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Review Arcle
Application and Medicinal of Terpenoids
Ana Borges1,2; Filipa Mandim1,2; Sandrina A Heleno1,2;
Ricardo C Calhelha1,2*
1Centro de Invesgação da Montanha (CIMO), Instuto
Politécnico de Bragança, Campus de Santa Apolónia,
Portugal.
2Laboratório Associado para a Sustentabilidade e
Tecnologia em Regiões de Montanha (SusTEC), Instuto
Politécnico de Bragança, Campus de Santa Apolónia,
Portugal
*Corresponding author: Ricardo C Calhelha
Centro de Invesgação da Montanha (CIMO), Instuto
Politécnico de Bragança, Campus de Santa Apolónia,
5300-253 Bragança, Portugal.
Email: calhelha@ipb.pt
Received: January 17, 2024
Accepted: February 17, 2024
Published: February 24, 2024
Citation: Savitha MR and Thanuja B. Food Allergens and Aero Allergens Sensitisation.
Austin J Asthma Open
Access
. 2020; 2(1): 1004.
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Ausn J Anal Pharm Chem
Volume 11, Issue 1 (2024)
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Calhelha RC © All rights are reserved
Citaon: Borges A, Mandim F, Heleno SA, Calhelha RC. Applicaon and Medicinal of
Terpenoids. Ausn J Anal Pharm Chem. 2024; 11(1): 1167.
Austin Journal of Analytical & Pharmaceutical Chemistry
Open Access
Abstract
There has been a rise in interest in terpenoids due to their va-
riety of chemical forms and their disnct biological features, pro-
viding a range of applicaons in various industries, and enabling a
signicant economic, social, and environmental value. A systemac
review was conducted based on the results of the collected scien-
c arcles using Web of Science, Scopus, Scielo, Science Direct,
and PubMed databases. This arcle examines the characteriscs of
terpenoids and their biological eects, concentrang on their an-
aging eects. Addionally, it discusses the various industrial appli-
caons and drawbacks of their applicaon. Thanks to their acvity,
terpenoids play a signicant part in various industries, making them
important compounds with a wide range of applicaons. They are
also frequently used and have excellent development prospects.
emphasizing in parcular their an-aging qualies. Future research
should focus on terpenoids’ broad toxicity, their catalyc mecha-
nism, bioavailability, pharmacodynamics, biomarkers, extensive ex-
aminaons of their bioacve qualies, and their usage in various
industries in light of their eecveness.
Keywords: Terpenoids; Essenal oils; Emerging extracon pro-
cesses; Bioacvies; Aging
Introducon
Since ancient mes, medicinal plants have been essenal
for treang and prevenng human diseases [1,2]. Endowed
with a wide variety of properes, plant species have been ex-
tensively studied in an aempt to idenfy which compounds
are responsible for the mulfaceted properes. In addion, the
current sustainable policies related to the adequate use of re-
sources and all their potenal, are dierenang factors for the
importance currently given to the natural resources research
area [2,3]. Recently, pharmaceucal companies have been pay-
ing more aenon and importance to this area of study. These
companies intend to idenfy possible molecules of interest,
which can be used in the development of new drugs. Medicines
with high therapeuc ecacy, economically viable and acces-
sible, safe, and with reduced adverse eects are some of the
main objecves [1-3].
Plants produce a wide variety of compounds through their
primary and secondary metabolism. Concerning the secondary
one, terpenoids, alkaloids, tannins, saponins, and phenolic ac-
ids, among others, are some of the classes of compounds of in-
terest [4-6]. Those classes have been studied due to the varied
bioacve properes they have been exhibing (e.g., ancancer,
an-inammatory, anviral, anmicrobial) [3]. Among the men-
oned secondary metabolites classes, terpenoids are one of the
largest and most structurally diverse [2-5]. This group of com-
pounds plays a crucial role in the physiological processes, en-
vironmental reacons, and plant growth and development [3].
Terpenoids are derived from isoprene and can be found in a vari-
ety of chemical forms [3,4,7]. They exhibit a linear hydrocarbon
or a cycle chain conguraon, with diverse chemical variaons
of the substuent groups [4,8]. Several studies in the literature
emphasize the mulfaceted properes of terpenoids, which as
a consequence of their mulple conguraons, result in disnct
biological features [5,8-10]. These characteriscs are the main
reason for the wide range of applicaons in several industrial
areas (e.g., pharmaceucal, food, and agricultural industries)
and therefore, for their economic valorizaon [3,5]. The grow-
ing knowledge about the potenal associated with terpenoids
has been the main contributor to the increased interest associ-
ated with this bioacve class [2-5]. Its consequent exploitaon
and increased applicability are important economic contribu-
ons to its valorizaon and their produced species [3].
This review arcle gathers recent ndings regarding terpe-
noids characteriscs and biological eects. As a result of major
concerns and a higher incidence of condions associated with
aging, parcular consideraon was given to terpenoids' an-
aging eects (namely skin aging, degenerave diseases, and
cancer). Addionally, industrial applicaons and the associated
side eects of their use will also be discussed. Scienc data-
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Calhelha RC
bases such as Web of Science, Scopus, Scielo, Science Direct,
and PubMed were used for collecng scienc arcles and
chapters. The keywords “terpenoids”, “essenal oils”, “bioac-
vies”, “anaging” and “emerging extracon processes” were
used isolated and in combined form.
Characterizaon and Biosynthesis
Plants synthesize a vast variety of metabolites through their
primary and secondary metabolism. Primary metabolites such
as sugars, proteins, and lipids, are found in all species and are
necessary for fundamental processes of growth and develop-
ment of the plant. On the other hand, secondary metabolites
have a great diversity and structural complexity, are synthesized
in response to external smulus, and are essenal for the sur-
vival and perpetuaon of the species [6]. Terpenes are a class
synthesized through secondary metabolism. Terpenoids corre-
spond to modied terpenes where methyl groups are moved
or removed, or addional funconal groups (usually oxygen-
containing) are added [6,8,10]. They present a great complex-
ity and structural diversity. To date, more than 90,000 terpenes
have been idened, being one of the largest classes and with a
higher structural variety [10].
Terpenes are classied according to the number of isoprene
units [6,8,10]. Table 1 contains the dierent terpenoid classes
and their main natural sources and biological properes known.
Although terpenoids have a wide structural variaon, all
of them are synthesized from two universal precursors of ve
carbon: dimethylallyl diphosphate (DMAPP), and isopentenyl
dyphosphate (IPP) [3,6]. In plants, these two molecules can
be synthesized from two independent biosynthec pathways:
the classic mevalonic acid (MVA) and deoxylulose phosphate
pathway (DMAPP) (Figure 1) [6,10]. The rst gives origin to IPP
from acetyl-CoA units, the condensaon of three molecules of
acetyl-SCoA results in the ester β-hydroxy-β-methylglutaryl-
CoA formaon. This ester aer reacons of hydrolysis and an
enzymac reducon originates the mevalonic acid [6]. Succes-
sive phosphorylaon reacons of hydroxyl groups, followed
by decarboxylaon and eliminaon of a pyrophosphate group
originate the intermediate IPP [6]. DMAPP, in turn, comprises
seven enzymac steps and is formed aer the removal of a C-2
proton from that isoprene unit by an isomerase. In turn, 1-de-
oxy-D-Xylulose-5-Phosphate (DXP), the intermediate involved in
the non-mevalonate biosynthec pathway, is formed from py-
ruvic acid and D-glyceraldehyde, with the coenzyme Thiamine
diphosphate (TPP) as a mediator (Figure 1) [6].
The biosynthesis of terpenoids occurs through "tail-head"
condensaon between the DMAPP and IPP units, and with
phenyl-transferase as the catalyc enzyme (Figure 2). This con-
densaon generates the C10 chain of Geranyl Pyrophosphate
(GPP), the precursor of monoterpenes. Its successive condensa-
on with IPP units gives rise to the dierent terpene precursor
chains, namely the farnesyl pyrophosphate (C15), geranylgeranyl
pyrophosphate (C20), and geranylfarnesyl pyrophosphate (C25)
chains, precursors of sesquiterpenes, diterpenes, and sesterter-
penes, respecvely. In turn, the condensaon of two farnesyl
pyrophosphate (C30) or two geranylgeranyl pyrophosphate (C40)
chains, are precursors of triterpenes and tetraterpenes, respec-
vely (Figure 2) [6].
Bioacve Properes
Terpenoids have been exhibing an extensive spectrum of
bioacve properes [31-34]. Those properes have been dem-
onstrated by several authors who consider these compounds
promising bioacve substances in the treatment and preven-
on of several diseases [3,35,36]. As a result of the mulfaceted
potenal that has been proven in various studies, terpenoids
could play a signicant role in discovering and developing new
therapeuc opons. The studies and principal ndings of the
last few years are summarized in the following secons.
An-Inammatory Properes
Recent research has demonstrated that terpenoids exhibit
the capacity to reduce inammaon. Studies describe that ter-
penoids can inhibit the inammatory process through the sup-
pression of several related inammatory processes [37,38].
Inammaon is a protecve reacon of live ssue with a
circulatory system to a variety of damaging causes, and it is
inmately associated with several diseases [19,39]. Numerous
events take place as a result of cellular processes that are es-
senal to the inammaon process, such as oxidave stress
and autophagy, as well as from the excessive producon of pro-
inammatory cytokines and inammatory mediators, such as
interleukin-1β (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α),
nitric oxide (NO), produced by non-reduced NO synthase (iNOS),
and prostaglandin E2 (PGE-2) synthesized by cyclooxygenase-2
(COX-2) [39]. In addion, a key transcripon factor called the
nuclear-κB (NF-κB) factor plays a crucial part in the producon
of proinammatory genes during inammaon [39].
Curcuma kwangsiensis was studied in vitro and in vivo for
its an-inammatory and annocicepve eects. These as-
says of various layers (methanol (ME), ethyl acetate (EA), and
aqueous (AQS)) from C. kwangsiensis were achieved by car-
Esquema
Figure 1: Synthesis of the universal precursors of terpenoids.
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rageenan-induced paw edema and acec acid-induced writh-
ing animal models, administrated in male mice randomly
assigned to groups. The results showed that ME and EA signi-
cantly inhibited the paw edema in comparison to the control
group (p<0.01/0.05), while AQS showed no signicant inhibi-
tory eect. The inhibitory raos of ME and EA amounted to
35.3/34.0%, and 41.3/31.7% at the dose of 200/100 mg/kg, re-
specvely (p<0.01/0.05). Furthermore, aspirin (ASP) was used
as the posive control and played a similar role in reducing paw
edema with a suppression rate of 69.7% at the dose of 200 mg/
kg. The above data suggested that ME and EA exhibited signi-
cant an-inammatory eects equivalent to that of ASP. Based
on the in vivo bioacvity evaluaon, the EA layer was selected
for phytochemical invesgaon next. In this layer, all the iso-
lated compounds were evaluated for their an-inammatory
eects via detecng inammatory mediator releases (COX-2,
IL-1β, and TNF-α) in RAW 264.7 macrophage cells induced by
LPS. LPS alone signicantly increased the COX-2 (98.5±3.0 ver-
sus 79.6±1.9 ng/L), IL-1ß (95.6±2.6 versus 76.5±1.4 ng/L), and
TNF-a (141.1±1.6 versus 115.8±1.4 ng/L) producon compared
to the normal group, respecvely. However, inammatory cy-
tokine secreons decreased aer the treatment of sesqui- and
diterpenoids. The majority of all the isolates exhibited excellent
an-inammatory acvies by inhibing LPS-smulated COX-
2, IL-1ß, and TNF-a producon at a concentraon of 20 µg/mL
in RAW 264.7 macrophage cells, equivalent to dexamethasone
(DXM) (p<0.05/0.01) [40].
In the same way, Nepeta bracteate compounds were iso-
lated and invesgated for their an-inammatory acvity. The
acvity was evaluated in lipopolysaccharide-smulated RAW
264.7 macrophages using the MTT colorimetric method. The
compounds were dissolved in dimethyl sulfoxide (DMSO) and
diluted appropriately just before cell treatments. Cells were
incubated with the extract at indicated concentraons, with
DMSO not exceeding 0.1% in all experiments. The cells were
cultured in DMEM (Dulbecco's Modied Eagle Medium) with
10% FBS (Fasng Blood Sugar) and anbiocs (100 U/mL peni-
cillin and 100 µg/mL streptomycin) at 37ºC with 5% CO2. NO re-
lease was measured as an indicator of the nitrite concentraon.
This test showed that all the abietane diterpenoids displayed
dierent degrees of inhibion eect. Among them, compounds
nepetabrate B and nepetabrate D displayed the greatest an-
inammatory acvies with IC50 values of 19.2 and 18.8 µM
and moderate cytotoxic acvies with IC50 values of 36.3 and
41.4 µM, further proving the correlaon between inammaon
and cancer [41].
Also, all compounds from the fruits of Arenga pinnata
(Wurmb) Merr were invesgated and evaluated for their an-
inammatory acvity. The cells were treated with LPS (Sigma, 1
µg/mL), and then pretreated with various concentraons. Aer
smulaon, the supernatants of cells were got through centrif-
ugaon (3000 g/min, 10 min) and hatching with the equal vol-
ume of Griess reagent (1% sulfanilamide in H2O and 0.1% naph-
thylenediamine in 5% phosphoric acid). The outcomes showed
that all of them exhibited dierent degrees of suppression on
NO producon, and Pinnasesquiterpene A and Linchuniinone
exposed moderate suppressive eects against NO generaon in
lipopolysaccharide-smulated RAW 264.7 cells [42].
Moreover, all of the compounds from the twigs and leaves
of Abelia macrotera were isolated and studied for the inhibi-
tory eects on NO producon in LPS-induced RAW 264.7 cells.
Compound methyl 4,5-di-O-caeoylquinate showed an obvi-
ous inhibitory eect on LPS-induced NO producon in RAW
264.7 cells with IC50 values of 23.77±1.61 μM, whereas com-
pounds 3β-hydroxyurs-12-en-28, 20β-olide, ursolic acid,
2α-hydroxyursolic acid, asiac acid, ilelafol B, 2α,3-dihydroxy-
3β-(trans-p-coumaroyloxy)urs-12-en-28-oic acid, vomifoliol, ro-
seoside, lamiuamplexoside C, methyl 3,4-di-O-caeoylquinate,
and methyl 3,5-di-O-caeoylquinate showed a moderate me
Table 1: Classicaon of terpenoids, distribuon in nature, and main properes.
Class Number of Carbons Natural Sources Properes References
Hemiterpenoids 5Found in plants and leaves of many
trees (conifers, willows, conifers).
Flavors, fragrances, an-inammatory, neuroprotec-
ve, cytotoxic, and apoptogenic [4,6,8,9,11,12]
Monoterpenoids 10
The main components of fruits are
essenal oils a and volale fracon of
Turpenne
Aroma or odor, an-tumor, anbacterial, anoxidant,
generaon of aging protecon [8,13–27]
Sesquiterpenoids 15 Found parcularly in higher plants,
marine organisms, and fungi
An-inammatory, an-allergic, annocicepve,
anoxidant, an-cancerous, gastrointesnal protec-
tor, anbacterial, local anesthec, generaon of aging
protecon
[8,13–27]
Diterpenoids 20 Widely distributed in plants (emphasiz-
ing coee and spices), and fungus
Anoxidant, an-aging, an-cancer, treatment of
neurodegenerave and cardiovascular condions,
metabolic disorders, anviral, anmicrobial, anpara-
sic, anprotozoal, plant protecon, generaon of
aging protecon
[8,13–16,18–
23,25–27]
Sesterterpenoids 25
Frequently reported from bacteria,
fungi, lichens, insects, marine inverte-
brates, and some higher plant families
Aroma, odor, phytotoxic, anmicrobial, nematocidal,
cytotoxic, anviral, and an-inammatory
[8,13,15,18,20,22,25–
28]
Triterpenoids 30 Biosynthesized by bacteria, plants,
fungus, and animals
An-aging, an-cancer, neurodegenerave, cardio-
vascular, metabolic disorders; migate obesity and
hyperlipidemia, anviral, anmicrobial, anparasic,
immunomodulator agent, generaon of aging protec-
on
[8,13–16,18–
22,25–27]
Tretraterpenoids 40 Found in roots, leaves, seeds, fruits,
and owers
Anoxidant, an-aging, food colorant, generaon of
aging protecon
[8,14–16,19–
22,25–27]
Polyterpenoids > 40 Found in a variety of natural com-
pounds (for example hardwoods)
Use in the food industry due to the resistant to
change in viscosity, color, and oxidaon (thermally
stable, low odor and volality)
[3,8,9,11,12,29–
31]
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dium inhibitory eect. Plus, the an-inammatory acvity of ur-
sane triterpenoids with 3-pcoumaroyloxy group was signicantly
improved compared to isolated ursane type triterpenoids. Com-
pound 3β-hydroxyurs-12-en-28,20β-olide had moderate an-
inammatory acvity, whereas compound 20β-hydroxyursolic
acid had none, and compound 2α-hydroxyursolic acid had
stronger an-inammatory acvity than the compound asiac
acid [43].
As well, the isolates from Croton laui leaves were isolated,
idened, and evaluated for their an-inammatory and cyto-
toxic acvies. The inhibion of Nitric Oxide (NO) producon
in lipopolysaccharide (LPS)-smulated RAW 264.7 macrophages
was used to evaluate the an-inammatory acvies of the dif-
ferent compounds. Dexamethasone (Sigma, USA) was used as a
posive control. From this research, compounds 6S-crotoeurin
C and crotoeurin C exhibited inhibitory acvies of Lipopoly-
saccharide (LPS)-induced Nitric Oxide (NO) producon in RAW
264.7 macrophages with IC50 values of 1.2 and 1.6 µM, respec-
vely. While dexamethasone served as a posive control with
an IC50 value of 0.19 µM [44].
The extracts of Piosporum qinlingense twigs, fruits, and
leaves were also invesgated. They described the inhibitory ef-
fects of the dierent compounds on Lipopolysaccharide (LPS)-
induced Nitric Oxide (NO) producon in BV-2 microglial cells.
The chosen posive control was quercen. With IC50 values of
12.56±0.12, 1.58±0.14, and 11.43±0.14, respecvely (the posi-
ve control had an IC50 of 2.56 μM), the compounds Pitqinlin-
goside O, Pitqinlingoside P, and Arvoside C showed considerably
greater inhibitory acon in these data. Addionally, with IC50
values of 25.67 and 28.74 μM, the substances Pitqinlingoside
N and Boscialin had mild inhibitory eects. The remaining sub-
stances, on the other hand, had poor an-inammatory eects
in macrophages with IC50 values greater than 50 μM. Pitqinlin-
goside P could signicantly reduce LPS-induced COX-2 and iNOS
expressions, according to Western blot analysis [45].
Furthermore, the various chemicals in Artemisia vulgaris L.
leaves were extracted and assessed for their an-inammatory
eecveness. By measuring the expression of the inamma-
tory mediator NO in LPS-induced RAW264.7 cells, all isolates
were assessed for their an-inammatory ecacy. The results
Figure 2: Synthesis of terpenoids.
showed that artemvulactone E had a strong an-inammatory
impact with an IC50 value of 0.9±0.2 µM. The posive control
group was the dexamethasone group. Addionally, western
blong tests showed that artemvulactone E may dose-depend-
ently lower LPS-induced COX-2 protein expression [46].
Sll, a few plant species employed in Zimbabwean poultry
ethnomedicine were assessed for their properes. The an-in-
ammatory acvity was assessed by the analysis of the lipoxy-
genase inhibitory acvity. The S. singueana extract, which had
an IC50 value of 1.72±0.28 μg/ml, and the B. madagascariensis
extract, which had an IC50 value of 4.41±0.37 μg/ml, had the
best an-lipoxygenase acvity, according to the results. The
excellent an-lipoxygenase acvity was also detected in the E.
abyssinica extract [47].
Senna tora (L.) Roxb. was explored for its potenal as a
source of drug candidate. The an-inammatory acvity was
determined by Bovine Serum Albumin (BSA) denaturaon and
red blood cell (RBC) hemolysis inhibion in vitro. The extracts
prevented hemolysis of the RBC membrane in a concentraon
range from 31.058±3.145% to 89.029±1.186%, with an IC50 val-
ue of 28.309 μg/mL. The extracts' resistance to BSA denatur-
aon ranged from 32.617±0.890% to 91.731±0.949, and their
IC50 value was 22.980 μg/mL. When the an-inammatory ac-
vity was compared to that of ibuprofen, it demonstrated an-
inammatory acvity with an IC50 range of 4.956 μg/mL for RBC
hemolysis inhibion and 38.260±2.081 to 97.116±0.679 for BSA
denaturaon inhibion [48].
In addion, the brous root of Alangium chinense (Lour.)
Harms compounds were invesgated. The obtained com-
pounds were evaluated for their an-inammatory acvity
against cyclooxygenase (COX-2). Results showed that the analy-
sis of the dierent compounds have an inhibitory eect against
COX-2 with IC50 values of 49.19±0.76, 23.29±0.99, 47.78±1.33,
44.44±0.12, and 20.43±4.72 µM [49].
An overview of the dierent studies made about the an-
inammatory properes of terpenoids is presented in Table 2.
Anbacterial Properes
Terpenoids have a wide range of biological acvity, and stud-
ies have shown that they also have anbacterial properes.
These substances might be very signicant in several areas,
including food chemistry, pharmacology, and pharmaceucs
[50,51].
The anbacterial acon against microorganisms that cause
foodborne illness was observed. Escherichia coli, Salmonella
enterica, and Staphylococcus aureus each had minimum in-
hibitory concentraon assay (MIC50) and Minimum Bactericidal
Concentraon assay (MBC) values that ranged from 0.420 to
1.598 mg/mL and 0.673 to 3.432 mg/mL, respecvely. The MBC
was found to be at a concentraon of 3.432 mg/mL for each of
the studied terpenoids. The three terpenoids without a hydrox-
yl group—pinene, limonene, and myrcene—showed anbacte-
rial acvity, with limonene exhibing the highest eects at a
dosage of 0.421 mg/mL. Among the four terpenoids containing
hydroxyl groups—geraniol, linalool, nerol, and terpineol—nerol
and geraniol showed comparable anbacterial acvity. Gram-
posive bacteria were found to be marginally more suscepble
than Gram-negave bacteria based on the results of MIC50 and
MBC values. The anbacterial acvity at the selected MIC50 lev-
els was also assessed using the me-kill curve test. The anbac-
terial acvity of all seven prominent terpenoids was observed
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Table 2: An-inammatory properes of terpenoids.
Source Experimental
Model Main Results References
Curcuma kwangsiensis
ICR male mice
(22–24 g) and LPS-
smulated RAW
264.7 macrophage
cell
The pharmacological evaluaon of various layers (ME, EA, AQS) from C. kwangsiensis
supported its tradional use for relieving inammaon. The in vivo study showed that
intragastrically administrated ME and EA signicantly inhibited the carrageenan-induced
paw edema in comparison to the control group, especially the EA layer with beer
an-inammatory acvity. The in vitro study results indicated that most of sesqui- and
diterpenoids isolated from the EA layer signicantly inhibited IL-1β, COX-2, and TNF-α
producon at a concentraon of 20 μg/mL in LPS-induced RAW 264.7 macrophage cells
[40]
Nepeta bracteate
Lipopolysaccharide-
smulated RAW
264.7 macrophages
using the MTT colo-
rimetric method
For the rst me, nine abietane diterpenoids, including four new compounds and one
new amide alkaloid, were isolated from the tradional medicine Nepeta bracteata
Benth., elucidang its acve components and laying the groundwork for future clinical
applicaons. All isolates were also examined for their cytotoxic and an-inammatory
eects. Compounds nepetabrate B and nepetabrate D demonstrated potenal biological
acvity. Both substances are acve chemicals that could be useful for research
[41]
Arenga pinnata
Murine RAW 264.7
macrophage cells
treated with LPS
(Sigma, 1 µg/mL)
The chemical research of A. pinnata fruits. caused the isolaon and idencaon of
26 compounds, including 2 undescribed terpenoids and 24 known compounds, among
them the absolute conguraon of arenterpenoid D. Furthermore, in the NO producon
bioassay of compounds, all of them exhibited dierent degrees of suppression on NO
producon, and compounds Pinnasesquiterpene A and Linchuniinone exposed moderate
suppressive eects against NO generaon in lipopolysaccharide-smulated RAW 264.7
cells
[42]
Abelia macrotera LPS-induced RAW
264.7 cells
In total, 17 compounds were discovered in the twigs and leaves of A. macrotera. These
ndings indicate that the an-inammatory acvity of 28-COOH and 20-OH in urso-
lic triterpenoids can be increased aer estericaon, and the presence of 23-OH will
weaken the an-inammatory acvity of the compound. Furthermore, compound methyl
4,5-di-O-caeoylquinate may play an an-inammatory role by combining with Cathepsin
G & Chymase, and HPG D
[43]
Croton laui
Inhibion of nitric
oxide (NO) produc-
on in lipopolysac-
charide (LPS)-sm-
ulated RAW 264.7
macrophages
The present results showed that clerodane diterpenoids could partly account for the
tradional uses of C. laui in the treatment of inammaon-related diseases, indicang
that this plant might have the potenal for further invesgaon as an an-inammatory
agent.
[44]
Piosporum qinlingense
Lipopolysaccha-
ride (LPS)-induced
nitric oxide (NO)
producon in BV-2
microglial cells
using the Western
blot analysis
The invesgaon of P. qinlingense led to the isolaon of seven sesquiterpenoid glycoside
esters, two monoterpenoids, two triterpenoids, two lignans, and others. Pitqinlingoside
O, Pitqinlingoside P, and arvoside C presented signicant nitric oxide producon inhibi-
on in LPS-induced BV-2 microglial cells
[45]
Artemisia vulgaris L
Expression of the
inammatory
mediator NO in LPS-
induced RAW264.7
cells
Eight undescribed sesquiterpenoids and two undescribed triterpenoids were isolated
from the leaves of A. vulgaris, together with thirteen known terpenoids. Biological acv-
ity research indicated that the compound Artemvulactone E has signicant an-inam-
matory acvity, by reducing LPS-induced COX-2 protein expression dose-dependently,
according to western blong experiments
[46]
Bobgunnia Madagascarien-
sis; Adenia gummifera; Senna
singueana; Aloe chabaudii; Aloe
greatheadii; Agave si-salana;
Albizia gummifera; Erythrina abys-
sinica; Euphorbia matabelensis;
Tridactyle bicaudate
Evaluaon of the
an-lipoxygenase
(15-LOX) acv-
ity of the dierent
extracts
This study showed the dierent biological acvies of the dierent plants. Regarding
an-lipoxygenase acvity, extracts of B. madagascariensis, S. singueana, T. bicaudata,
and E. matabelensis were more acve than toxic (selecve index >5) indicang the an-
inammatory potenal
[47]
Senna tora (L.) Roxb. leaves
Heat-induced
hemolysis of Red
blood cell (RBC) and
Bovine serum albu-
min (BSA) protein
denaturaon assays
The ndings of this study concluded that Senna tora (L.) Roxb. leaves contain vari-
ous acvies due to the presence of some biologically acve phytochemicals, such as
terpenoids. The extract showed dose-related an-inammatory acon by prevenng RBC
hemolysis and BSA denaturaon, according to the an-inammatory acvity assays. Col-
lecvely, this may contribute to the development of anbacterial agents for humans
[48]
Alangium chinense Fluorometric assay
of COX-2 inhibitors
In summary, one new sesquiterpene and four known compounds were obtained from the
roots of A. chinense. The new compound 1-carbonyl-2,8-dihydroxy-11-oxabicyclo [4,4,1]
germacra-2(3),4(5),6(7), 8(9)-tetraene and oleanane-type triterpenoids showed strong
inhibing eects to COX-2, which may reveal the material basis of an-inammatory
[49]
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to plateau between 16 and 24 hours, whereas the growth con-
trol demonstrated a sharp rise in anbioc acvity. As a result,
they discovered that aer 16 hours, the seven main terpenoids
in wine showed eecve anbacterial acon against all three
bacterial species at their set MIC50 [52].
Also, Eclipta prostrata (L.) L. terpenoid compounds were ex-
amined. The liquid growth inhibion method was used to as-
sess the anbacterial acvity against two Gram-posive strains,
Staphylococcus aureus, and Bacillus sublis. Only substances ex-
hibing growth inhibion rates more than 50% were subjected
to further tesng at concentraons higher than 50 μM to deter-
mine their IC50 values. The posive control ulized was cepha-
losporin. Only compound 3-O-(6-O-crotonyl-D-glucopyranosyl)-
16-hydroxy-olean-12-en-28-oic acid 28-O-D-glucopyranosyl
ester was shown to have anbacterial acvity against S. aureus,
with an IC50 value of 37.36 μM, according to the data [53].
Addionally, Lavandula Atlanca essenal oils (LAEO) were
studied to determine their anbacterial eecveness against
resistant microorganisms. This acvity was esmated by mea-
suring the inhibitory diameters of nine strains of bacteria:
Methicillin-resistant Staphylococcus aureus, Escherichia Coli,
Enterobacteraerogenes, Pseudomonasaeruginosa, klebsiella
pneumonia, Klebsiellaoxytoca, Salmonella spp., Acinetobacte-
rbaumanii, Enterobactercloacae. The acvity of the substances
under invesgaon was rst assessed using the disc diusion
method, and then the MIC and MBC concentraons were cal-
culated using the microdiluon method. The outcomes demon-
strate that LAEO was eecve against all examined strains, with
MIC values for the invesgated bacteria varying from 3.13 mg/L
to 25 mg/L. The same study also found that against Escherichia
coli, Acinetobacter baumanii, and Enterobacter cloacae, all ter-
penoids were even more eecve than Gentamicin (control)
[54].
Likewise, the potenal of several Paeonia osi T. organs
as anbacterial agents was invesgated. Eight Gram-posive
and Gram-negave bacteria were used as test subjects for the
anbacterial acvity. The quantave test showed that P. os-
i hydrosols eecvely inhibited the growth of Streptococcus
hemolys- β and Staphylococcus aureus. The inhibion zones
and Minimum Inhibitory Concentraons (MICs) of freshly devel-
oped leaf hydrosols were 10.65-17.5 mm and 0.78-12.5 mg/mL,
respecvely, showing more pronounced anbacterial eects
than those from other organs [55].
In the same lane, the anbacterial eect of the terpenoid
compounds from Ferula haussknechi was studied by measur-
ing their MIC values against S. aureus, B. cereus, P. aeruginosa,
E. coli, clinical isolate of H. pylori, b-lactamase producing clini-
cal strain of K. pneumonia and clinical isolate of vancomycin-
resistant E. faecium. According to the results, the overall inhibi-
tory acvies of the compounds were higher against the tested
Gram-posive bacteria than the Gram-negave bacteria. All of
the compounds had a signicant eect on S. aureus but a mod-
erate eect on K. pneumonia and P. aeruginosa. Among these
compounds, Hawraman 8-p-hydroxybenzoyl-tovarol had the
widest anbacterial spectrum (anbacterial eect on B. cereus
with the MIC of 16 µg/mL) [56].
Lemnalia sp., a so coral found in the Xisha region, was the
subject of research. Five bacterial strains were used, including
Bacillus sublis, Staphylococcus aureus, Methicillin-resistant
Staphylococcus aureus, Pseudomonas aeruginosa, and Salmo-
nella paratyphi, to assess the anbacterial acvies by MIC as-
say. Gentamicin served as a posive control. The various com-
pounds displayed dierent concentraons, being Nardosinoid
A, Nardosinoid B, and em-nal-1(10)-ene-7,12-diol, displayed
moderate anbacterial acvies against Bacillus sublis (MICs
4-8 μg/mL), and Nardosinoid B and Lemnal-1(10)-ene-7,12-diol
also showed moderate acvity against Staphylococcus aureus
(MICs 4-16 μg/mL) [57].
As before menoned, the properes of a few plant species
employed in Zimbabwean poultry ethnomedicine were as-
sessed. Regarding the anbacterial acvity, the Minimum In-
hibitory Concentraons (MICs) of the acetone extracts against
three pathogens (Staphylococcus aureus, Escherichia coli, Sal-
monella Enteridis), as well as two clinical strains (Escherichia
coli and Salmonella Gallinarum), recovered from hens, were
used to determine the anbacterial acvity. Erythrina abys-
sinica displayed the best anbacterial acvity against both
strains in these experiments, with MIC values ranging from 0.02
to 0.156 mg/ml. All plants demonstrated anbacterial acvity.
First, the eects of terpenes (carvacrol, thymol, nootkatone, eu-
genol, limonene, carvone, and geraniol) on the growth of each
bacterial strain were invesgated [47].
In a dierent approach, the anbacterial acvity of several
terpenoid combinaons against various bacterial species were
invesgated. Four terpenoid combinaons—C1 (carvacrol and
thymol), C2 (carvacrol, thymol, and eugenol), C3 (carvacrol, thy-
mol, and nootkatone), and C4 (carvacrol, thymol, eugenol, and
nootkatone)—were used against eight bacterial strains (Salmo-
nella enteridis, Escherichia coli, Acinetobacter baumannii, Ba-
cillus cereus, Enterococcus faecalis, Staphylococcus aureus, Lis-
teria monocytogenes, Corynebacterium diphtheriae). Growth
suppression was observed to be more eecve when the terpe-
noids were used in combinaons rather than alone. The various
combinaons of terpenoids eecvely inhibited the growth of
all of the examined bacterial strains; however, gram-negave
bacteria (such as A. baumannii, E. coli, and S. enteridis) were
more eecvely inhibited than gram-posive bacteria. The bac-
tericidal acon of all combinaons against E. coli and S. enter-
idis was complete at 1 mM, regardless of how the terpenoids
were combined. At 0.5 mM, C4 demonstrated potent bacteri-
cidal acon against C. diphtheriae and S. enteridis. The other
bacilli were more sensive than B. cereus, in comparison. Lile
bactericidal acvity was seen for gram-posive cocci (E. faecalis
and S. aureus) with C1, and combinaons of three or four ter-
penoids at 1 mM were required for bactericidal acvity against
E. faecalis and S. aureus [58].
As aforemenoned, the potenal of Senna tora (L.) Roxb.
as a source of drug candidate was explored. The anbacteri-
al acvity was evaluated by agar-well diusion methods. The
Figure 3: Overview of the use of terpenoids in the dierent indus-
tries.
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two-fold serial diluon method was used to test the Minimum
Inhibitory Concentraon (MIC) and Minimum Bactericidal Con-
centraon (MBC) against Bacillus infans, Exiguobacterium sp.,
Staphylococcus aureus, and Enterococcus sp., Escherichia coli,
Vibrio cholerae, Salmonella typhi, Pseudomonas aeruginosa,
and Haemophilus inuenzae. The ndings revealed that, at
rates ranging from 62.5 to 500 mg/mL, the compounds of the
extract can prevent the proliferaon of bacteria, with inhibion
zones ranging from 14±1 to 23±1 mm for Gram-posive bacte-
ria and 11.5±0.5 to 22±1 mm for Gram-negave bacteria. This
Table 3: Anbacterial properes of terpenoids.
Source Experimental Model Main Results Referenes
Myrcene, limonene, geraniol,
linalool, nerol, α-pinene, and
terpineol compounds
Reducing power assays - Minimum inhibitory
concentraon assay (MIC50) and Minimum
bactericidal concentraon assay (MBC) – and
me-kill curve test, against Escherichia coli,
Salmonella enterica, and Staphylococcus aureus
The seven predominant wine terpenoids displayed eecve an-
bacterial acvity against typical foodborne pathogenic bacteria,
at a predetermined MIC50 aer the 16-h mepoint. Proving that
they could be new potenal sources of natural anbacterial and
anoxidant agents for use in the food industry
[51]
Screening of these isolates in an array of bioassays revealed
anbacterial, cytotoxic, and α-glucosidase inhibitory acvies for
selecve compounds. According to the results, only compound
3-O-(6-O-crotonyl-D-glucopyranosyl)-16-hydroxy-olean-12-en-28-
oic acid 28-O-D-glucopyranosyl ester showed to have anbacterial
acvity against S. aureus
Eclipta prostrata L. Liquid growth inhibion method against Staphy-
lococcus aureus and Bacillus sublis
All studied terpenoids were even more acve than Gentamicin
against escherichia Colii, Acinetobacterbaumanii, and Enterobac-
ter cloacae, proving that LAEO compounds have an
[53]
Lavandula Atlanca
Disc diusion method, and MIC and MBC
concentraons by microdiluon method against
Methicillin-resistant Staphylococcus aureus,
Escherichia Coli, Enterobacteraerogenes,
Pseudomonasaeruginosa, klebsiella pneumonia,
Klebsiellaoxytoca, Salmonella spp., Acinetobac-
terbaumanii, Enterobactercloacae
eect on the anbacterial power. So, the use of this essenal oil
or its constuent in the formulaon of drugs is recommended [54]
Paeonia osi T.
Standard broth-microdiluon method,
examinaon of minimum inhibitory concen-
traons (MICs), and Oxford cup technique,
against Staphylococcus aureus, Streptococcus
hemolys-β, Propionibacterium acnes, Listeria
monocytogenes, Pseudomonas aeruginosa,
Escherichia coli, Proteus vulgaris, and Salmo-
nella enterica subsp. enterica
The hydrosols from dierent P. osi organs possessed anbacte-
rial acvies against some ordinary skin-infecng and food-borne
bacterial pathogens. Consequently, the P. osi hydrosols may be
used as organic anbacterials in food, nourishment, pharmaceu-
cal, and cosmec industries to improve the safety of correspond-
ing products
[55]
Ferula haussknechi
MIC values against S. aureus, B. cereus, P.
aeruginosa, E. coli, clinical isolate of H. pylori,
b-lactamase producing clinical strain of K.
pneumonia, and clinical isolate of vancomycin-
resistant E. faecium
These compounds were assayed for anbacterial acvity and
the results showed that all of them were generally more acve
against S. aureus compared with other species. Overall, the study
demonstrated that F. haussknechi may be appropriate natural
anbacterial agents and potent lead compounds
[56]
Lemnalia sp.
MIC values against Bacillus sublis, Staphylococ-
cus aureus, MRSA, Pseudomonas aeruginosa
and Salmonella paratyphi
The various compounds were tested against gram-posive and
gram-negave bacteria. The results showed that the compounds
had acvity against them, notably against Bacillus sublis and
Staphylococcus aureus
[57]
Bobgunnia Madagascariensis;
Adenia gummifera; Senna sin-
gueana; Aloe chabaudii; Aloe
greatheadii; Agave sisalana;
Albizia gummifera; Erythrina
abyssinica; Euphorbia mata-
belensis; Tridactyle bicaudata
MICs of the acetone extracts were determined
using a serial two-fold diluon method using
bacterial strains: S. aureus, S. Enteridis, E.
coli, and clinical strains: E. coli and Salmonella
Gallinarum
This study showed the dierent biological acvies of the dif-
ferent plants. Regarding the anbacterial acvity, three extracts
were noted: E. abyssinica extract which had signicant anbacte-
rial acvity; S. singueana acetone extract which had moderate
anbacterial acvity and A. greatheadii, which had reasonable
anbacterial acvity
[47]
Pure compounds supplied by
FUJIFILM Wako Pure Chemical
Corporaon, Tokyo, Japan
(Carvacrol, thymol, eugenol,
nootkatone, perillyl alcohol,
limonene, cineole, carvone,
and geraniol)
Evaluaon of the growth inhibitory eect of the
dierent compounds, individually and in com-
binaon, against bacterial strains: S. enteridis,
E. coli, A. baumannii, B. cereus, S. aureus, E.
faecalis, L. monocytogenes, and C. diphtheriae
This study revealed that combinaons of terpenoids have acvi-
es against a spectrum of bacteria. The most eecve bactericidal
acvity was observed for gram-negave bacteria and in combina-
ons. Thus, this provides new candidates for the development of
anbacterial
[58]
Senna tora (L.) Roxb. leaves
Agar well diusion, MBC, and MIC assays,
against Bacillus infans, Exiguobacterium sp.,
Staphylococcus aureus, Enterococcus sp., Esch-
erichia coli, Vibrio cholerae, Salmonella typhi,
Pseudomonas aeruginosa, and Haemophilus
inuenza
The ndings of this study concluded that Senna tora (L.) Roxb.
leaves contain various acvies due to the presence of some bio-
logically acve phytochemicals, such as terpenoids. Based on the
anbacterial acvity assays, the extract can prevent the prolifera-
on of bacteria, with visible inhibion zones. Collecvely, this may
contribute to the development of anbacterial agents for humans
[48]
Xerophyta spekei (whole plant
without roots) and Grewia
tembensis (leaves and stem
barks)
Disc diusion, minimum inhibitory concentra-
ons, and bactericidal concentraons tests
against Salmonella Typhi, Bacillus sublis,
Staphylococcus aureus, and Escherichia coli
The studied plant extracts demonstrated anbacterial potenals
with X. spekei extract, exhibing acvity on S. aureus and B. sub-
lis. While both the stem bark and leaf extracts of G. tembensis
exhibited acvity on S. aureus alone. Overall, these current nd-
ings indicate that the studied extracts can be potenal candidates
to extract therapeuc anbacterial agents for managing and treat-
ing bacterial illnesses
[59]
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result demonstrates that the compounds of the extract of Sen-
na tora (L.) Roxb. leaves have anbacterial eecveness across
a broad range of microorganisms. The MBC values ranged from
3.270±1.133 to 6.541±2.266 mg/mL, which were higher than
those for MIC [48].
Furthermore, the extracts from Xerophyta spekei and Grewia
tembensis were studied. Tests for anbacterial acvity against
Salmonella Typhi, Bacillus sublis, Staphylococcus aureus, and
Escherichia coli included disc diusion, minimum inhibitory
concentraons, and bactericidal concentraons. G. temben-
sis exhibited eects on S. aureus only with Mean Zone Inhibi-
on (MZI) of 07.07±0.07 to 12.33±0.33 mm and 08.33±0.33
to 11.67±0.33 mm for stem bark and leaf extracts respecve-
ly. While X. spekei extract had eects on S. aureus with MZI
of 07.67±0.33 to 14.67±0.33 mm and B. sublis with MZI of
09.67±0.33 to 14.33±0.33 mm [59].
An overview of the dierent studies made about the anbac-
terial properes of terpenoids is presented in Table 3.
Hypoglycemic Eect
High blood sugar levels are a dening feature of diabetes,
a metabolic disease [19,65]. Diabetes paents' chronically ex-
cessive blood sugar levels can harm and be dysfunconal in a
variety of ssues [19]. Medicine and insulin are used to treat
this condion, but they have several adverse eects, including
gastrointesnal problems like diarrhea, atulence, and abdomi-
nal pain. Phytochemicals are the natural substances from which
new and more potent medicaons for the treatment of diabetes
can be developed, according to the present study ndings [19].
Thus, research into some naturally occurring, plant-derived bio-
acve chemicals are deemed vital to control and treat diabetes
mellitus with fewer complicaons and negave eects [65].
Terpenoids' acon plays a signicant part in the creaon of
new medicines and enhancements to current therapeuc op-
ons [19].
The anhyperglycemic acvity of the ethanol extract of An-
nona diversifolia leaves (EEAd), chloroformic (CHCl3Fr), ethyl
acetate (EtOAcFr), aqueous residual (FrAcR), secondary 5 (Fr5)
fracons, and two acyclic terpenoid isolates from this plant,
farnesol and farnesal were explored. Using the oral sucrose and
lactose tolerance (OSTT and OLTT, respecvely) and Intesnal
Sucrose Hydrolysis (ISH) tests, the potenal as α-glucosidase
inhibitors of products were assessed. Addionally, tests for
Oral Glucose Tolerance (OGTT), Intesnal Glucose Absorpon
(IGA), and Urine Glucose Excreon (UGE) were used to assess
the potenal as Sodium-Glucose cotransporter 1 protein (SGLT-
1) inhibitors. Male normoglycemic and streptozocin-induced
diabetes type 2 (SID2) mice were used to assess the impact on
blood glucose levels. At two and four hours, all treatments in
OSTT and OLTT had appreciable acon. Half maximum eecve
concentraons (CE50) for ISH were calculated to be 565, 662,
and 590 μg/mL, 682, and 802 μM, respecvely. At two hours in
the OGTT, all therapies demonstrated meaningful acon. IGA
calculated respecve CE50 values of 1059, 783, and 539 μg/mL,
1211, and 327 μM. In comparison to canagliozin, farnesol, and
farnesal compounds signicantly reduced the amount of glu-
cose excreted in UGE Fr5 [66].
As before menoned, Eclipta prostrata L. terpenoid com-
pounds were examined. The α-glucosidase inhibitory acvity
was studied by the calculaon of the dierent concentraons
of the absorbance recorded. Only the isolates with > 50% inhi-
bion rao were sent on to be evaluated at an IC50 concentra-
on aer all the isolates had inially been tested at a primary
concentraon of 100 μM. Being 103 mes more acve than the
posive control acarbose, the tetracyclic triterpenoid demon-
strated very signicant inhibion against α-glucosidase with an
IC50 of 0.82 0.18 μM [53].
In a dierent approach, the ecacy of Ganoderma Lucidum
Ethanol Extract (GLEE) against metabolic syndrome (MetS) com-
plicaons in rats was evaluated. Thirty male rats were random-
ized into six dierent groups (containing 25 MetS and 5 nor-
mal rats). Animals were sacriced following two weeks of GLEE
treatment post-MetS inducon. Biochemical and histological
studies were performed on blood, pancreas, hearts, livers, and
kidneys. A digital glucometer was used to measure blood sugar
levels. Results showed that GLEE, compared to the MetS con-
trol, which had a 40% increase in blood sugar compared to the
normal control, eecvely reversed MetS-induced hyperglyce-
mia in a dose-dependent manner up to 4-folds. Comparable to
the impact achieved in the other GLEE group, where a 3.9-fold
decline followed, the combined acon of glibenclamide and
atenolol caused a 3.4-fold decrease in hyperglycemia [67].
In the same lane, the in vivo hypoglycemic, anhypergly-
cemic, and andyslipidemic eects of the solvent fracons of
Hagenia abyssinica leaf extract were invesgated. In normal,
oral glucose-loaded, and streptozotocin-induced diabec mice,
the an-diabec eects of the solvent fracons were assessed.
Aer administering three dierent doses of the solvent fracons
(100, 200, and 400 mg/kg), the hypoglycemic, anhyperglyce-
mic, andyslipidemic, and eect on body weight change were
assessed. Both the aqueous and the ethyl acetate fracons of H.
abyssinica leaves demonstrated considerable (P<0.05) hypogly-
cemic ecacy in normoglycemic mice. At 60 and 120 minutes
aer oral glucose loading, the two doses of the aqueous frac-
on—200 mg/kg (p<0.05) and 400 mg/kg (p<0.001)—showed a
signicant anhyperglycemic eect, whereas the ethyl acetate
fracon also demonstrated a signicant anhyperglycemic ef-
fect at 60 min (P<0.05 for 200 mg/kg and P<0.001 for 400 mg/
kg) and 120 min (P<0.01). With the excepon of 100 mg/kg of
the aqueous and chloroform fracons, all doses of the solvent
fracons signicantly (P<0.05) decreased blood glucose levels in
diabec mice receiving a single dose of treatment. Addionally,
daily administraon of the aqueous fracon for several weeks
dramacally decreased hyperglycemia, prevented weight loss,
and enhanced [68].
Also, the an-diabec properes of a terpenoid-rich extract
from Dillenia indica L. bark (TRDI) in Palmic Acid-induced In-
sulin Resistance (PA-IR) in C2C12 myotube and a streptozotocin
(STZ)-induced diabec mouse model were studied. TRDI's IC50
value of 3.03±1.01 μg/mL, which was 92-fold greater than the
value for the posive control, acarbose (IC50 = 279.49±μg/mL),
substanally inhibited α-glucosidase acvity. Furthermore, TRDI
increased glucose transporter 4 (GLUT4) translocaon to the
plasma membrane (PM), which increased glucose absorpon.
TRDI also smulated the insulin receptor substrate-1 (INS-1),
downregulated Phosphoinoside-Dependent Kinase-1 (PDK1),
and protein kinase B (Akt) in both normal and PAIR C2C12 cells
as well as in STZ-induced diabec mice [69].
Using acvity-guided fraconaon as a strategy, was in-
vesgated the potenal andiabec eects of Salvia polys-
tachya Cav. and its isolated products, parcularly its eect as
an α-glucosidase and sodium-glucose cotransporter 1 (SGLT1)
inhibitor using in vivo (in mice), ex vivo (treatments in the intes-
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ne porons), and in silico (molecular docking of ursolic acid,
oleanolic acid, acarbose on α-Glucosidase enzyme, and cana-
gliozin on SGLT1 Cotransporter) assays. All of the therapies
during the tests for glucose tolerance decreased the postpran-
dial peak, much like the control medicaons. Ursolic Acid (UA)
and Oleanolic Acid (OA) were determined to have IC50 values of
739.9 and 726.3 μM, respecvely, during the Intesnal Sucrose
Hydrolysis (ISH). Calculated IC50 values for UA and OA during In-
tesnal Glucose Absorpon (IGA) were 966.6 and 849.3 μM, re-
specvely. Finally, during the molecular docking studies, UA and
OA demonstrated ∆G values on -glucosidase enzymes of -6.41
and -5.48 kcal/mol-1, respecvely. Both UA and OA displayed ∆G
values of -10.55 and -9.65 during SGLT1 [70].
Hypericum perforatum's terpenoid-based bicyclic dihydropy-
ran enanomers ((±)-Hyperpyran A) with hypoglycemic acon
were explored. The compounds' hypoglycemic potenal was
examined in human liver cancer cell line HepG2 and mice with
normal liver cell line AML12. The glucose concentraon in the
supernatant of AML12 and HepG2 cells was determined using a
glucose test kit following the manufacturer's instrucons aer
treatment with 40 μM of the tested compounds for 24 hoPosi-
veive control was ulized, which was meormin (150 μM).
The ndings showed that (+)-Hyperpyran A compound moder-
ately promoted glucose absorpon acvity in hepatocytes [71].
An overview of the dierent studies made about the hypo-
glycemic eect of terpenoids is presented in Table 5.
Anoxidant Acvity
One of the most studied bioacvies of natural compounds,
as well as the capability to prevent oxidave stress and several
diseases, is the ability of natural extracts to scavenge free radi-
cals [72,73]. An imbalance between prooxidant and anoxidant
species causes oxidave stress, which is a surprisingly signi-
cant and frequent occurrence that damages macromolecules
and interferes with cellular regulaon and redox signaling.
Here, signicantly elevated free radical levels and concurrently
low anoxidant levels cause oxidave stress to have a consider-
able impact on the organism as a whole [74]. Finding out how
free radicals contribute to the formaon and progression of the
disease has garnered increasing aenon in recent years [74].
Parcular focus has been placed on cancer, cardiovascular ill-
ness, and accelerated aging, as well as neurological disorders
such as Alzheimer's and Parkinson's disease [74-76]. Results
from the vast majority of research that has been conducted link
free radicals to the development of diseases [74].
The presence of hydroxyl groups in phenolic substances de-
termines their ability to scavenge reacve radicals, which in turn
determines their anoxidant potenal [75]. One of the most de-
sirable biological qualies of natural compounds is their capac-
ity to scavenge free radicals. Finding novel substances with high
anoxidant acvity has become a focus of a growing number
of studies. This paern has become parcularly notable in the
elds of biology, pharmacognosy, and pharmacotherapy. Inter-
est in this topic is sparked by knowledge of the harmful eects
of free radicals on the human body, the diseases caused by the
acvity of the reacve forms, and the fact that anoxidants can
eliminate the reacve species [74].
The anoxidant terpenoids from the red alga Laurencia tris-
cha were invesgated. By measuring the hydroxyl free radi-
cal's (OH) scavenging acvity using Electron Paramagnec Reso-
nance (EPR) spectroscopy, anoxidant acvity was determined.
The 1,10-epoxy moiety was discovered to be essenal for the
Table 4: Anviral properes of terpenoids.
Source Experimental Model Main Results Refer-
ences
Alpinia er-
emochlamys,
Etlingera exuo-
sa, and Etlingera
acanthoides
Viral-ToxGlo colorimetric method
against HIV-infected MT-4 cells
The screening of anviral acvity showed that the ethanol extract of E. acanthoides and A.
eremochlamys rhizomes have the potency to inhibit the replicaon of HIV-1 on MT-4 cells in
vitro. E. acanthoides rhizome showed the best anviral acvity with the lowest IC50 value, less
cytotoxicity on MT-4 cells, and the highest selecvity index
[60]
Lippia alba
MTT colorimetric assay for Zika
virus (ZIKV) in VERO cells, and
molecular docking assay to
idenfy the interacon between
β-caryophyllene and ZIKV enzyme
This plant is widely used in ethnomedicine and popular medicine, primarily in the form of infu-
sions, syrups, and poulces. The essenal oil of Lippia alba demonstrated an anviral acon
against ZIKV and minimal cytotoxicity. The primary component of essenal oils, ß-caryophyl-
lene, was found to be tested for its ability to suppress ZIKV replicaon only at the beginning
of the viral life cycle. The molecular docking experiments showed that ß-caryophyllene had a
stronger anity for the NS2B-NS3 protein complex and the NS5 protein
[61]
Arthrospira ma-
xima, Chlorella
vulgaris, Duna-
liella salina, and
Haematococcus
pluvialis
Tissue Culture Infecous Dose
50 (TCID50) in Vero cells against
Mayaro virus (MAYV)
The ndings of this study demonstrated that all microalgal extracts had levels of MAYV inac-
vaon that were higher than those of the reference compound ribavirin. As a result, the ex-
tracts have a signicant potenal for use in the treatment of Mayaro Fever, which is currently
not managed by any medicaons or vaccines
[62]
Lemnalia sp.
Inhibitory cytopathic eects (CPE)
assay against inuenza A virus
(H1N1) and Herpes Simplex Virus
Type 1 (HSV-1)
The various compounds were tested against H1N1 and HSV-1 virus. The results showed that
the compounds parathyrsoidin I and linardosinene E had inhibitory acons against inuenza A
virus H1N1
[57]
Diterpenic
Mannich bases
compounds
Hemagglunaon assay against
inuenza virus A/Puerto Rico/8/34
(H1N1) in MDCK cells and SARS-
CoV-2 pseudovirus in BHK-21-
hACE2 cells
Collecvely, the data suggested the potency of diterpenic Mannich bases as eecve an-
inuenza and an-COVID-19 compounds. [63]
Lippia mulora
and Zingiber of-
cinale essenal
oils
Cell culture cytopathic inhibion
test against poliovirus type I and
enterovirus type I
From results obtained regarding the anviral assay, Zingiber ocinale signicantly inhibited
type I enterovirus’ (EV-1) acvity as compared to Lippia mulora. However, in general, these
two essenal oils could be considered a source of natural therapeuc agents in the treatment
of viral infecons
[64]
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anoxidant acvity because all sesquiterpenes with this moi-
ety were found to be acve while those without it were found
to be less acve. The molecules with acetyl groups connecng
to 1-OH were less acve, and the aliphac hydroxy exhibited
less inuence, however, the phenolic hydroxy greatly increased
the anoxidant acvity. Addionally, the an-oxidant eect was
marginally reduced by the Br group on the phenyl ring, while
the C-10 conguraons had no discernible impact [77].
Also, the bioacvity acvity of Pinus merkusii needle and
bark was evaluated. The anoxidant capacity of extracts was in-
vesgated using the extract's ability in inhibing DPPH (2,2-di-
phenyl-1-picrylhydrazyl) radical. The scavenging acvity values
are expressed as IC50 for each extract. Pine needles and bark
extract both exhibited the same tendency in dose-dependent
ways about their DPPH scavenging abilies. The needle and
bark extracts both demonstrated signicant levels of scaveng-
ing acvity, with values of 97,98% and 93,93%, respecvely.
However, the anoxidant acvity (IC50) of P. merkusii bark ex-
tract was 59.32±1.74 μg/mL, stronger than needle extract at
68.67±1.47 μg/mL [78].
As before menoned, the ecacy of Ganoderma Lucidum
Ethanol Extract (GLEE) against metabolic syndrome (MetS) com-
plicaons in rats was evaluated. Thirty male rats were random-
ized into six dierent groups (containing 25 MetS and 5 normal
Table 5: Hypoglycemic eect of terpenoids.
Source Experimental Model Main Results Refer-
ences
Annona
diversifolia
Assessment for the potenal α-glucosidase inhibi-
tors: Oral sucrose (OSTT) and lactose tolerance
(OLTT) and intesnal sucrose hydrolysis (ISH) tests
These results provide informaon about the possible mechanisms of acon of
farnesal and farnesol, conrming their anhyperglycemic acvity mediated by
the inhibion of α-glucosidase and selecve inhibion of SGLT-1. Addionally, the
ethanolic extract obtained from the leaves of A. diversifolia was found eecve in
vivo for controlling fasng and postprandial blood glucose levels in animal models
of diabetes mellitus. Thus, leaves from A. diversifolia represent a good phytothera-
peuc agent for the treatment of this disease. So, the results reported from this
study provide a starng point for the development of new drugs for the treatment of
diabetes mellitus
[66]
Assessment for the potenal as sodium-glucose
cotransporter 1 protein (SGLT-1) inhibitors: tests
for oral glucose tolerance (OGTT), intesnal glu-
cose absorpon (IGA), and urine glucose excreon
(UGE)
In male normoglycemic and streptozocin-induced
diabetes type 2 (SID2) mice
Eclipta
prostrata L.
Calculaon of the dierent concentraons of the
absorbance recorded
Screening of these isolates in an array of bioassays revealed anbacterial, cytotoxic,
and α-glucosidase inhibitory acvies for selecve compounds. Of all the com-
pounds tested, the C30H50O2 compound represents an undescribed type of triter-
penoid inhibitor and proved to be one of the most potent natural ones, and it thus
could serve as a template compound for future an-diabetes drug development
[53]
Gano-
derma
lucidum
Thirty male rats were randomized into six dierent
groups (containing 25 MetS and 5 normal rats),
following two weeks of Ganoderma lucidum
ethanol extract (GLEE) treatment post- metabolic
syndrome (MetS) inducon. Biochemical and
histological studies were performed on blood,
pancreas, hearts, livers, and kidneys
Taken together, GLEE showed tremendous biological eects. Results revealed that
GLEE (70 mg/kg) reversed signicantly (p < 0.05) the MetS-induced hyperglyce-
mia. Besides, rats treated with GLEE did not show any pathological features in the
pancreas, heart, liver, and kidneys. This study, therefore, showed that Ganoderma
lucidum might be a candidate regimen in the management of MetS
[67]
Hagenia
abyssinica
Normal, oral glucose-loaded, and streptozotocin-
induced diabec mice, were administrated with
three dierent doses of the solvent fracons
(100, 200, and 400 mg/kg). One-way ANOVA fol-
lowed by Tukey’s post hoc test was used for data
analysis, and p<0.05 was considered a stascally
signicant
The results of the current study proved that Hagenia abyssinica leaf solvent fracons
have andiabec eects in normoglycemic, oral glucose-loaded, and streptozotocin-
induced diabec mice. Addionally, the solvent fracons improved the changes in se-
rum lipid proles and body weight associated with diabetes. As a result, this research
supports the use of Hagenia abyssinica in the treatment of diabetes
[68]
Dillenia
indica
Palmic acid-induced insulin resistance (PA-IR)
in C2C12 myotube and a streptozotocin (STZ)-
induced diabec mice model
Dillenia indica L. bark (TRDI) compevely inhibited α-glucosidase acvity in a dose-
dependent manner. Addionally, it enhanced GLUT4 translocaon and acvated
the insulin signaling pathway (e.g., IRS-1 and Akt signaling) in basal and PA-IR C2C12
myotubes. These results may help formulate novel glucose management therapeu-
cs in the future using Dillenia indica in the treatment of diabetes
[69]
Salvia
polys-
tachya
Tests of the hyperglycemia acvity in mice of etha-
nolic extract from Salvia polystachya (EESpS), ethyl
acetate fracon (EtOAcFr), secondary-6-fracon
(SeFr6), ursolic acid (UA), and oleanolic acid (OA) In diabec rats, blood glucose levels were decreased by the ethanolic extract from
Salvia polystachya, EtOAcFr, SeFr6, and UA and OA discovered in the EtOAcFr. Studies
conducted in silico, ex vivo, and in vivo all supported this acvity. Inhibion of the
α-glucosidase enzyme and the SGLT1 cotransporter is thought to play a role in the
andiabec eect of the products made from the stems of S. polystachya. This study
conrms S. polystachya's phytochemical and pharmacological origins and ulity as a
source of prospecve an-diabec drugs
[70]
α-glucosidase inhibion evaluated with oral
sucrose and starch tolerance tests (OSuTT and
OStTT), intesnal sucrose hydrolysis (ISH) assay,
and molecular docking studies using acarbose as
a control
SGLT1 inhibion was evaluated with oral glucose
and galactose tolerance tests (OGTT and OGaTT),
an intesnal glucose absorpon (IGA) assay, and
molecular docking studies using canagliozin as
the control
Hypericum
perforatum
Human liver cancer cell line HepG2 and mice nor-
mal liver cell line AML12 using a glucose test kit
The compounds (+)-Hyperpyran A and (-)-Hyperpyran A were invesgated for their
hypoglycemic acvity. The results showed that compound (+)-Hyperpyran A exhib-
ited a moderate promoon of glucose uptake acvity in hepatocytes
[71]
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rats). In vitro was used the 2,2-Diphenyl-1-Picrylhydrazyl (DPPH)
radical scavenging acvity of the G. lucidum, Ferric ion Reduc-
ing Anoxidant Potenal (FRAP), and Total Anoxidant Capacity
(TAC) assays to assess the anoxidant proling of GLEE. Ascorbic
acid was used as the posive reference standard. In vivo was
used Malondialdehyde (MDA) level, assay for Superoxide Dis-
mutase (SOD) and Catalase (CAT) acvity. A dose-dependent
total anoxidant capacity and, a near dose-dependent DPPH
radical scavenging, and ferric ion reducing ability were exhib-
ited by GLEE. Besides, MDA level measures (pancreas: 37%,
heart: 65.58%, liver: 43.17%, and kidneys: 73.2%), SOD acvity
(pancreas: 33.11%, heart: 26.97%, liver: 13.69%, and kidneys:
25.16%), CAT acvity (pancreas: 9.33%, heart: 31.06%, liver:
30.21%, and kidneys: 25.22%), and NRF2 protein level, which
were increased in the MetS group, were signicantly reduced in
the GLEE-treated groups [67].
The essenal oil of the Vietnamese plant Alseodaphne ve-
luna Chev was studied. Ulizing the DPPH (2,2-diphenyl-1-
picrylhydrazyl), ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-
sulphonic acid), and FRAP (ferric reducing anoxidant power)
assays, the anoxidant potenal of leaf essenal oil was as-
sessed. The results showed moderate to high acvity compa-
rable to the well-known anoxidant standard Trolox. Trolox
equivalent anoxidant capacity (mg TEAC/g dw), which repre-
sents the level of anoxidant acvity in comparison to conven-
onal Trolox, is shown aer the results. The DPPH assay showed
a modest acvity (1.08 mg TEAC/g dw). The ABTS+ test had a
scavenging capacity of 2.53 mg TEAC/g dw, which was 2.34 mes
greater than the DPPH test. In comparison to DPPH and ABTS,
FRAP analysis showed the strongest ability to degrade Fe3+ into
Fe2+ (2.79 mg TEAC/g dw) and the highest anoxidant acvity.
Table 6: Anoxidant acvity of terpenoids.
Source Experimental Model Main Results References
Laurencia
trischa
Hydroxyl free radical's (OH) scavenging acvity
using electron paramagnec resonance (EPR)
spectroscopy
The anoxidant properes of eleven laurane-type sesquiterpenes obtained from
L. trischa were evaluated. The laurane-type sesquiterpenes with 1,11-epoxy
moiety showed potenal anoxidant acvity
[77]
Pinus
merkusii
DPPH (2,2-diphenyl-1-picryl-hydroxyl) scavenging
acvity
Pinus merkusii extracts have the potenal as a natural source of anoxidants and
anaging and might be benecial in these subjects. With parcular regard to the
anoxidant properes of bark extract that are stronger than the needle extract
[78]
Gano-
derma
lucidum
Thirty male rats were randomized into six dier-
ent groups (containing 25 MetS and 5 normal
rats), following two weeks of Ganoderma lucidum
ethanol extract (GLEE) treatment post- metabolic
syndrome (MetS) inducon. Biochemical and
histological studies were performed on blood,
pancreas, hearts, livers, and kidneys
Taken together, GLEE showed tremendous biological eects. GLEE demonstrated
a dose-dependent total anoxidant capacity, a nearly dose-dependent DPPH
radical scavenging ability, and ferric ion reducon capability. In comparison to the
MetS control group, the GLEE-treated group displayed elevated CAT (pancreas and
heart) and SOD (the four organs) acvity as well as dramacally decreased NRF2
protein levels. This study, therefore, showed that Ganoderma lucidum might be a
candidate regimen in the management of MetS
[67]
Alseodaph-
ne veluna
Chev.
DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS
(2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic
acid) and FRAP (ferric reducing anoxidant power)
assays comparable with Trolox
The terpenoids present in the leaf essenal oil of A. veluna plants from Vietnam
are highly concentrated (89.18%), with b-patchoulene and b-caryophyllene being
two of the main constuents. Natural essenal oil demonstrated great reducing
an-oxidant power and high free radical scavenging acvity, indicang that it may
be a viable source of natural anoxidant
[79]
Senna tora
(L.) Roxb.
leaves
2,2-diphenyl-1-picrylhydrazyl (DPPH)- and H2O2-
scavenging tests comparable with Ascorbic acid
The ndings of this study concluded that Senna tora (L.) Roxb. leaves contain
various acvies due to the presence of some biologically acve phytochemicals,
such as terpenoids. Based on the anoxidant acvity assays, when comparing
the outcomes of Senna tora (L.) Roxb. leaves' ethyl acetate extract (EAESTL) and
ascorbic acid, the extract demonstrated comparable anoxidant acvity with the
established anoxidant. Collecvely, this shows the potenal of the extract to
ght against oxidants
[48]
Carissa
edulis and
Pappea
capensis
Hydroxyl radical, DPPH radical, and ferric reduc-
on acvies
The anoxidant properes of C. edulis and P. capensis extracts have been estab-
lished. The existence of phytocompounds, which have the capacity to contribute
hydrogen atoms or electrons and thereby quench the radicals, is responsible for
the acons. Addionally, the phytocompounds are linked to higher levels of enzy-
mac anoxidants' expression. According to the research, one of the underlying
reasons for the therapeuc eects of C. edulis and P. capensis extracts could be
their anoxidant properes.
[80]
Acvies of catalase, superoxide dismutase and
glutathione reductases of the extracts
Addionally, they highlight that according to the results, A. ve-
luna leaf oil's anoxidant acvity was probably connected to
terpenoids' dominance (89.18%) [79].
As aforemenoned, Senna tora (L.) Roxb. was invesgated
for its potenal as a source of therapeuc candidate. H2O2-scav-
enging tests and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays
were used to measure the in vitro anoxidant acvity. Senna
tora (L.) Roxb. leaves' ethyl acetate extract (EAESTL) demon-
strated dose-dependent anoxidant acvity with a range from
33.041±1.166% to 91.068±1.950% DPPH inhibion and an IC50
value of 24.425 μg/mL at doses ranging from 2.5 to 200 μg/
mL. Ascorbic acid had comparable anoxidant ecacy, DPPH
restraint ranging from 40.455±2.019% to 98.190±0.863%, with
an IC50 value of 2.585 μg/mL. For EAESTL and ascorbic acid, an
H2O2-scavenging assay was also conducted. With an IC50 value
of 17.434 μg/mL and concentraon-dependent anoxidant
acvity, EAESTL was shown to scavenge H2O2 with a range of
34.595±1.104% to 93.734±0.336%. Addionally, ascorbic acid
had H2O2-scavenging acvity that was equivalent to EAESTL,
with a range of 39.238±2.040 to 99.154±0.115% and an IC50 val-
ue of 1.923 μg/mL. So, when comparing the outcomes of vari-μg/mL. So, when comparing the outcomes of vari-g/mL. So, when comparing the outcomes of vari-
ous scavenging studies, EAESTL and an established anoxidant
(ascorbic acid) demonstrated comparable anoxidant acvity
[48].
Addionally, Carissa edulis and Pappea capensis extracts
were tested for their anoxidant acvity. Using the iron chelat-
ing, hydroxyl radical, DPPH radical, and ferric reducon acvi-
es, the extracts' in vitro anoxidant capabilies were assessed.
The extracts' catalase, superoxide dismutase, and glutathione
reductase acvies were also discovered. The anoxidant prop-
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eres of the extracts were concentraon-dependent. Addion-
ally, has an impact by increasing the expression of enzymac
anoxidants [80].
An overview of the dierent studies made about the anoxi-
dant acvity of terpenoids is presented in Table 6.
An-Aging Properes
Over me, many of the body's primary systems experience
degenerave deterioraon as part of the extremely complicat-
ed process of aging. Hereditary, behavioral, and environmental
factors all have an impact on this unavoidable process [81,82].
The aging process is accompanied by a variety of outward and
internal indicaons and symptoms, such as changes to the skin,
and neurological diseases like Alzheimer's disease, cancer, etc
[81,83,84].
The majority of this aging process is linked to inammatory
factors and oxidave stress [85]. One of the primary iniang
factors causing aging-related damages and concerns is oxidave
stress, which is a result of an imbalance between pro- and an-
oxidants. This is because metabolism produces highly reacve
byproducts like reacve oxygen and nitrogen species, which
cause cellular damage and apoptosis. Due to their capacity to
suppress the generaon of free radicals or stop their spread,
anoxidants can lower oxidave stress, prevenng harmful pro-
cesses and extending healthy life. Natural an-aging substanc-
es, including vitamins, polyphenols, hydroxy-acids, polysaccha-
rides, and a host of others, are essenal for slowing down the
aging process [81].
An enormous economic and social burden is being placed
on the world by the rise in the aging populace [83]. An-aging
medicine is a relavely new branch of medicine that is expand-
ing extremely quickly. It is well known that certain nutrients
can delay aging and support healthy aging, including specied
vitamins, minerals (as micronutrients), essenal and branched
amino acids, polyunsaturated fay acids, probiocs, and plant
metabolites like polyphenols and terpenoids [81].
The scienc community will need to pay close aenon
to the mely creaon of medicaons that can reduce the ag-
ing process, either alone or as mulple agents, as a new era of
an-aging drug discovery dawns [86]. Natural substances give
us the movaon to advance in our quest to comprehend and
enhance the health span, extending life expectancy and en-
hancing health and quality of life by reducing the onset of some
age-related chronic diseases [81,86].
Skin Aging: The skin is a complex organ that shields the body
from the outside environment [8,14]. It has several purposes,
including serving as a physical permeability barrier, safeguard-
ing against pathogenic agents, regulang body temperature,
enhancing sensaon, guarding against Ultraviolet (UV) rays, and
promong regeneraon and wound healing [87].
As stated in study (88), skin aging is a situaon when the skin
is unable to maintain its structural and physiological integrity.
There are numerous causes of skin aging, but external factors
are the primary ones (for example, ultraviolet UV rays). These
variables aected Reacve Oxygen Species (ROS) levels in the
body through a variety of routes. The condion known as oxida-
ve stress is characterized by an imbalance between the gen-
eraon of ROS and its removal, which is frequently observed
in older skin. As a result of the up-regulaon of several types
of collagenases and elastases, the structural protein created by
the skin's connecve ssue was prone to disintegraon in aged
skin. They concluded that reducing the eects of free radicals is
a crucial strategy for combang skin aging.
Anoxidants are therefore crucial in avoiding skin aging since
they can destroy free radicals by providing or accepng an elec-
tron to complete the unpaired molecules. Furthermore, anoxi-
dants' an-inammatory properes boost their ability to delay
the aging process of the skin [72,89].
Researchers in the cosmec industry have become interest-
ed in bioacve natural materials due to their potenal use in
treang skin-related issues including wrinkles because of their
anoxidave capabilies [87,90].
One example is the potenal of mushroom acve compounds
to acvate the skin’s immune system and reduce cell apoptosis,
resulng in delaying the process of senescence as skin aging
[91]. Moreover, study [90] proved that lupeol (terpenoid) can
be recommended as an anwrinkle agent, and therefore be rec-
ommended to be incorporated in topical formulaons.
According to study [92], terpenoids are eecve enhancers
from natural sources that are useful in transdermal medicine
delivery because they have low toxicity, high bioavailability, and
are easily absorbed via the skin. As a result, they can help the
primary medicine penetrate through the skin when employed
as excipients in formulaons. As an illustraon, they provide
invasomes, which are now the most widely used nanosystem
formulaon using terpenoids as excipients. They are made of
phosphadylcholine, ethanol, and a variety of terpenoids. They
funcon as penetraon-enhancing vesicles because of their
exibility and deformability, which facilitate penetraon across
epidermal layers.
The cosmecs business and dermatological research are
both focused on developing an-aging soluons. Although the
development of modern skincare products necessitates a thor-
ough understanding of ingredients, natural product chemistry,
and skin biology, there has been a steady rise in research into
the use of biodegradable materials, largely as a result of grow-
ing environmental concerns and the ecological eects of using
synthec alternaves [89].
Degenerave Diseases: Alzheimer's disease is a chronic,
progressive neurological condion that most frequently aects
elderly people and is associated with demena and cognive
decline [93,94]. This is the most typical type of demena that
is currently recognized [95]. The condion has a signicant eco-
nomic burden in addion to its detrimental consequences on
human health and quality of life [94,96].
The second most common neuro-degenerave ailment to
cause morbidity and mortality in elderly populaons is Parkin-
son's disease. As the disease progresses, symptoms start to be-
come more noceable. This illness is characterized by a neuro-
degenerave disorder of the central nervous system, by loss of
nerve cells in the area of the brain [97].
One of the main causes of these disorders is neuroinamma-
on. The so-called "damage signals" are where the processes
for inammatory process in the human brain begin. Palliave
care can halt the evoluon of cognive symptoms and stop any
worsening of the paent's symptoms, but there is currently no
eecve medicaon that can cure the condion. Massive ef-
forts are put towards nding medicaons that target molecu-
lar pathways and stop progression as well as dierent disease-
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modifying therapies. Intervenon therapy employing natural
products high in anoxidant and avonoid content is now more
important than ever due to the limitaons of current prevenve
methods [93].
We can uncover compounds with an-aggregate acvity, as
well as compounds with anoxidave and an-inammatory
acons when searching for nutraceucal bioacve principles
[94]. The invesgaon of an-inammatory and neuroprotec-
ve phytochemicals, such as terpenoids, phenolic derivaves,
alkaloids, glycosides, and steroidal saponins, reveals therapeu-
c potenal for the amelioraon and prevenon of severe neu-
rodegeneraon [93]. Terpenoids are the largest and most diver-
sied collecon of chemical molecules among several natural
products [98]. Terpenoids are more likely to be discovered to
have substanal an-demena acvity [98] as a result of the
invesgaon of these compounds, making them prospecve
neuroprotecve agents [97].
Numerous secondary plant metabolites have reportedly
been found as potenal therapeuc candidates for use in the
management of various forms of demena, according to study
[95]. Based on both in vitro studies of this invesgaon, the rec-
ommended terpenoids had low cytotoxicity, and carvone stood
out as having the strongest acetylcholinesterase inhibitory ef-
cacy.
Aromatherapy using essenal oils is one of the treatments
in use and has been shown to improve cognive performance
in demena paents. These substances pass the blood-brain
barrier, are absorbed through the skin, and enter the systemic
circulaon. Consequently, topical treatment or inhalaon may
have a nervous system eect that is not just psychological.
The hydrocarbon terpenoids with the shortest molecular size
and highest lipophilicity had the highest expected penetraon.
The size of molecules, which poses issues with distribuon to
the brain, is one key drawback of innovave multarget com-
pounds created for the treatment of Alzheimer's disease, ac-
cording to this research. Therefore, they explain the necessity
for smaller molecules with specic biological eects and more
desired physicochemical features and pharmacokinecs [99].
Ancancer
Worldwide, cancer is recognized as a serious public health
issue and a life-threatening disease [100-102]. It is the biggest
cause of death globally and is seen as one of the main barriers
prevenng the rise in life expectancy [103]. It is characterized
by unchecked cell growth that invades the ssues around it and
the development of tumor masses [100,104]. This disease can
manifest itself in various parts of the body, such as breast can-
cer (abnormalies in the proliferaon of breast cells and is the
most common cancer with high mortality in women), brain can-
cer (glioblastoma mulforme that grows and develops rapidly),
colon cancer (develops in the large intesne), liver cancer (aber-
rant growth of liver ssue that mutates and develops a tumor),
uterus cancer (a malignant tumor that develops commonly in
the uterus in women with menopause or over 50 years of age),
lung cancer (malignancy in the lung ssue originang from cells
inside and outside of the lungs), leukemia (the body produces
excess white blood cells), and many others [24].
Despite decades of research into the disease, there is sll a
need for highly eecve ancancer medicaons with low tol-
erance and fewer side eects [100]. Chemotherapy, radiaon
therapy, and surgical therapy are some of the therapeuc op-
ons. These treatments, however, result in signicant ssue
damage and other unfavorable side eects [23,24]. The main
challenges in treang cancer include chemoresistance, extreme
toxicity, recurrence, and metastasis [102]. To expand the num-
ber of ecient, risk-free, and aordable cancer treatments, it
is therefore sll important to develop new therapeuc agents
[102,104,105].
A new approach to treang cancer is therefore urgently re-
quired [104,106]. The trend towards using natural products has
sparked the emergence of novel bioacve metabolites that may
be targeted for specialized medicinal applicaons [23]. The ma-
jority of pharmaceucals used now in therapy are derived from
natural substances [107]. Drugs made from natural sources con-
nue to occupy a major role, despite advancements and the
creaon of synthec pharmaceucal chemistry [103,104,107].
Due to their wide chemical variety, there is a higher likelihood
of discovering novel compounds with disncve structures and
possible biological acvies [103,107].
Many researchers are interested in natural substances like
terpenoids [107]. Terpenoids, which make up the majority of
the secondary metabolites generated by plants, are frequently
thought of as medicines [23]. Terpenoids have excellent an-
cancer properes, according to a large number of studies
[23,24,100,101]. Their an-tumor acons, which are among
their many biological characteriscs and include an-prolifer-
ave, apoptoc, an-angiogenic, and an-metastac acvies,
are parcularly interesng [103,107].
Apoptosis is the main method by which terpenoids cause
cell death [103]. Terpenoids, specically autophagy, have been
linked to dierent types of cell death [103]. Numerous in vitro
and in vivo invesgaons have been conducted to comprehend
the 'terpenoid-induced autophagy phenomena in cancer cells
[103]. The complex balancing act between acvang or silenc-
ing certain proteins, with the result being expressed through
connected signaling pathways, is what causes the laer cross-
talk. Targeng autophagic signaling pathways may oer an in-
novave therapeuc opon for the treatment of cancer since
mounng data suggest that autophagy plays a signicant role
in the development of cancer. It's interesng to note that ter-
penoids have been shown to acvate the molecular processes
that cause cancer cells to undergo autophagic cell death. The
funcon of autophagy remained unclear, though. Furthermore,
some terpenoids also have an ancancer impact by prevenng
or accelerang several stages of cancer development. For in-
stance, they can stop carcinogenesis in its early stages by caus-
ing cell cycle arrest, prevenng cancer cell dierenaon, and
acvang apoptosis [102].
Authors have looked into a few instances, like study [107]
which highlighted the potenal of salvicine, sesquiterpene lac-
tones, and diterpenoids as alternave cancer treatment opons
because of their preferenal selecvity over parcular tumors
and cell lines in addion to acng on parcular signaling path-
ways. Parthenolide also exhibits ancancer properes against a
variety of tumor types, including colorectal, melanoma, pancre-
ac, breast, prostate, cervical, renal, and thyroid cancers [103].
Addionally, study [101] demonstrates that the terpenoids
isolated from Curcumae Rhizoma, such as (β -elemene, Fura-
nodiene, Furanodienone, Germacrone, Curcumol, Curdione,
etc.), are promising ancancer agents based on data from vari-
ous cancer cell lines, animal models, and clinical trials, as well
as their mechanisms of inhibing cell proliferaon, autocrine
growth factor producon, and DNA synthesis.
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The use of terpenoids does have some restricons, though,
as other authors have noted. Study [102] highlights the dis-
connect between terpenoids' preclinical evidence and clinical
outcomes, in addion to their poor absorpon and low bio-
availability. Terpenoids were reportedly explored in a relavely
small number of experimental sengs in preclinical models.
The dicules presented by the diverse genec composion
of the human populaon and the complexity and heterogene-
ity of cancer arise as a result when terpenoids are nally tested
in cancer paents. Given the ecacy of terpenoids, they con-
cluded that, before undertaking extensive clinical studies, fu-
ture research should concentrate on thorough preclinical tox-
icity, bioavailability, pharmacodynamics, biomarkers, and wide
invesgaons of tumor suppression using appropriate animal
models. Study [101] also emphasized the scant research done
to compare the ancancer properes of various terpenoids.
Given the benets of these phytoconstuents, terpenoids
may be used with other chemotherapeuc medicaons and ra-
diaon therapy to improve their therapeuc ecacy as well as
provide new opons for chemoprevenve strategies [104].
Other Biological Acvity
In addion to the previously menoned an-inammatory,
anbacterial, anviral, hypoglycemic, anoxidant, and an-ag-
ing properes, terpenoids also have other biological and phar-
macological acvies.
Some studies have menoned its involvement in processes
like plant growth (used as signal molecules to mediate plant de-
fense in response to herbivorous insects and patho-genic bac-
teria’s invasion) [3,11,12,108]; development, and defense, im-
munoregulaon, acvity in the olfactory system (sensed in the
olfactory epithelium could be the lateral/ventral areas, which
project their axons from sensory neurons to the lateral/ventral
domain in the olfactory bulb) [34,51]; gastroprotecve acv-
ity (modulate gastric acid secreon, enhance mucosal defense
mechanisms, and inhibit the growth of Helicobacter pylori bac-
teria) [34,38]; food addive (approved to be used as avorings
and food preservaves) [12,38,51]; anparasic acvity (ter-
penoids have shown promise in combang parasic infecons,
including malaria, by interfering with parasite growth, replica-
on, and survival [3,12]; and cardioprotecve acvity (have sig-
nicant therapeuc eects on various cardiovascular diseases,
such as regulang vascular funcon, inhibing cardiomyocyte
hypertrophy, and inhibing thrombosis) [3,10,109].
Industry Applicaons
The preference for natural products has sparked the iden-
caon of new bioacve metabolites that may be targeted for a
variety of applicaons [23].
Terpenoids, which are the most prevalent plant secondary
metabolites and have a variety of structural characteriscs as
previously menoned, comprise the largest family of natural
products and have widespread applicaons in various elds
[16,83,110].
Indeed, terpenoids have been crucial to numerous aspects
of human life [111], and their applicaon can be grouped into
ve main industries [112]: pharmaceucal, cosmec, food, ag-
riculture, and other industries. An overview of the use of terpe-
noids in dierent industries is presented in Figure 3.
Terpenoids have a substanal eect on human health due to
their ulity in the pharmaceucal industry [14,16,20,113-116]
and their abundance in bioacve components [112]. Numer-
ous studies have emphasized the vast range of biological and
pharmacological acvies that demonstrate the acvity shown
by terpenoids has a signicant role in the creaon and develop-
ment of new medicaons and improvements in available treat-
ment choices [15,17,24,25,39,52,92,111,112,117-120].
The fragrance sector is one of the major markets for these
kinds of chemicals [14]. Terpenoids are oen used in the cre-
aon of cosmecs [14,16,19,39,112,118,121], especially per-
fumes [14,24,39,115,118], as they have wide market potenal
and provide economic advantages [19].
The food industry is one of these compounds' other im-
portant markets [14,25,39,81,86,114-116,118]. Terpenoids
in herbs and spices are frequently employed to preserve
food because of their microbicidal and inseccidal properes
[14,39,111,112,122]. Becoming an alternave eco-friendly
food preservave [39]. They are also responsible for the a-
vor found in food, beverages (tea), alcoholic drinks, and wine
[19,52,111,112].
Plus, some terpenoids play an important role in the agricul-
ture industry [14,19,118]. They are used as pescides [14,19,25],
as inseccides [112,117], and as repellents [112] and they also
contribute to the producers' defense against or aracon to
benecial organisms [14,20]. Addionally, they serve several
physiological and ecological roles in plant life through direct
and indirect plant defenses, by luring pollinators, and through
various interacons between the plants and their surroundings
(such as acng as vectors for the transfer of pollen, for example)
[19,25,27,116].
Moreover, some researchers have found that terpenoids
have applicaons in synthec and bulk chemicals (39,115),
rubber products [39], and some industrial raw materials
[19,39], as well as being precursor compounds to biofuel
[14,16,19,26,39,114,115,121].
Terpenoids have a variety of funcons in numerous indus-
tries, as was already indicated, and have grown to have sig-
nicant economic value [19]. However, many connue to em-
phasize the need for greater research on this chemical so that
industrializaon and producon of it in the future can be safer
and more advantageous [19,39,116,121].
Disadvantages
Despite the terpenoid’s diverse uses and great demand
[115], their promising ability to prevent and treat various dis-
eases [92], and their wide range of applicaons [115], a few
studies have revealed certain disadvantages to their use.
The dicules menoned included their low water solubility
[21,92,123,124], dicult stability [92,125], dicult extracon
[22,102,115,126], low bioavailability [21,27,92,102,124], high
producon costs [115], and organolepc eects [39], as well as
other side eects that could restrict their use in clinics [92,124],
including irritant index [92], poor absorpon [21,102], unfavor-
able eects on reproducve funcons [13], and gastrointesnal
upsets [13].
Specically, research [115] talks about how dicult it is to
chemically synthesize this family of compounds. Addionally, it
draws aenon to the fact that making these compounds re-
quires several complex synthec procedures, which raises the
cost of manufacture. It further claries that the extracon of
terpenoids chemicals from natural sources is me-consuming,
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yields are low, and important resources are used up excessively.
In addion, study [21] points out that terpenoids have high
polarity and poor bioavailability due to their structure, which
limits their biolm permeability and absorpon [57]. Therefore,
they concluded that chemical or pharmaceucal methods must
improve the dissoluon and absorpon ability.
The eciency of terpenoids [102] has led many to point out
the need for more research into this substance to comprehend
the biological features' underlying mechanisms in a way to
overcome these issues [23,39,102,110,115,124,127].
Conclusions
The preference for natural products has sparked the dis-
covery of novel metabolites that may be targeted for certain
therapeuc purposes. The majority of secondary metabolites
produced are terpenoids, which have been found to have sev-
eral important health benets, including an-inammatory
properes, antumor and ancancer eects, anbacterial and
anviral properes, anmalarial properes, the ability to pre-
vent and treat cardiovascular diseases, the promoon of trans-
dermal absorpon, and an-aging properes.
Terpenoids play a signicant part in various industries thanks
to their acvity, making them important compounds with a
wide range of applicaons. They are also frequently used and
have excellent development prospects. emphasizing in parcu-
lar their an-aging qualies. Due to age-related medical issues
like cancer, neurological illnesses, and skin aging, the consid-
erable increase in the world's aging populaon is placing eco-
nomic and social responsibilies.
Terpenoids may have geroprotecve qualies, and the dis-
covery and applicaon of eecve geroprotecve strategies can
lead to an increase in health span and the prevenon or ame-
lioraon of age-related diseases. This substance has a strong
potenal to launch a new class of an-aging medicaons. To aid
in the creaon of viable intervenons to lessen the detrimental
eects on health, further research on the biological process of
aging is required.
Their low water solubility, dicult stability, dicult extrac-
on, low bioavailability, high producon costs, and organolep-
c eects are some of these compounds’ drawbacks. They also
have addional side eects that may limit their use in clinics,
such as irritant index, poor absorpon, unfavorable eects on
reproducve funcons, and gastrointesnal upsets. Research-
ers also have certain concerns about this compound's biosyn-
thesis, extracon, and producon processes. Future research
should focus on terpenoids' broad toxicity, their catalyc mech-
anism, bioavailability, pharmacodynamics, biomarkers, exten-
sive examinaons of their bioacve qualies, and their usage in
various industries in light of their eecveness.
Future breakthroughs in cung-edge high-throughput ap-
proaches will be necessary to nd novel and ecient natural
candidates that prolong lifespan and delay aging and related
disorders, such as terpenoids.
Author Statements
Author Contribuons
Ana Borges and Filipa Mandim: Conceptualizaon, wring—
original dra preparaon; Sandrina A. Heleno and Ricardo C.
Calhelha: Conceptualizaon, formal analysis, wring—review
and eding. All authors have read and agreed to the published
version of the manuscript.
Acknowledgements
The authors are grateful to the Foundaon for Science and
Technology (FCT, Portugal) for nancial support through na-
onal funds FCT/MCTES (PIDDAC) to CIMO (UIDB/00690/2020
and UIDP/00690/2020) and SusTEC (LA/P/0007/2020). Naonal
funding by FCT, P.I., through the scienc employment program
contract for the contract of R. Calhelha (CEEC Instuonal).
Conicts of Interest
The authors declare that they have no known compeng -
nancial interests or personal relaonships that could have ap-
peared to inuence the work reported in this paper.
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