investigated the effects of the extracts from
6.1.7 Larvicidal activity three Vitex species on Anopheles gambiae s.s. larvae, revealing
Vitex trifolia demonstrated effective repellency against that the methanol extract of V. trifolia leaves and acetone
mosquitoes at a minimal dosage, as evidenced by Gou et al., in extracts of V. schiliebenii stem bark and leaves, as well as V.
2020 (Gou et al., 2020). Additionally, a study by Tandon et al., in payos (Lour.) Merr. root bark, exhibited significant potency,
2008 compared the essential oils (EOs) of both Vitex trifolia and causing 100% mortality at a concentration of 100 ppm within
Vitex agnus-castus L. and found that although the EO of Vitex 72 h. The larvicidal efficacy of four different Vitex species was
agnus-castus L. was less effective than that of Vitex trifolia, both EOs evaluated against C. quinquefasciatus larvae, revealing that V.
increased larval duration, larval mortality, pupal duration, and adult trifolia exhibited the highest larvicidal activity with an LC50 value
deformity, while decreasing adult emergence, fecundity, and egg of 41.41 ppm (Kannathasan et al., 2007). Among the species
fertility (Tandon et al., 2008). examined for their fatty acid methyl ester extracts, V. trifolia
Chandrasekaran et al. in an in vivo study conducted in 2019, demonstrated the highest larvicidal activity with an LC50 value of
revealed that the EO of Vitex trifolia exhibited potent larvicidal 9.25 ppm, highlighting its potent properties (Kannathasan
activity, resulting in 100% mortality against third instar stages of et al., 2008).
Aedes aegypti and Culex quinquefasciatus larvae at 125 ppm. The Additionally, a comparative in vivo study on the effects of
GC-MS analysis of the Vitex trifolia EO identified several bioactive extracts from three Vitex species on A. gambiae s.s. larvae at
metabolites, including eucalyptol (197), which accounted for 16.35% concentrations ≤ 50 ppm and 24 h time interval, found
of the total peak area, followed by sabinene (193) with 9.44%, and β- significant potency in the methanol extract of V. trifolia leaves,
caryophyllene (202) with 8.91%, which might contribute to its acetone extracts of V. schiliebenii stem bark and leaves, and acetone
larvicidal properties (Chandrasekaran et al., 2019). Comparative extract of V. payos (Lour.) Notably, V. schiliebenii and V. payos
evaluations of larvicidal efficacy among different Vitex species found extracts demonstrated a faster mortality rate in A. gambiae s.s. larvae

compared to V. trifolia, indicating their potential as effective agents In another in vitro study, the antifungal and cytotoxic activities
for controlling A. gambiae s.s. larvae, and their promise for further of hexane, methanol, and distilled water extracts of V. trifolia were
investigation in mosquito control programs to combat malaria screened against six standard organisms. Results showed that all
transmission (Nyamoita et al., 2013). three extracts were active against Ceratocystis paradoxa with MIC in
the range of 1.25–5.0 mg/mL, and methanolic and hexanoic extracts
6.1.8 Antimicrobial activity showed MIC values of 1.25 and 2.5 mg/mL, respectively. However,
The V. trifolia leaf extracts, tested at a concentration of 200 μg/ these extracts were not potent against A. niger, P. citrinum, M.
mL for 30 min incubation time, demonstrated varying degrees of phaseoli, and R. nigricans (Haripyaree et al., 2021). The hexanoic
inhibition against different microorganisms in an in vitro extract obtained from V. trifolia leaves showed remarkable efficacy
experiment. The inhibition zone sizes (in mm) for each tested against the fungal plant pathogen Fusarium sp. Within the first
organism were as follows: Bacillus subtilis: 15.3 mm; 2 days of the experiment, the hexanoic extract completely inhibited
Staphylococcus aureus: 14.0 mm; Pseudomonas aeruginosa: the growth of the Fusarium sp. However, its inhibitory activity
13.6 mm; Proteus mirabilis: 13.5 mm; Candida tropicalis: dropped significantly to 15% on day six of the experiment. On the
12.8 mm; and Escherichia coli (E. coli): 12.5 mm; Candida other hand, the dichloromethane extract displayed a significant
albicans: 12.0 mm. The zinc oxide nanoparticles (ZnO NPs) growth inhibition of 54% against Fusarium sp. within 4 days of
coated with an extract of V. trifolia exhibited improved MIC the experiment (Hernandez et al., 1999).
value compared to uncoated ZnO NP. The increased
antimicrobial activity of the V. trifolia leaf extract can be 6.1.9 Antiviral activity
attributed to the presence of vitrifolin A (59), the major V.trifolia demonstrated significant antiviral activity against
metabolite in the extract. Vitrifolin A is believed to play a crucial Molluscum contagiosum and Herpes simplex, with effective
role in enhancing the antimicrobial properties of the extract. It concentrations of approximately 0.25 μg/mL and 0.5 μg/mL,
achieves this by binding to the surface of nanoparticles, thus leading respectively, at a 0.4 μg/mL concentration in an in vitro assay.
to a more effective and targeted delivery of antimicrobial agents. Importantly, this antiviral efficacy was achieved without causing
This mechanism enables vitrifolin A to exert a stronger impact on notable toxicity. These findings highlight the potential of V. trifolia
the microorganisms, contributing to the overall enhanced activity of as a promising natural source for developing safe and effective
the leaf extract against a range of pathogens (Elumalai et al., 2015). antiviral agents. Further exploration into the specific bioactive
The in vivo antibacterial activity of the ethanolic extract of V. metabolites and their mechanisms of action, as well as broader
trifolia leaves was evaluated at concentrations of 1%, 5%, or 25% applications in clinical settings, would enhance our understanding
against S. aureus in the Drosophila infection model. The results of the therapeutic potential of V. trifolia in antiviral interventions
indicated that 5% and 25% concentrations of the extract exhibited (Vimalanathan et al., 2009).
comparable activities. Therefore, the findings suggest that a 5%
extract concentration would be sufficient to combat S. aureus 6.1.10 Anti-HIV activity
infection (Sukarsih et al., 2021). Moreover, petrol extract (500 µg/ In a research study, the impact of aqueous and 80% ethanol
disk) and EtOH extract (400 µg/disk) of V. trifolia leaves were extracts from 20 medicinal plants of Thai on HIV type 1 reverse
moderately active against most of the tested Gram-positive and transcriptase activity was investigated. The results revealed that the
Gram-negative bacteria except Klebsiella sp., Vibrio cholera, and water extracts of Vitex glabrata R. Br. (branch), V. trifolia. (aerial
Vibrio mimicus with a diameter of the zone of inhibition in the range part), and Vitex negundo L. (aerial part) displayed a remarkably
of 8–15 mm (Hossain et al., 2001). good inhibition ratio (% IR) higher than 90% at a concentration of
The in vitro antibacterial activity of the leaf methanol extracts of 200 μg/mL in 1 h incubation. Doxorubicin hydrochloride, as a
Vitex altissima L. f, Vitex diversifolia Bak., Vitex negundo L., Vitex positive control, inhibited the HIV-1 RT activity at 1 mM by
peduncularis Wall. ex Schauer and Vitex trifolia was examined. V. 98.3%. These findings suggest that these specific extracts from V.
peduncularis showed the highest antimicrobial activity with a zone glabrata, V. trifolia, and V. negundo possess a strong potential as
of inhibition ranging between 11.00 and 22.67 mm; the MIC values candidates for further investigation in the development of anti-HIV
were from 62.5 to 1,000.0 μg/mL and the MBC values were from therapies due to their significant inhibitory effects on HIV-1 reverse
125.0 to 2000.0 μg/mL (Kannathasan et al., 2011). Methanol, transcriptase activity (Woradulayapinij et al., 2005).
ethanol, and ethyl acetate extract V. trifolia were prepared to
evaluate the antibacterial activities and showed MIC values of 25, 6.1.11 Anti-malaria activity
50, 50, 50, 50, and 25 against E. coli, S. flexneri, P. mirabilis, P. In an investigation utilizing semi-structured questionnaires and
diminuta, E. cloacae, and S. aureus ATCC 6538, respectively informant interviews to gather knowledge about plants associated
(Natheer et al., 2012). Screening of antimicrobial activities on the with malaria and related symptoms, the antimalarial potential of the
methanolic extracts of V. trifolia, against common freshwater extracts from 70 plant species, representing 62 genera and
pathogens showed an inhibition zone of 15 mm for A. hydrophila 34 families, was evaluated. The results highlighted Solanaceae as
and 11 mm for S. agalactiae, with no inhibition against E. cloacae. the most frequently cited family, with 7 species showing promising
Preliminary phytochemical screening of the plant extract showed antimalarial properties. Noteworthy results were observed within
the presence of tannins, flavonoids, and glycosides (Manaf and the Lamiaceae family, specifically Vitex negundo L. and Vitex trifolia
Daud, 2016). Antibiofilm screening of V. trifolia against H. pylori L., identified as antimalarial agents, with documentation from the
was moderately active (15 mm) with around 60% inhibition at Soon Valley region in Pakistan for the treatment of malaria. These
100 µM (Prasad et al., 2019). findings underscore the ethnobotanical importance of certain plant

species within communities for their potential antimalarial Six flavonoids, persicogenin (143), artemetin (138), luteolin
properties (Shah and Rahim, 2017). (127), penduletin (141), vitexicarpin (135) and chrysosplenol-D
(140), were isolated from V. trifolia inhibited the proliferation of
6.1.12 Respiratory disorder sFT210 cancer cells with the IC50s > 100 μg/mL (inhibition rate at
In an in vitro study screening the inhibitory effect of alcoholic 100 mg/mL was 21,47.9%) for persicogenin > 100 μg/mL (inhibition
and hexanoic extracts of V. trifolia on histamine release from RBL- rate at 100 mg/mL was 49.6%) for artemetin, 10.7 μg/mL for
2H3 cells revealed that 0.5 mg/mL resulted in more than 80% luteolin, 19.8 μg/mL for penduletin, 0.3 μg/mL for vitexicarpin,
inhibition of IgE-dependent histamine release from RBL-2H3 and 3.5 μg/mL for chrysosplenol-D in 17 h treatment. It was
cells (Ikawati et al., 2001). A separate study demonstrated that shown that the mentioned metabolites exerted their anti-
combining Curcuma xanthorrhiza Roxb. rhizome (Zingiberaceae; proliferative effect on tsFT210 cells via inhibiting the cell cycle
Curcumae xanthorrhizae rhizoma), V. trifolia leaves, Zingiber and inducing apoptosis (Li et al., 2005c).
officinale Roscoe. rhizome (Zingiberaceae; Zingiberis rhizoma) A variety of diterpenoids, including vitetrifolin I, D, E, F, H,
and Echinacea purpurea (L.) Moench herb (Asteraceae) exhibited (75–79), vitexoid (15), as well as vitexilactone (30), 6-acetoxy-9-
synergistic immunomodulatory effects. The combination, hydroxy-13 (14)-labdane-16,15-olide (39), previtexilactone (41),
administered at 490 mg/kg and 980 mg/kg, significantly enhanced and 6-acetoxy-9,13; 15,16-diepoxy-15-methoxylabdane (53), were
the macrophage phagocytic index, reaching 15.29 µgr/mL and 26.78 isolated from the fruits of V. trifolia. These metabolites
µgr/mL, respectively. These values were compared to E. purpurea as demonstrated inhibitory effects on the proliferation of Hela cells,
a positive control, with a phagocytic index of 12.53 ± 1 µgr/mL at with IC50 values ranging from 4 to 28 μM. Vitetrifolin I exhibited the
750 mg. Moreover, the combination increased the production of IgG strongest potency, inducing cell cycle arrest at the G0/G1 phase and
antibodies, with concentrations reaching 35 µgr/mL and 38 µgr/mL promoting apoptosis in Hela cells (Wu et al., 2009a). On the other
at doses of 490 mg/kg and 980 mg/kg, respectively. Again, these hand, seven labdane-type diterpenoids, namely, vitextrifolins A−G
values were compared to E. purpurea as a positive control, which (18–19, 21–25), derived from the fruits of V. trifolia, did not exhibit
showed a 35 µgr/mL concentration at 750 mg. This study highlights significant toxicity (IC50 < 5 μg/mL) against various cell lines,
the potential synergistic immunomodulatory effects of combining including human colon carcinoma (HCT116) in an in vitro
these botanical drugs (Ikawati et al., 2019). study, human lung adenocarcinoma (A-549), human
promyelocytic leukaemia (HL-60), and human breast carcinoma
6.1.13 Wound healing effect (ZR-75–30) (Zheng et al., 2013a). Twenty-seven diterpenoids
In a comparative analysis of wound healing potential, the derived from V. trifolia were examined for their inhibitory
ethanol leaf extract of V. trifolia demonstrated superior activity activity against DNA topoisomerase I. Among these metabolites,
compared to Vitex altissima L. f.. The incision wound tissue tensile vitextrifloxide G (72) and vitextrifloxide I (83) demonstrated
strength for the positive control was 600.00, while it was 578.20 for remarkable potency by exhibiting more than 81% inhibition at a
V. trifolia and 529.08 for V. altissima. Hydroxyproline levels, concentration of 100 µM. To further assess the effectiveness of
indicative of collagen formation, were higher in the ethanol leaf vitextrifloxide G, Luo et al.evaluated it using the MTT method in
extract of V. trifolia (2,567 µg/100 mg) compared to V. altissima human colorectal carcinoma cells (HCT116), resulting in an IC50
(2012 µg/100 mg), with a negative control registering at 1943 µg/ value of 20.3 µM (Luo et al., 2017c).
100 mg. Granuloma dry weight, a measure of tissue healing, was Diaporxanthone A (161) and diaporxanthone F (166) displayed
notably higher in V. trifolia (157.30 mg/100 g) compared to V. notable antifungal properties against Nectria sp. and C. musae
altissima (136.50 mg/100 g), with the control at 33 mg/100 g. (ACCC 31244), in the in vitro study. Diaporxanthone A
Additionally, in dead space wound tissue tensile strength, V. exhibited antifungal activity at a minimum dosage of 10.0 μg/
trifolia demonstrated enhanced strength (491.20 g) compared to scrip, while diaporxanthone F demonstrated effectiveness at a
V. altissima (430.50 g), surpassing the positive control (181 g). These lower dosage of 2.5 μg/scrip (Peng et al., 2021).
findings indicate that V. trifolia significantly improves the quality of In vitro minimum lethal concentrations of the isolated
wound healing and scar formation, outperforming V. altissima in metabolites of V. trifolia against epimastigotes of Trypanosoma
various wound healing parameters (Manjunatha et al., 2007). cruzi were 11 mM for 9,13-epoxy-16-norlabda-13E-en-15-aL (61),
36 mM for 6β-acetoxy-9α,13-epoxy-16-norlabd-13E-en-15-aL (63),
34 for mM vitexifolin E (60), 34 mM of vitexifolin F (78), 66 mM of
6.2 Bioactivities of pure metabolites vitexilactone (30), 66 mM of (6-acetoxy-9-hydroxy-13 (14)-labden-
16,15-olide) (39), and 265 mM of previtexilactone (41) (Kiuchi et al.,
Labdane-type diterpenes isolated from V. trifolia, namely, 2004). Besides the bioactivities of the isolated metabolites from V.
vitexilactone (30), (5S,6R,8R,9R, 10S)-6-acetoxy-9-hydroxy-13 trifolia, the following metabolites can be highlighted as the
(14)-labden-16,15-olide (39), rotundifuran (26), vitetrifolin D major known ones.
(76), and vitetrifolin E (77), exhibited remarkable effects on
cellular processes. In an in vitro study, at higher concentrations 6.2.1 Casticin
(100.0 μg/mL), these metabolites demonstrated a significant Casticin (135), a flavonoid isolated from V. trifolia, has
induction of apoptosis in both tsFT210 and K562 cells. demonstrated anti-inflammatory and antitumor effects on
Conversely, at lower concentrations, they impeded the cell cycle ADTC5 cells. However, it exhibited significant toxicity at a
progression of both tsFT210 and K562 cells, specifically at the G0/ concentration of 40 μM after 2 h of treatment. In a dose-
G1 phase (Li et al., 2005b). dependent manner at concentrations of 10, 20, and 30 μM, in

2 h incubation time, casticin reduced proinflammatory cytokines respectively. Moreover, after 48 h of incubation, artemetin
such as IL-6, TNF-α, and prostaglandin E2 (PGE2), as well as displayed inhibitory effects on the cell growth in
oxidative stress markers including MDA and inducible nitric U937 macrophages, with IC50 values of 125.6 ± 15.3 μg/mL
oxide synthase (iNOS) expression. Specifically, at 30 μM, casticin (323.4 ± 39.3 μM). These results suggest the potential of
downregulated IL-6 protein expression in IL-1β-stimulated artemetin in modulating inflammatory responses and
ADTC5 to 40 pgr/mL compared to 67 pgr/mL in the control inhibiting the growth of U937 macrophages (Wee et al., 2020).
group. It also downregulated TNF-α protein expression to
50 pgr/mL from 110 pgr/mL in the control group and reduced 6.2.4 Methyl-p-hydroxybenzoate
PGE2 protein expression to 600 pgr/mL from 1,150 pgr/mL in the In an in vivo study, the larvicidal activities of methyl-p-
control group. These findings highlight the potential of casticin hydroxybenzoate (182), isolated from the methanol extract of V.
in modulating inflammatory responses and oxidative stress (Chu trifolia leaves, were evaluated against early 4th instar larvae of C.
et al., 2020). quinquefasciatus and A. aegypti mosquitoes. Remarkably, the
In a murine asthma model, administering casticin at doses of metabolite exhibited complete mortality of the larvae for both
5 or 10 mg/kg b. w. effectively mitigated airway mosquito species at a concentration of 20 ppm. The LC50 values
hyperresponsiveness, airway inflammation, and oxidative stress in were 5.77 ppm for C. quinquefasciatus and 4.74 ppm for A. aegypti.
the lungs. These beneficial effects were attributed to regulating These findings underscore the potent larvicidal activity of methyl-
Th2 cytokine and chemokine gene expression within the lung. phydroxybenzoate against the larvae of these disease-carrying
Casticin also demonstrated significant suppression of mosquito species, suggesting its potential application as an
proinflammatory cytokine levels and eotaxin. Specifically, casticin effective and eco-friendly agent in mosquito control programs
reduced the IL-6 levels compared to the ovalbumin (OVA)-induced (Kannathasan et al., 2011).
asthma group (70.4 ± 4.4 pg/mL in the control group vs. 37.4 ±
4.1 pg/mL in the prednisolone positive control; casticin at doses of 5: 6.2.5 Vitepyrroloid A
57.7 ± 5.9 pg/mL, and casticin at doses of 10: 42.1 ± 7.1 pg/mL). The metabolite vitepyrroloid A (64), when evaluated on the
Furthermore, casticin increased the INF-γ levels compared to the human nasopharyngeal carcinoma cell line CNE1, exhibited
OVA group (93.6 ± 11.7 pg/mL in the control group vs 49.6 ± 9.5 pg/ cytotoxic activity with an IC50 value of 8.7 μM after 3 days. This
mL in the prednisolone positive control; casticin at doses of 5: is compared to cisplatin as positive control, which had an IC50 value
109.5 ± 9.5 pg/mL, and casticin at doses of 10: 121.9 ± 23.7 pg/mL). of 4.6 ± 0.1 μM. These findings suggest the potential cytotoxic
Additionally, it successfully reduced the adherence of THP-1 efficacy of the metabolite against CNE1 cells, although cisplatin
monocyte cells to BEAS-2B cells by suppressing ICAM-1 demonstrated a slightly lower IC50 value in this context (Luo
expression, with ICAM-1 level decreasing from 1,300 pgr/mL in et al., 2017c).
control to approximately 600 pgr/mL with 20 µM casticin. These
findings underscore the potential of casticin as a therapeutic 6.2.6 Vitextrifloxide G
intervention for asthma-related inflammation (Liou et al., 2018). Vitextrifloxide G (72) exhibited an IC50 value of 20.3 µM against
HCT 116 human colorectal carcinoma cells in an in vitro study (Luo
6.2.2 Rotundifuran et al., 2017c).
Rotundifuran (26) demonstrates notable suppression of cervical
cancer cell lines, particularly HeLa and SiHa cells, with an IC50 of 6.2.7 Vitexilactone
less than 10 μM in 24 and 48 h treatments, indicating its potent anti- In an in vitro experiment, vitexilactone (30) demonstrated
proliferative activity. This suppression is attributed to the induction the ability to enhance lipid accumulation and promote the
of apoptosis in vitro, underscoring its potential as an effective expression of adiponectin and GLUT4 on the membrane of
antitumor agent. Antitumor properties of rotundifuranare 3T3-L1 cells. Moreover, it effectively reduced the size of
associated with its capability to target ROS-induced adipocytes and suppressed the phosphorylation of IRS-1,
mitochondrial-dependent apoptosis involving the MAPK and ERK1/2, and JNK in 3T3-L1 cells through PPARγ mediation.
PI3K/Akt signalling pathways. In vivo studies further validate the These findings suggest that vitexilactone holds promise as a
antitumor effects of rotundifuran, showcasing a reduction in tumor potential candidate for developing improved antidiabetic
size to around 190 mm3 at 40 mg/kg, in comparison to cis-platinum agents (Nishina et al., 2017).
treatment as a positive control at 3 mg/kg/3 days, resulting in tumor
size of 200 mm3. These findings highlight the promising potential of 6.2.8 (-)-O-Methylcubebin
rotundifuran as a therapeutic agent against cervical cancer (Gong In an in vitro study, (-)-O-methylcubebin (149) exhibited
et al., 2021). significant antidiabetic properties at doses ranging from 1.5 to
50 µM. (-)-O-Methylcubebin showed no toxicity at 50 µM or less
6.2.3 Artemetin after 48 h of incubation in 3T3-L1 cells. It reduced the size of the
In an in vitro study, artemetin (138) demonstrated adipocyte and facilitated the expression of proteins associated with
suppressive effects on TNF-α and IL-1β at concentrations of adipogenesis, including adiponectin. Molecular analysis revealed
50 μg/mL and 100 μg/mL, leading to a reduction of TNF-α levels that methylcubebin acted as an agonist for PPARγ, thereby
to 20% and IL-1β levels to 30% of their original concentrations promoting adipogenesis by inhibiting the phosphorylation of
after 48 h treatment. Dexamethasone at 64.4 ng/mL was the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK
positive control, exhibiting a 0.25 and 40-fold change, (Ukiya et al., 2019a).

6.2.9 Vitexicarpin experimental testing of pharmaceutical interventions. With this

Vitexicarpin (135) exhibited substantial inhibitory effects on the strategic approach, the intention is to position V. trifolia and its
growth of human cancer cells. In an in vitro study, it displayed IC50 bioactive metabolites as potential sources for the development of
values of 0.44 µM and 0.28 µM against HT-1080 and K562 cells, effective treatments across a broader spectrum of diseases, including
respectively, after 24 h and IC50 values of 19 μM and 0.66 µM against neurodegenerative disorders, cardiovascular diseases, metabolic
A2780 and HCT-15 cells after 48 h of treatment. This metabolite disorders, and infectious diseases. This potential is attributed to
also led to distinct morphological changes indicative of apoptosis, their high concentrations of antioxidants, phenolic metabolites, and
and flow cytometric analysis revealed a dose-dependent sub-G0/ flavonoids. By broadening the focus beyond the initial therapeutic
G1 peak (Wang et al., 2005). targets, efforts will be made to uncover new possibilities and
contribute to the growing body of knowledge on the versatile
6.2.10 9-Hydroxy-13 (14)-labden-15,16-olide pharmacological effects of V. trifolia.
9-hydroxy-13 (14)-labden-15,16-olide (36) displayed Beyond the traditional approach to drug development, cutting-
noteworthy efficacy against Mycobacterium tuberculosis H37Rv, edge methodologies are incorporated to harness nanotechnology for
with a MIC of 100 μg/mL in an in vitro study, compared to enhanced drug delivery and improved bioavailability. The feasibility
streptomycin, a reference antibiotic, exhibited a lower MIC value of nanoformulations derived from V. trifolia should be investigated,
of 2.0 μg/mL. These results highlight the potential antimycobacterial exploring their potential in targeted drug delivery systems designed
activity of 9-hydroxy-13 (14)-labden-15,16-olide, despite its MIC to enhance efficacy, reduce side effects, and facilitate the penetration
being higher than the reference streptomycin (Tiwari et al., 2013). of bioactive metabolites into specific cells or tissues.
Finally, the intention was to present a roadmap for future
6.2.11 Isoambreinolide research directions, emphasizing the translation of laboratory
In the BACTEC-460 assay, isoambreinolide (55) displayed findings into clinical applications and the continued
notable antimycobacterial properties, demonstrating significant investigations into the therapeutic potential of V. trifolia and its
antitubercular activity against M. tuberculosis H37Rv. The MIC bioactive metabolites. This comprehensive approach aims to bridge
of isoambreinolide was determined to be 25 μg/mL, while the gap between traditional knowledge and practical medical
streptomycin, a reference antibiotic, showed a lower MIC value applications, with the boundaries of V. trifolia research intended
of 2.0 μg/mL. These results indicate the potential of isoambreinolide to improve healthcare.
as an antimycobacterial agent, albeit with a slightly higher MIC than
the reference (Tiwari et al., 2013).
8 Conclusion
6.2.12 Diaporxanthone D
In an in vitro experiment, diaporxanthone D (164) exhibited This comprehensive review has documented the intricate
notable cytotoxic effects on EC109, A2870, HepG2, PC3, A549, and phytochemical profile of V. trifolia, particularly emphasizing its
HBE cell lines, with IC50 values of 1.88, 8.11, 4.49, 1.66, 8.4 and diverse ethnomedicinal applications. The identification of a myriad
6.5 μM, respectively (Peng et al., 2021). of bioactive compounds, encompassing a broad spectrum of
terpenoids, flavonoids, lignans, phytosterols, phenylpropanoids,
6.2.13 Miscellaneous and xanthones, with a notable abundance of labdane
In an in vitro study, Bao et al. evaluated diterpenoid glucoside, diterpenoids, adds depth to our understanding.
(3S,5S,6S,8R,9R, 10S)-3,6,9-trihydroxy-13 (14)-labdean-16,15-olide Furthermore, the elucidation of the biosynthetic pathways for
3-O-β-D-glucopyranoside (69), and an iridoid glucoside, (1S, 5S,6R, terpenoids, flavonoids, and iridoids provides a crucial foundation for
9R)-10-O-p-hydroxybenzoyl-5,6β-dihydroxy iridoid 1-O-β-D- exploring the molecular mechanisms underlying the synthesis of
glucopyranoside (3) along with viteagnuside A (70), 10-O- these bioactive constituents in V. trifolia.
vanilloylaucubin (2), agnusoside (6), nishindaside (7), 3-normal- Modern pharmacological investigations affirm the extensive
butyl-nishindaside (8) and 3-normal-butyl-isonishindaside (9) therapeutic role of V. trifolia in addressing diverse health issues,
isolated from V. trifolia on nitric oxide production in LPS- ranging from tendon-and-bone-related conditions to infections and
induced RAW 264.7 macrophages. Among the tested metabolites, inflammations. Notably, the research underscores the potent biological
(1S,5S,6R, 9R)-10-O-p-hydroxybenzoyl-5,6β-dihydroxy iridoid 1- activities of the plant, highlighting its antioxidant, anti-inflammatory,
O-β-D-glucopyranoside, 10-O-vanilloylaucubin, agnusoside, and hepatoprotective, and anti-cancer properties. The confirmed
3-normal-butyl-nishindaside displayed moderate inhibitory antimicrobial, antiviral, anti-malarial, and anti-spasmodic effects
activities, with IC50 values of 90.05 μM, 88.51 μM, 87.26 μM, and further underscore the medicinal efficacy inherent in V. trifolia.
76.06 μM, respectively. These values were compared to Moreover, advancements in analytical techniques offer deeper
hydrocortisone as a positive control, which exhibited an IC50 insights into the phytochemistry of V. trifolia, paving the way for
value of 58.79 ± 3.32 μM (Bao et al., 2018). identifying and characterizing novel secondary metabolites.
Integrating highly precise analytical methods with bioassay-
guided fractionation enriches our understanding of the plant’s
7 Therapeutic development goals phytochemistry and establishes a framework for future
pharmacological explorations. This review, thus, contributes to
Utilizing the identified bioactive metabolites, the initiation of a the evolving landscape of V. trifolia research, providing a
new phase of research focuses on the targeted design and platform for continued investigation into its therapeutic potential.

Furthermore, due to the lack of clinical trials, our study Investigation, Methodology, Software, Writing–original draft. AD:
emphasizes the necessity to conduct such trials to test the plant Formal Analysis, Investigation, Methodology, Validation,
products’ efficacy. However, it is essential to highlight that further Writing–original draft. MN: Data curation, Formal Analysis,
toxicological investigations are required to explore safety aspects Methodology, Visualization, Writing–review and editing. FR:
comprehensively. Moreover, investigating the bioavailability of the Data curation, Formal Analysis, Funding acquisition, Software,
plant’s bioactive chemicals provides valuable insights into their Writing–original draft. MH: Conceptualization, Project
absorption and distribution, making a substantial contribution to administration, Supervision, Validation, Writing–review and
a more profound understanding of their potential applications. editing. AI: Investigation, Methodology, Project administration,
The investigation of medicinal plants, including V. trifolia, Validation, Writing–original draft, Writing–review and editing.
encounters challenges and limitations such as variability in
bioactive compounds, complex synergistic effects, and a lack of
standardization; asides from limited clinical evidence, potential Funding
adverse effects, regulatory issues, and ethical concerns in
harvesting further constrain research. Our study proposes The author(s) declare that no financial support was received for
conducting rigorous scientific investigations and fostering the research, authorship, and/or publication of this article.
collaboration to bridge the gap between traditional and modern
methodologies, using V. trifolia as a focal point.
Acknowledgments
9 Perspectives The authors thank the Vice-Chancellor for Research of Shiraz
University of Medical Sciences.
The exploration of the compounds within V. trifolia is
recommended, with a specific focus on integrating advanced
bioinformatics tools, particularly machine learning algorithms, Conflict of interest
and simulated modelling applications such as Swiss ADME,
Pkcsm, and Qikprop. The objective is to anticipate the potential The authors declare that the research was conducted in the
of predicting the interactions and characteristics of the bioactive absence of any commercial or financial relationships that could be
compounds present in V. trifolia. The application of predictive construed as a potential conflict of interest.
modelling holds promise in the pathway from initial compound
discovery to therapeutic application. Moreover, recognizing the
imperative need for translational research, the call for clinical Publisher’s note
trials within this category is underscored. Including clinical trials
is anticipated to bridge the gap between experimental findings and All claims expressed in this article are solely those of the authors
real-world therapeutic applications. This crucial step validates the and do not necessarily represent those of their affiliated
efficacy of V. trifolia-derived compounds and generates essential organizations, or those of the publisher, the editors and the
data for potential future pharmaceutical advancements. Integrating reviewers. Any product that may be evaluated in this article, or
bioinformatics and clinical trials will synergistically propel V. trifolia claim that may be made by its manufacturer, is not guaranteed or
research into a transformative phase, offering novel therapeutic endorsed by the publisher.
possibilities for global health improvement.
Supplementary material
Author contributions
The Supplementary Material for this article can be found online
JM: Conceptualization, Supervision, Validation, Visualization, at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1322083/
Writing–review and editing. MK: Data curation, Formal Analysis, full#supplementary-material
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*CORRESPONDENCE Javad Mottaghipisheh 1†, Marzie Kamali 2†,

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Vitex trifolia L., secondary metabolites, ethnomedicine, phytochemistry, bioactivities

1 Introduction plant parts and extracts utilized, also different separation

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6.2.9 Vitexicarpin experimental testing of pharmaceutical interventions. With this

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