Available via license: CC BY 4.0
Content may be subject to copyright.
plants
Article
Medicinal Properties of Lilium candidum L.
and Its Phytochemicals
Michele Zaccai 1, Ludmila Yarmolinsky 2, Boris Khalfin 2,3 , Arie Budovsky 4,
Jonathan Gorelick 2, Arik Dahan 3and Shimon Ben-Shabat 3, *
1Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel;
mzaccai@bgu.ac.il
2Eastern R&D Center, Kiryat Arba 9010000, Israel; liorayarl@mail.com (L.Y.); boriskh83@gmail.com (B.K.);
jonathangorelick@gmail.com (J.G.)
3
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; arikd@bgu.ac.il
4Research & Development Authority, Barzilai University Medical Center, Ashkelon 7830604, Israel;
abudovsky@gmail.com
*Correspondence: sbs@bgu.ac.il; Tel.: +972-54-599-1056
Received: 9 July 2020; Accepted: 27 July 2020; Published: 29 July 2020
Abstract:
Lilium candidum L., known as Madonna, meadow, or white lily, is a bulbous plant from the
Liliaceae family, originating in the Middle East. L. candidum has been abundantly used in folk medicine
since ancient times to relieve a variety of ailments, including age-related diseases, burns, ulcers, and
coughs. The aim of this article is to investigate the anti-inflammatory and anti-diabetic activities of
L. candidum extracts and its active phytochemicals. Some active volatile phytochemicals were identified
using gas chromatography–mass spectrometry (GC-MS) analysis.
Significant (p<0.001)
anti-diabetic
properties of the extracts kaempferol, linalool, citronellal, and humulene were demonstrated by
an elevation in glucose uptake by adipocytes. The significant (p<0.01) effect of the plant extracts
kaempferol, citronellal, and humulene on the secretion of pro-inflammatory cytokines interleukin
6 (IL-6) and interleukin 8 (IL-8) was demonstrated using enzyme-linked immunosorbent assay.
Altogether, L. candidum and its rich collection of phytochemicals hold promising medicinal potential,
and further investigations of its therapeutic prospects are encouraged.
Keywords: Lilium candidum; phytochemicals; medicinal activities
1. Introduction
The prevalence of age-related diseases (ARDs) including cardiovascular diseases, cancer, type 2
diabetes, neurodegenerative diseases, and obesity is rapidly increasing worldwide [
1
]. Recent studies
provide strong evidence suggesting an essential role of chronic inflammation in the pathogenesis of the
above-mentioned ARDs [
2
–
4
]. In addition, genotoxic stress, which is a component of a wide variety of
pathological conditions, not only causes extensive DNA damage but also activates pathways leading to
chronic inflammation (the ERK, JNK, and p38 MAPK pathways) and transcription of pro-inflammatory
cytokines (TNF-
α
, IL-1
β
, interleukin 6 (IL-6)), chemokines (interleukin 8 (IL-8)), adhesion molecules
(VCAM-1, ICAM-1, P-, E-selectin), and other pro-inflammatory enzymes including iNOS and COX-2 [
5
].
This in turn leads to an elevated pro-inflammatory status that is likely to set the stage for increased
vulnerability to many ARDs [6].
Unfortunately, current therapeutic agents have inadequate efficacy and many serious adverse
effects in treating all kinds of ARDs [
7
]. All possible options should be considered in order to develop
new drugs that are more effective. In fact, many medicinal plants are able to cope with inducers
and/or consequences of stress such as thermal or oxidative insults, ionizing radiation, DNA damage,
Plants 2020,9, 959; doi:10.3390/plants9080959 www.mdpi.com/journal/plants
Plants 2020,9, 959 2 of 11
exposure to carcinogens, and inflammatory burden, which is one of the important determinants of
survival and longevity [8,9].
Lilium candidum L. has been well known in folk medicine for a long time, not only in the plant’s
native regions (Balkans, Middle East) but also in other parts of the world in which it was naturalized,
such as various European countries, North Africa, and Mexico. In folk medicine worldwide, L. candidum
is prominently associated with dermal conditions, cosmetics, and anti-inflammatory remedies [
10
–
12
].
A vast ethnopharmacological research study performed in the Campidano Valley and Urzulei district
in Italy revealed many medicinal benefits of L. candidum. Among them were application of lily
petals and a decoction of bulbs soaked in milk as pectoral poultices, application of petals soaked
in spirit as a wound-healing remedy, and the use of oil prepared from flowers as a treatment for
mastitis [
13
]. In addition, ethnopharmacological research in Lucca province in Italy demonstrated
the use of L. candidum bulbs as an anti-viral agent to treat shingles (Herpes zoster), and its bulbs
and flowers for treatment of skin and articular diseases [
14
]. L. candidum was also successfully used in
anti-inflammatory and dermatological remedies in the Catalan district of the Eastern Pyrenees [14].
L. candidum L., commonly known as Madonna, meadow, or white lily, is a geophyte from the
Liliaceae family growing in the wild in several countries of the Middle East. The origin of L. candidum is
believed to be in Lebanon and Israel, as well as several parts of Greece [
15
–
17
], thus Israel represents the
Southern border of L. candidum distribution and only few populations are found in the Carmel and the
Galilee regions. It is considered an endangered species and as such the plants are protected [
15
,
18
].
A collection of wild L. candidum ecotypes from different locations exhibited genetic variation in
morphologic and phenologic traits, as well as in phytotoxicity of their leaf extracts [18,19].
Effective delivery of herbal compounds and plant extracts is a very important issue,
since drawbacks such as hydrophobicity, insolubility in water, high volatility, and instability pose
a challenge [
20
,
21
]. The application of innovative drug delivery systems including phytosomes,
nanoparticles, hydrogels, microspheres, transferosomes and ethosomes, self-nanoemulsifying drug
delivery systems (SNEDDS), self-microemulsifying drug delivery systems (SMEDDS) and so on may
improve the biopharmaceutical features of the delivered compounds [22,23].
Owing to its rare beauty, its fragrance, and its glorious symbolism, L. candidum appears to
be a fascinating plant. It is therefore not surprising that Madonna lily has also been sought for
therapeutic reasons. However, most L. candidum therapeutic properties known from folk tradition
have not yet been investigated by scientific methods except anti-fungal [
24
], anti-cancer [
25
,
26
],
and anti-viral [
27
] properties. Thus, the present study is aimed at identifying the presence of selected
volatile compounds of the plant, assessing the medicinal potential of all known compounds using
bioinformatics, and investigating anti-inflammatory and anti-diabetic activities of L. candidum extract
and its active phytochemicals.
2. Results
We identified the presence of many novel volatile compounds using gas chromatography–mass
spectrometry (GC-MS) analysis, which, to the best of our knowledge, were not mentioned in the
literature. Among those, we found linalool, citronellal, caryophyllene, humulene (Figure 1), and neridiol
(not represented), which were isolated and identified not only from L. candidum but from other plants
as well.
Plants 2020,9, 959 3 of 11
Plants 2020, 9, x FOR PEER REVIEW 3 of 12
Figure 1. Chemical structures of compounds isolated from L. candidum. A computerized GC-MS (GC-
6890N) equipped with a mass selective (MS)—5973 network (electron ionization 70 eV) detector from
Agilent Technologies (Santa Clara, CA, USA) was used. Component recognition was performed by a
comparison of the retention time index (RI) of the components to commercial standards and the
samples’ mass spectrum with GC-MS libraries: Adams 2001, NIST 98, and QuadLib 1607.
Table 1 provides a list of these phytochemicals and their medicinal properties.
Table 1. Medicinal properties of phytochemicals present in Lilium candidum.
Compound Medicinal Uses References
Kaempferol
Anti-apoptotic, pro-wound healing, anti-cancer, cardioprotective,
anti-oxidant, pro-apoptotic, anti-allergic, anti-parasitic, anti-
diabetic, anti-adipogenic, anti-thrombotic, anti-inflammatory,
anti-metabolic syndrome, anti-bacterial, immunoregulatory,
hepatoprotective, anti-atherosclerosis
[28–35]
Linalool
Anti-parasitic, anti-convulsant, anti-cancer, anti-bacterial,
neuroprotective, anti-oxidant, anti-inflammatory, anti-Alzheimer,
anxiolytic, hepatoprotective, anti-hyperalgesic, neuroprotective
[36–43]
Citronellal Anti-fungal, insect repellant, hepatoprotective, anti-nociceptive,
anti-inflammatory, anti-bacterial [44–46]
Caryophyllene
Anti-cancer, anti-mutagenic, anti-bacterial, oxygen deprivation
protective, neuroprotective, hepatoprotective, anti-convulsant,
anti-diabetic, anti-microbial, anti-Alzheimer, pro-longevity,
analgesic, nephroprotective
[47–56]
Humulene Insecticidal, anti-cancer, anti-inflammatory [51,57,58]
Neridiol Anti-parasitic, antioxidant, neuroprotective, pro-wound healing,
anti-microbial [59–62]
While it is clear that L. candidum possesses many valuable compounds with considerable
therapeutic potential, to the best of our knowledge, no bioinformatical research has been carried out
to assess their medicinal potential. In order to close this gap, we analyzed the potential human
therapeutic targets (proteins and other biomolecules) of the above-mentioned compounds, using the
STITCH database (http://stitch.embl.de/) [63–65].
In the case of kaempferol, a significant number of interacting protein targets were found to be
associated with three large groups: UGT (uridine 5’-diphospho-glucuronosyltransferase), AHR (aryl
hydrocarbon receptor), and CYP1B1 (cytochrome P450 family 1 subfamily B member 1) (Figure 2).
The majority of the targets are connected to the UGT enzymes, which participate in cellular
detoxification in different tissues of the digestive system [66]. Their involvement in various cancer-
associated processes is also well-known [66,67]. AHR is a ligand-activated transcription factor, which
may interact with different pathways regulating cellular homeostasis including cellular regeneration
Figure 1.
Chemical structures of compounds isolated from L. candidum. A computerized GC-MS
(GC-6890N) equipped with a mass selective (MS)—5973 network (electron ionization 70 eV) detector
from Agilent Technologies (Santa Clara, CA, USA) was used. Component recognition was performed
by a comparison of the retention time index (RI) of the components to commercial standards and the
samples’ mass spectrum with GC-MS libraries: Adams 2001, NIST 98, and QuadLib 1607.
Table 1provides a list of these phytochemicals and their medicinal properties.
Table 1. Medicinal properties of phytochemicals present in Lilium candidum.
Compound Medicinal Uses References
Kaempferol
Anti-apoptotic, pro-wound healing, anti-cancer, cardioprotective,
anti-oxidant, pro-apoptotic, anti-allergic, anti-parasitic, anti-diabetic,
anti-adipogenic, anti-thrombotic, anti-inflammatory, anti-metabolic
syndrome, anti-bacterial, immunoregulatory, hepatoprotective,
anti-atherosclerosis
[28–35]
Linalool
Anti-parasitic, anti-convulsant, anti-cancer, anti-bacterial, neuroprotective,
anti-oxidant, anti-inflammatory, anti-Alzheimer, anxiolytic,
hepatoprotective, anti-hyperalgesic, neuroprotective
[36–43]
Citronellal Anti-fungal, insect repellant, hepatoprotective, anti-nociceptive,
anti-inflammatory, anti-bacterial [44–46]
Caryophyllene
Anti-cancer, anti-mutagenic, anti-bacterial, oxygen deprivation protective,
neuroprotective, hepatoprotective, anti-convulsant, anti-diabetic,
anti-microbial, anti-Alzheimer, pro-longevity, analgesic, nephroprotective
[47–56]
Humulene Insecticidal, anti-cancer, anti-inflammatory [51,57,58]
Neridiol Anti-parasitic, antioxidant, neuroprotective, pro-wound healing,
anti-microbial [59–62]
While it is clear that L. candidum possesses many valuable compounds with considerable therapeutic
potential, to the best of our knowledge, no bioinformatical research has been carried out to assess their
medicinal potential. In order to close this gap, we analyzed the potential human therapeutic targets
(proteins and other biomolecules) of the above-mentioned compounds, using the STITCH database
(http://stitch.embl.de/) [63–65].
In the case of kaempferol, a significant number of interacting protein targets were found
to be associated with three large groups: UGT (uridine 5’-diphospho-glucuronosyltransferase),
AHR (aryl hydrocarbon receptor), and CYP1B1 (cytochrome P450 family 1 subfamily B member 1)
(Figure 2). The majority of the targets are connected to the UGT enzymes, which participate in
cellular detoxification in different tissues of the digestive system [
66
]. Their involvement in various
cancer-associated processes is also well-known [
66
,
67
]. AHR is a ligand-activated transcription
factor, which may interact with different pathways regulating cellular homeostasis including cellular
regeneration in the context of aging and diseases [
68
]. In addition, AHR regulates CYP1B1 [
69
],
Plants 2020,9, 959 4 of 11
which belongs to the cytochrome P450 superfamily of enzymes. Cytochrome P450 plays an important
role in cellular detoxification and in the formation of reactive intermediates of thousands of
chemicals [
70
]. Thus, the medicinal effects of kaempferol are apparently mediated by its direct
involvement in many pathological processes.
Plants 2020, 9, x FOR PEER REVIEW 4 of 12
in the context of aging and diseases [68]. In addition, AHR regulates CYP1B1 [69], which belongs to
the cytochrome P450 superfamily of enzymes. Cytochrome P450 plays an important role in cellular
detoxification and in the formation of reactive intermediates of thousands of chemicals [70]. Thus,
the medicinal effects of kaempferol are apparently mediated by its direct involvement in many
pathological processes.
Figure 2. Direct protein–protein and protein–compound interactions between human targets of
kaempferol. This figure was constructed using the default settings of the STITCH database
(http://stitch.embl.de/). The uridine 5’-diphospho-glucuronosyltransferase (UGT), aryl hydrocarbon
receptor (AHR), and cytochrome P450 family 1 subfamily B member 1 (CYP1B1) proteins groups are
dominant.
It is well acknowledged that diabetes mellitus (DM) pathogenesis is linked to oxidative stress
[71]. Although many phytochemicals from L. candidum have anti-oxidant properties (Table 1), to the
best of our knowledge, no research on its anti-diabetic properties has been performed so far. Thus,
we investigated the anti-diabetic activity of bulbs and leaves of L. candidum. For this purpose, we
treated adipocytes with an ethanolic extract from L. candidum bulbs and leaves, while the glucose
uptake of the adipocytes was estimated after these treatments, as previously. L. candidum extracts
increased glucose uptake in 3T3-L1A cells better than insulin. Importantly, the anti-diabetic activity
of leaf extracts was higher than those from bulb extracts and of insulin, which was used as a positive
control (Figure 3). The difference between negative control (untreated adipocytes) and cells that were
treated with extracts was highly significant (p < 0.001). All known phytochemicals of L. candidum were
tested in this experiment. As seen in Figure 3, kaempferol, linalool, citronellal, and humulene
significantly increased glucose uptake in 3T3-L1 adipocytes (p < 0.001).
Figure 2.
Direct protein–protein and protein–compound interactions between human targets
of kaempferol. This figure was constructed using the default settings of the STITCH database
(http://stitch.embl.de/)
. The uridine 5’-diphospho-glucuronosyltransferase (UGT), aryl hydrocarbon
receptor (AHR), and cytochrome P450 family 1 subfamily B member 1 (CYP1B1) proteins groups
are dominant.
It is well acknowledged that diabetes mellitus (DM) pathogenesis is linked to oxidative stress [
71
].
Although many phytochemicals from L. candidum have anti-oxidant properties (Table 1), to the best
of our knowledge, no research on its anti-diabetic properties has been performed so far. Thus, we
investigated the anti-diabetic activity of bulbs and leaves of L. candidum. For this purpose, we treated
adipocytes with an ethanolic extract from L. candidum bulbs and leaves, while the glucose uptake of
the adipocytes was estimated after these treatments, as previously. L. candidum extracts increased
glucose uptake in 3T3-L1A cells better than insulin. Importantly, the anti-diabetic activity of leaf
extracts was higher than those from bulb extracts and of insulin, which was used as a positive control
(Figure 3). The difference between negative control (untreated adipocytes) and cells that were treated
with extracts was highly significant (p<0.001). All known phytochemicals of L. candidum were tested
in this experiment. As seen in Figure 3, kaempferol, linalool, citronellal, and humulene significantly
increased glucose uptake in 3T3-L1 adipocytes (p<0.001).
Elevated levels of circulating inflammatory mediators including cytokines and chemokines are
hallmarks of chronic inflammation and progression of metabolic diseases [
2
]. The extracts and their
phytochemicals (identified by us and known) were investigated from the perspective of chronic
inflammation. As seen in Figure 4, plant extracts, kaempferol, citronellal, and humulene significantly
decreased secretion of IL-6 and IL-8 cytokines by senescent human pulmonary fibroblasts (HPFs)
and human dermal fibroblasts (HDFs) as measured by enzyme-linked immunosorbent assay (ELISA)
(p<0.01).
Plants 2020,9, 959 5 of 11
Plants 2020, 9, x FOR PEER REVIEW 5 of 12
Figure 3. Anti-diabetic activity of L. candidum extracts and compounds. The glucose uptake of the 3T3
adipocytes was determined. Adipocytes were treated with ethanol extracts of L. candidum and with
the compounds detected in those extracts. Negative control consisted of untreated adipocytes; insulin
was used as a positive control. Data from three independent experiments are shown (mean ± SD). ***
p < 0.001.
Elevated levels of circulating inflammatory mediators including cytokines and chemokines are
hallmarks of chronic inflammation and progression of metabolic diseases [2]. The extracts and their
phytochemicals (identified by us and known) were investigated from the perspective of chronic
inflammation. As seen in Figure 4, plant extracts, kaempferol, citronellal, and humulene significantly
decreased secretion of IL-6 and IL-8 cytokines by senescent human pulmonary fibroblasts (HPFs) and
human dermal fibroblasts (HDFs) as measured by enzyme-linked immunosorbent assay (ELISA) (p
< 0.01).
Figure 3.
Anti-diabetic activity of L. candidum extracts and compounds. The glucose uptake of the 3T3
adipocytes was determined. Adipocytes were treated with ethanol extracts of L. candidum and with
the compounds detected in those extracts. Negative control consisted of untreated adipocytes; insulin
was used as a positive control. Data from three independent experiments are shown (mean
±
SD).
*** p<0.001.
Plants 2020, 9, x FOR PEER REVIEW 6 of 12
Figure 4. Effect of L. candidum ethanolic extracts and compounds on the release of pro-inflammatory
cytokines interleukin 6 (IL-6) (A,C) and interleukin 8 (IL-8) (B,D) from human pulmonary fibroblasts
(HPFs) (A,B) or human dermal fibroblasts (HDFs) (C,D). The ethanolic extracts were diluted in
medium to a final ethanol concentration of 0.1%. Cells treated only with 0.1% ethanol (the vehicle)
were used as controls to exclude the effect of ethanol on the cells. Data from three independent
experiments are shown (mean ± SE). ** p < 0.01, *** p < 0.001.
3. Discussion
Taking into account the therapeutic properties of L. candidum known from folk tradition, we
expected to discover anti-inflammatory and anti-diabetic activities in L. candidum extracts. It is
important to emphasize here that senescent cells (HPFs and HDFs) are one of the most widely used
models for studying inflammatory processes. Accumulation of senescent cells in an organism leads
to disruption of tissues and cellular structure and function [72]. The phenomenon of cellular
senescence has been demonstrated to play a causal role in driving ageing [72] and chronic diseases
[7,9,72]. Namely, the above-mentioned cells are accepted models [7,9] used to investigate the effect
of plant extracts and pure compounds on inflammation.
Our hypothesis was confirmed, as the plant extracts indeed possess anti-inflammatory and anti-
diabetic properties (Figures 3 and 4). We also identified selected phytochemicals behind these
properties: anti-diabetic properties were associated with kaempferol, linalool, citronellal, and
humulene (Figure 3). In turn, kaempferol, citronellal, and humulene had a significant impact on the
secretion of pro-inflammatory cytokines IL-6 and IL-8 (p < 0.01), (Figure 4). It is known that the above-
mentioned cytokines are directly connected to delay in the wound healing process and are known to
Figure 4.
Effect of L. candidum ethanolic extracts and compounds on the release of pro-inflammatory
cytokines interleukin 6 (IL-6) (
A
,
C
) and interleukin 8 (IL-8) (
B
,
D
) from human pulmonary fibroblasts
(HPFs) (
A
,
B
) or human dermal fibroblasts (HDFs) (
C
,
D
). The ethanolic extracts were diluted in medium
to a final ethanol concentration of 0.1%. Cells treated only with 0.1% ethanol (the vehicle) were used
as controls to exclude the effect of ethanol on the cells. Data from three independent experiments are
shown (mean ±SE). ** p<0.01, *** p<0.001.
Plants 2020,9, 959 6 of 11
3. Discussion
Taking into account the therapeutic properties of L. candidum known from folk tradition,
we expected to discover anti-inflammatory and anti-diabetic activities in L. candidum extracts. It is
important to emphasize here that senescent cells (HPFs and HDFs) are one of the most widely used
models for studying inflammatory processes. Accumulation of senescent cells in an organism leads to
disruption of tissues and cellular structure and function [
72
]. The phenomenon of cellular senescence
has been demonstrated to play a causal role in driving ageing [
72
] and chronic diseases [
7
,
9
,
72
].
Namely, the above-mentioned cells are accepted models [
7
,
9
] used to investigate the effect of plant
extracts and pure compounds on inflammation.
Our hypothesis was confirmed, as the plant extracts indeed possess anti-inflammatory
and anti-diabetic properties (Figures 3and 4). We also identified selected phytochemicals behind
these properties: anti-diabetic properties were associated with kaempferol, linalool, citronellal, and
humulene (Figure 3). In turn, kaempferol, citronellal, and humulene had a significant impact on
the secretion of pro-inflammatory cytokines IL-6 and IL-8 (p<0.01), (Figure 4). It is known that the
above-mentioned cytokines are directly connected to delay in the wound healing process and are
known to be secreted by HPFs [
9
,
73
]. Thus, our results might provide an explanation of the effect
of L. candidum extract on wound healing, as described in ethnopharmacological publications [
13
,
14
].
Further investigation is important in order to establish which phytochemicals are connected with
wound healing directly, and to elucidate their modes of action.
Although the therapeutic activity of L. candidum extract and its phytochemicals was
demonstrated [74–76], their mechanism of action is still unknown.
In addition, pro-inflammatory cytokines IL-6 and IL-8 are associated with various
diseases including ARDs, such as cancer, diabetes, cardiovascular diseases, multiple sclerosis,
asthma, rheumatoid arthritis, and so on [
7
–
9
]. It is obvious that the stand-alone and
combinational anti-inflammatory effects of kaempferol, citronellal, and humulene warrant further
investigation. These results are in agreement with those obtained by Vach
á
lkov
á
et al. [
76
],
which show that some compounds of L. candidum (spirostanol saponins, two pyroline derivatives,
jatropham and its glucoside, 2-fenylethyl-alpha-L-arabinopyranosyl-(1–>6)-beta-D-glucopyranoside,
2-phenylethylpalmitate, methylsuccinic acid and kaempferol) had significant anti-cancer properties [
76
].
With its rich collection of phytochemicals, L. candidum has promising therapeutic potential.
Our results demonstrate a bright future for this plant and its compounds as prophylactic and therapeutic
agents. However, additional clinical studies are warranted in order to establish the effectiveness of
compounds from L. candidum in the treatment of chronic diseases.
4. Materials and Methods
4.1. Bioinformatic Assessment
For bioinformatical assessment, we selected the STITCH database found at http://stitch.embl.de/.
This database contains most of the available information regarding proteins’ interaction with different
chemicals. It can be searched according to the name of the chemical or its PubChem ID [63–65].
4.2. Preparation of Plant Material
Aerial parts of L. candidum were collected from the greenhouse at Ben-Gurion University of the
Negev, Beer-Sheva, Israel. Leaves, flowers, and bulbs of L. candidum were dried by lyophilization and
grounded for GC-MS analysis.
Ethanolic extracts were prepared from leaves and bulbs of L. candidum as described previously [
27
].
Plant tissues were homogenized, incubated at room temperature for 48 h in ethanol, centrifuged at
2000 rpm for 10 min, and the supernatant was evaporated by lyophilization. The pellet was dissolved
in a minimal amount of 95% ethanol (0.5 mL) and diluted with water to a final concentration of
10 mg/mL.
Plants 2020,9, 959 7 of 11
4.3. GC-MS Analysis
Identification of volatile compounds is described in our previous publication [7].
4.4. Cell Cultures
All cell culture reagents including Dulbecco’s modified Eagle’s medium (DMEM), fetal bovine
serum (FBS), L-glutamine, and antibiotics were purchased from Biological Industries (Kibbutz Beit
Haemek, Israel).
Human pulmonary fibroblasts (HPFs), human dermal fibroblasts (HDFs), and 3T3-L1 adipocytes
were propagated in DMEM supplemented with 10% FBS, 1% L-glutamine, and 1% antibiotic mixture,
which included a combination of penicillin, streptomycin, and nystatin. The cells were grown in
an incubator at 37 ◦C. The relative humidity was set at 95%, and the CO2content was 5%.
4.5. Cytotoxicity Examination
Nontoxic concentrations of Lilium candidum extracts and compounds were determined
by XTT assay. Succinctly, metabolically active cells reduce yellow salt, XTT (sodium
3’-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy6-nitro) benzene sulfonic acid hydrate),
to form an orange formazan compound, as described in [
7
]. For measuring IL-6 and IL-8 levels,
only non-toxic concentrations were used.
4.6. Measurement of Anti-Diabetic Activity
Ethanolic bulb and leaf extracts of L. candidum were tested for their anti-diabetic properties.
The glucose uptake of the 3T3 adipocytes was determined as described previously [
7
,
71
].
Briefly, before the measurement, adipocytes were transferred to low-glucose serum-free media.
After an overnight incubation, the cells were treated with bulb or leaf ethanol extracts of L. candidum
for 1 h. For negative control, adipocytes were treated with the vehicle only. Insulin at a concentration
of 100 nM was used as a positive control. After the 1-h incubation, the fluorescent glucose analog
2-(N-(7-nitrobenz-2-oxa1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) was added for 30 min.
The cells were then rinsed with PBS, and the fluorescence of intracellular 2-NBDG with excitation at
467 nm and emission at 538 nm was measured using a fluorescence microplate reader (POLARstar
Omega, BMG LABTECH GmbH, Ortenberg, Germany).
4.7. Measurement of Interleukin Release
Senescent HPFs or HDFs were treated with specified concentrations of the extracts or compounds.
After 3 days of exposure, we collected the medium and measured the concentrations of interleukin
6 and 8. The measurement was performed with R&D Systems ELISA kits according to the manufacturer’s
instructions. For each experiment, standard curves were built, and the concentrations of interleukins
were calculated.
4.8. Statistical Analysis
Experiments were repeated at least three times. All data were analyzed using Statistica, version 7,
for Windows software (StatSoft, Inc., Tulsa, Oklahoma), and p<0.05 was chosen as the minimal
acceptable level of significance. Simple regression models were subsequently used to eliminate
non-significant effects. Values are presented as means ±SD.
Author Contributions:
Conceptualization, L.Y. and S.B.-S.; methodology, L.Y., B.K., and A.B.; validation, L.Y.,
B.K., and A.B.; resources, L.Y. and J.G.; data curation, B.K. and A.B.; writing—original draft preparation, M.Z.
and A.D.; writing—review and editing, M.Z., A.D., L.Y., B.K., and A.B.; visualization, B.K.; supervision, L.Y.
and S.B.-S.; project administration, L.Y. and J.G. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Plants 2020,9, 959 8 of 11
Acknowledgments:
We are pleased to acknowledge Yulia Solomonov for her assistance in data analysis
and preparation of the figures and Rima Kozlov for preparation of plant extracts.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Robbins, G.R.; Wen, H.; Ting, J.P. Inflammasomes and metabolic disorders: Old genes in modern diseases.
Mol. Cell 2014,54, 297–308. [CrossRef] [PubMed]
2.
Accardi, G.; Virruso, C.; Balistreri, C.R.; Emanuele, F.; Licastro, F.; Monastero, R.; Porcellini, E.; Vasto, S.;
Verga, S.; Caruso, C.; et al. SHIP2: A “new” insulin pathway target for aging research. Rejuvenation Res.
2014,17, 221–225. [CrossRef] [PubMed]
3.
L
ó
pez-Ot
í
n, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell
2013
,153,
1194–1217. [CrossRef] [PubMed]
4.
Thammisetty, S.S.; Pedragosa, J.; Weng, Y.C.; Calon, F.; Planas, A.; Kriz, J. Age-related deregulation of TDP-43
after stroke enhances NF-
κ
B-mediated inflammation and neuronal damage. J. Neuroinflamm.
2018
,15, 312.
[CrossRef]
5.
Kim, D.H.; Bang, E.; Arulkumar, R.; Ha, S.; Chung, K.W.; Park, M.H.; Choi, Y.J.; Yu, B.P.; Chung, H.Y.
Senoinflammation: A major mediator underlying age-related metabolic dysregulation. Exp. Gerontol.
2020
,
134, 110891. [CrossRef]
6.
Rea, I.M.; Gibson, D.S.; McGilligan, V.; McNerlan, S.E.; Alexander, H.D.; Ross, O.A. Age and Age-Related
Diseases: Role of Inflammation Triggers and Cytokines. Front. Immunol. 2018,9, 586. [CrossRef]
7.
Yarmolinsky, L.; Budovsky, A.; Ben-Shabat, S.; Khalfin, B.; Gorelick, J.; Bishitz, Y.; Miloslavski, R.;
Yarmolinsky, L. Recent updates on the phytochemistry and pharmacological properties of Phlomis viscosa
Poiret. Rejuvenation Res. 2019,22, 282–288. [CrossRef]
8.
Budovsky, A.; Fraifeld, V.E. Medicinal plants growing in the Judea region network approach for searching
potential therapeutic targets. Netw. Biol. 2012,2, 84–94.
9.
Budovsky, A.; Shteinberg, A.; Maor, H.; Duman, O.; Yanai, H.; Wolfson, M.; Fraifeld, V.E. Uncovering the
geroprotective potential of medicinal plants from the Judea region of Israel. Rejuvenation Res.
2014
,17,
134–139. [CrossRef]
10.
Eisenreichova, E.; Haladova, M.; Mucaji, P.; Bud
˘
es
í
nsk
ý
, M.; Ubik, K. A new steroidal saponin from the bulbs
of Lilium candidum.Pharmazie 2000,55, 549–550.
11.
Jari´c, S.; Maˇcukanovi´c-Joci´c, M.; Djurdjevi´c, L.; Mitrovi´c, M.; Kosti´c, O.; Karadži´c, B.; Pavlovi´c, P.
An ethnobotanical survey of traditionally used plants on Suva Planina mountain (south-eastern Serbia).
J. Ethnopharmacol. 2015,175, 93–108. [CrossRef] [PubMed]
12.
Rigat, M.; Vall
è
s, J.; Gras, A.; Igl
é
sias, J.; Garnatje, T. Plants with topical uses in the ripoll
è
s district
(Pyrenees, Catalonia, Iberian Peninsula): Ethnobotanical survey and pharmacological validation in the
literature. J. Ethnopharmacol. 2015,164, 162–179. [CrossRef] [PubMed]
13.
Bruni, A.; Ballero, M.; Poli, F. Quantitative ethnopharmacological study of the campidano valley and urzulei
district, Sardinia, Italy. J. Ethnopharmacol. 1997,57, 97–124. [CrossRef]
14.
Pieroni, A. Medicinal plants and food medicines in the folk traditions of the upper Lucca province, Italy.
J. Ethnopharmacol. 2000,70, 235–273. [CrossRef]
15.
Feinbrun-Dothan, N.; Danin, A.L. Candidum. In Analytical Flora of Eretz-Israel; Plitman, U., Ed.; CANA
Publishing: Jerusalem, Israel, 1991; p. 779.
16. Polunin, O. Flowers of Greece and the Balkans; Oxford University Press: Oxford, UK, 1987; pp. 1–592.
17.
Mouterde, P. Lilium candidum. In Nouvelle Flore du Liban et de la Syrie; Imprimerie, C., Ed.; Editions de l’Impr.
Catholique: Beyrouth, Lebanon, 1966; Volume 1, p. 236.
18.
Zaccai, M.; Ram, A.; Mazor, I. Lilium candidum: Flowering characterization of wild Israeli ecotypes. Israel J.
Plant Sci. 2010,57, 297–302. [CrossRef]
19.
Rubin, N.; Huleihel, M.; Zaccai, M. Stress conditions during plant growth increase the anti-herpetic properties
of Lilium candidum leaf extracts and fractions. J. Med. Plants Res. 2015,9, 954–961.
20.
Trinetta, V.; Morgan, M.T.; Coupland, J.N.; Yucel, U. Essential oils against pathogen and spoilage
microorganisms of fruit juices: Use of versatile antimicrobial delivery systems. J. Food Sci.
2017
,82,
471–476. [CrossRef]
Plants 2020,9, 959 9 of 11
21.
Carbone, C.; Martins-Gomes, C.; Caddeo, C.; Silva, A.M.; Musumeci, T.; Pignatello, R.; Puglisi, G.; Souto, E.B.
Mediterranean essential oils as precious matrix components and active ingredients of lipid nanoparticles.
Int. J. Pharm. 2018,548, 217–226.
22.
Bruni, N.; Stella, B.; Giraudo, L.; Della Pepa, C.; Gastaldi, D.; Dosio, F. Nanostructured delivery systems with
improved leishmanicidal activity: A critical review. Int. J. Nanomed. 2017,12, 5289–5311. [CrossRef]
23.
Ben-Shabat, S.; Yarmolinsky, L.; Porat, D.; Dahan, A. Antiviral effect of phytochemicals from medicinal
plants: Applications and drug delivery strategies. Drug Deliv. Transl. Res. 2020,10, 354–367. [CrossRef]
24.
Mucaji, P.; Hudecova, D.; Haladov
á
, M.; Eisenreichov
á
, E. Anti-yeast activity of ethanol extracts of
Lilium candidum L. Ceska Slov. Farm. Cas. Ceske Farm. Spol. Slov. Farm. Spol. 2002,51, 297–300.
25.
Galova, E.; Kopaskova, M.; Sevcovicova, A.; Hadjo, L.; Yankulova, B.; Gregan, F.; Chankova, S.; Miadokova, E.
The role of antioxidants from Lilium candidum L. and Salvia officinalis L. Extracts in phytomedicine. Toxicol. Lett.
2011,205, S60. [CrossRef]
26.
Tokgun, O.; Akca, H.; Mammadov, R.; Aykurt, C.; Deniz, G. Convolvulus galaticus, Crocus antalyensis,
and Lilium candidum extracts show their antitumor activity through induction of p53-mediated apoptosis on
human breast cancer cell line MCF-7 cells. J. Med. Food 2012,15, 1000–1005. [CrossRef] [PubMed]
27.
Yarmolinsky, L.; Zaccai, M.; Ben-Shabat, S.; Mills, D.; Huleihel, M. Antiviral activity of ethanol extracts of
Ficus binjamina and Lilium candidum in vitro.New Biotechnol. 2009,26, 307–313. [CrossRef] [PubMed]
28.
Bolaños, V.; D
í
az-Mart
í
nez, A.; Soto, J.; Marchat, L.A.; Sanchez-Monroy, V.; Ram
í
rez-Moreno, E. Kaempferol
inhibits Entamoeba histolytica growth by altering cytoskeletal functions. Mol. Biochem. Parasitol.
2015
,204,
16–25. [CrossRef]
29.
Choi, J.H.; Park, S.E.; Kim, S.J.; Kim, S. Kaempferol inhibits thrombosis and platelet activation. Biochimie
2015,115, 177–186. [CrossRef]
30.
Devi, K.P.; Malar, D.S.; Nabavi, S.F.; Sureda, A.; Xiao, J.; Nabavi, S.M.; Daglia, M. Kaempferol and inflammation:
From chemistry to medicine. Pharmacol. Res. 2015,99, 1–10. [CrossRef]
31.
Hoang, M.H.; Jia, Y.; Mok, B.; Jun, H.J.; Hwang, K.Y.; Lee, S.J. Kaempferol ameliorates symptoms of metabolic
syndrome by regulating activities of liver x receptor-β.J. Nutr. Biochem. 2015,26, 868–875. [CrossRef]
32.
Li, H.; Yang, L.; Zhang, Y.; Gao, Z. Kaempferol inhibits fibroblast collagen synthesis, proliferation and
activation in hypertrophic scar via targeting tgf-
β
receptor type i. Biomed. Pharmacother.
2016
,83, 967–974.
[CrossRef]
33.
Shin, D.; Park, S.H.; Choi, Y.J.; Kim, Y.H.; Antika, L.D.; Habibah, N.Y.; Kang, M.K.; Kang, Y.H.
Dietary compound kaempferol inhibits airway thickening induced by allergic reaction in a bovine serum
albumin-induced model of asthma. Int. J. Mol. Sci. 2015,16, 29980–29995. [CrossRef]
34.
Suchal, K.; Malik, S.; Gamad, N.; Malhotra, R.K.; Goyal, S.N.; Bhatia, J.; Arya, D.S. Kampeferol protects
against oxidative stress and apoptotic damage in experimental model of isoproterenol-induced cardiac
toxicity in rats. Phytomedicine 2016,23, 1401–1408. [CrossRef] [PubMed]
35.
Suchal, K.; Malik, S.; Gamad, N.; Malhotra, R.K.; Goyal, S.N.; Chaudhary, U.; Bhatia, J.; Ojha, S.; Arya, D.S.
Kaempferol attenuates myocardial ischemic injury via inhibition of mapk signaling pathway in experimental
model of myocardial ischemia-reperfusion injury. Oxid. Med. Cell. Longev.
2016
,2016, 7580731. [CrossRef]
[PubMed]
36.
Alves, S.; Duarte, A.; Sousa, S.; Domingues, F.C. Study of the major essential oil compounds of coriandrum
sativum against acinetobacter baumannii and the effect of linalool on adhesion, biofilms and quorum sensing.
Biofouling 2016,32, 155–165. [CrossRef] [PubMed]
37.
Dutra, F.L.; Oliveira, M.M.; Santos, R.S.; Silva, W.S.; Alviano, D.S.; Vieira, D.P.; Lopes, A.H. Effects of linalool
and eugenol on the survival of Leishmania (L.) infantum chagasi within macrophages. Acta Trop.
2016
,164,
69–76. [CrossRef]
38.
Li, X.J.; Yang, Y.J.; Li, Y.S.; Zhang, W.K.; Tang, H.B. A-pinene, linalool, and 1-octanol contribute to the topical
anti-inflammatory and analgesic activities of frankincense by inhibiting cox-2. J. Ethnopharmacol. 2016,179,
22–26. [CrossRef]
39.
Mehri, S.; Meshki, M.A.; Hosseinzadeh, H. Linalool as a neuroprotective agent against acrylamide-induced
neurotoxicity in wistar rats. Drug Chem. Toxicol. 2015,38, 162–166. [CrossRef]
40.
Park, H.; Seol, G.H.; Ryu, S.; Choi, I.Y. Neuroprotective effects of (
−
)-linalool against oxygen-glucose
deprivation-induced neuronal injury. Arch. Pharmacal Res. 2016,39, 555–564. [CrossRef]
Plants 2020,9, 959 10 of 11
41.
Sabogal-Gu
á
queta, A.M.; Osorio, E.; Cardona-G
ó
mez, G.P. Linalool reverses neuropathological and behavioral
impairments in old triple transgenic alzheimer’s mice. Neuropharmacology 2016,102, 111–120. [CrossRef]
42.
Seol, G.H.; Kang, P.; Lee, H.S.; Seol, G.H. Antioxidant activity of linalool in patients with carpal tunnel
syndrome. BMC Neurol. 2016,16, 17. [CrossRef]
43.
Souto-Maior, F.N.; Fons
ê
ca, D.V.D.; Salgado, P.R.R.; Monte, L.D.O.; de Sousa, D.P.; de Almeida, R.N.
Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide. Pharm. Biol. 2017,55, 63–67.
44.
Du, E.J.; Ahn, T.J.; Choi, M.S.; Kwon, I.; Kim, H.W.; Kwon, J.Y.; Kang, K. The mosquito repellent citronellal
directly potentiates drosophila trpa1, facilitating feeding suppression. Mol. Cells 2015,38, 911.
45.
Maßberg, D.; Simon, A.; Häussinger, D.; Keitel, V.; Gisselmann, G.; Conrad, H.; Hatt, H. Monoterpene
(
−
)-citronellal affects hepatocarcinoma cell signaling via an olfactory receptor. Arch. Biochem. Biophys.
2015
,
566, 100–109. [CrossRef] [PubMed]
46.
Singh, S.; Fatima, Z.; Hameed, S. Citronellal-induced disruption of membrane homeostasis in Candida albicans
and attenuation of its virulence attributes. Rev. Soc. Bras. Med. Trop.
2016
,49, 465–472. [CrossRef] [PubMed]
47.
Basha, R.H.; Sankaranarayanan, C. B-caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia
mediated oxidative and inflammatory stress in experimental diabetic rats. Chem. Biol. Interact.
2016
,245,
50–58. [CrossRef] [PubMed]
48.
De Oliveira, C.C.; de Oliveira, C.V.; Grigoletto, J.; Ribeiro, L.R.; Funck, V.R.; Grauncke, A.C.B.;
de Souza, T.L.; Souto, N.S.; Furian, A.F.; Menezes, I.R.A. Anticonvulsant activity of
β
-caryophyllene
against pentylenetetrazol-induced seizures. Epilepsy Behav. 2016,56, 26–31. [CrossRef] [PubMed]
49.
Di Giacomo, S.; Mazzanti, G.; Di Sotto, A. Mutagenicity of cigarette butt waste in the bacterial reverse
mutation assay: The protective effects of
β
-caryophyllene and
β
-caryophyllene oxide. Environ. Toxicol.
2016
,
31, 1319–1328. [CrossRef] [PubMed]
50.
Fidyt, K.; Fiedorowicz, A.; Strz ˛adała, L.; Szumny, A. B-caryophyllene and
β
-caryophyllene oxide—Natural
compounds of anticancer and analgesic properties. Cancer Med. 2016,5, 3007–3017. [CrossRef]
51.
Govindarajan, M.; Benelli, G. A-humulene and
β
-elemene from syzygium zeylanicum (myrtaceae) essential
oil: Highly effective and eco-friendly larvicides against anopheles subpictus, aedes albopictus, and culex
tritaeniorhynchus (diptera: Culicidae). Parasitol. Res. 2016,115, 2771–2778. [CrossRef]
52.
Govindarajan, M.; Rajeswary, M.; Hoti, S.; Bhattacharyya, A.; Benelli, G. Eugenol,
α
-pinene
and
β
-caryophyllene from plectranthus barbatus essential oil as eco-friendly larvicides against malaria,
dengue and japanese encephalitis mosquito vectors. Parasitol. Res. 2016,115, 807–815. [CrossRef]
53.
Kelany, M.E.; Abdallah, M.A. Protective effects of combined
β
-caryophyllene and silymarin against
ketoprofen-induced hepatotoxicity in rats. Can. J. Physiol. Pharmacol. 2016,94, 739–744. [CrossRef]
54.
Ojha, S.; Javed, H.; Azimullah, S.; Haque, M.E. B-caryophyllene, a phytocannabinoid attenuates oxidative
stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of parkinson
disease. Mol. Cell. Biochem. 2016,418, 59–70. [CrossRef] [PubMed]
55.
Pieri, F.A.; Souza, M.C.; Vermelho, L.L.; Vermelho, M.L.; Perciano, P.G.; Vargas, F.S.; Borges, A.P.;
da Veiga-Junior, V.F.; Moreira, M.A. Use of
β
-caryophyllene to combat bacterial dental plaque formation in
dogs. BMC Vet. Res. 2016,12, 216. [CrossRef] [PubMed]
56.
Tian, X.; Peng, J.; Zhong, J.; Yang, M.; Pang, J.; Lou, J.; Li, M.; An, R.; Zhang, Q.; Xu, L. B-caryophyllene
protects
in vitro
neurovascular unit against oxygen-glucose deprivation and re-oxygenation-induced injury.
J. Neurochem. 2016,139, 757–768. [CrossRef]
57.
Lan, Y.H.; Wu, Y.C.; Wu, K.W.; Chung, J.G.; Lu, C.C.; Chen, Y.L.; Wu, T.S.; Yang, J.S. Death receptor 5-mediated
TNFR family signaling pathways modulate
γ
-humulene-induced apoptosis in human colorectal cancer HT29
cells. Oncol. Rep. 2011,25, 419–424. [PubMed]
58.
Rogerio, A.P.; Andrade, E.L.; Leite, D.F.; Figueiredo, C.P.; Calixto, J.B. Preventive and therapeutic
anti-inflammatory properties of the sesquiterpene
α
-humulene in experimental airways allergic inflammation.
Br. J. Pharmacol. 2009,158, 1074–1087. [CrossRef]
59.
Baldissera, M.D.; Souza, C.F.; Grando, T.H.; Moreira, K.L.; Schafer, A.S.; Cossetin, L.F.; da Silva, A.P.;
da Veiga, M.L.; da Rocha, M.I.; Stefani, L.M.; et al. Nerolidol-loaded nanospheres prevent behavioral
impairment via ameliorating Na
+
, K
+
-ATPase and AChE activities as well as reducing oxidative stress in
the brain of Trypanosoma evansi-infected mice. Naunyn Schmiedebergs Arch. Pharmacol.
2017
,390, 139–148.
[PubMed]
Plants 2020,9, 959 11 of 11
60.
Ferreira, M.O.G.; Leite, L.L.R.; de Lima, I.S.; Barreto, H.M.; Nunes, L.C.C.; Ribeiro, A.B.; Osajima, J.A.;
da Silva Filho, E.C. Chitosan Hydrogel in combination with Nerolidol for healing wounds. Carbohydr. Polym.
2016,152, 409–418. [CrossRef]
61. Javed, H.; Azimullah, S.; Abul Khair, S.B.; Ojha, S.; Haque, M.E. Neuroprotective effect of nerolidol against
neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci. 2016,17, 58. [CrossRef]
62.
Kaur, D.; Pahwa, P.; Goel, R.K. Protective effect of nerolidol against pentylenetetrazol-induced kindling,
oxidative stress and associated behavioral comorbidities in mice. Neurochem. Res. 2016,41, 2859–2867.
63.
Kuhn, M.; von Mering, C.; Campillos, M.; Jensen, L.J.; Bork, P. STITCH: Interaction networks of chemicals
and proteins. Nucleic Acids Res. 2008,36, 684–688. [CrossRef]
64.
Kuhn, M.; Szklarczyk, D.; Franceschini, A.; Campillos, M.; von Mering, C.; Jensen, L.J.; Beyer, A.; Bork, P.
STITCH 2: An interaction network database for small molecules and proteins. Nucleic Acids Res.
2010
,38,
552–556. [CrossRef] [PubMed]
65.
Kuhn, M.; Szklarczyk, D.; Pletscher-Frankild, S.; Blicher, T.H.; von Mering, C.; Jensen, L.J.; Bork, P. STITCH 4:
Integration of protein-chemical interactions with user data. Nucleic Acids Res.
2014
,42, 401–407. [CrossRef]
[PubMed]
66.
Strassburg, C.P.; Strassburg, A.; Nguyen, N.; Qing, L.; Manns, M.P.; Tukey, R.H. Regulation and function of
family 1 and family 2 udp-glucuronosyltransferase genes (ugt1a, ugt2b) in human oesophagus. Biochem. J.
1999,338, 489–498. [CrossRef] [PubMed]
67.
Yilmaz, L.; Borazan, E.; Aytekin, T.; Baskonus, I.; Aytekin, A.; Oztuzcu, S.; Bozdag, Z.; Balik, A. Increased
ugt1a3 and ugt1a7 expression is associated with pancreatic cancer. Asian Pac. J. Cancer Prev.
2014
,16,
1651–1655.
68.
Casado, F.L. The aryl hydrocarbon receptor relays metabolic signals to promote cellular regeneration.
Stem Cells Int. 2016,2016, 4389802. [CrossRef] [PubMed]
69.
Rasmussen, M.K.; Balaguer, P.; Ekstrand, B.; Daujat-Chavanieu, M.; Gerbal-Chaloin, S. Skatole
(3-methylindole) is a partial aryl hydrocarbon receptor agonist and induces cyp1a1/2 and cyp1b1 expression
in primary human hepatocytes. PLoS ONE 2016,11, e0154629.
70.
Nebert, D.W.; Dalton, T.P. The role of cytochrome p450 enzymes in endogenous signalling pathways
and environmental carcinogenesis. Nat. Rev. Cancer 2006,6, 947–960. [CrossRef]
71.
Gorelick, J.; Kitron, A.; Pen, S.; Rosenzweig, T.; Madar, Z. Anti-diabetic activity of Chiliadenus iphionoides.
J. Ethnopharmacol. 2011,137, 1245–1249. [CrossRef]
72.
Song, P.; An, J.; Zou, M.H. Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases.
Cells 2020,9, 671. [CrossRef]
73.
Budovsky, A.; Yarmolinsky, L.; Ben-Shabat, S. Effect of medicinal plants on wound healing. Wound Repair Regen.
2015,23, 171–183.
74.
Patocka, J.; Navratilova, Z.; Yokozawa, T. Bioactivity of Lilium candidum L.—A Mini Review. Biomed. J. Sci.
Tech. Res. 2019,18, 13859–13862. [CrossRef]
75.
Haladova, M.; Eisenreichova, E.; Mucaji, P.; Budesinsky, M.; Ubik, K. Steroidal Saponins from Lilium candidum L.
Collect. Czechoslov. Chem. Commun. 1998,63, 205–210. [CrossRef]
76.
Vach
á
lkov
á
, A.; Eisenreichov
á
, E.; Haladov
á
, M.; Mucaji, P.; J
ó
zov
á
, B.; Novotn
ý
, L. Potential carcinogenic
and inhibitory activity of compounds isolated from Lilium candidum L. Neoplasma 2000,47, 313–318.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
