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Daphnetin: A bioactive natural
coumarin with diverse
therapeutic potentials
Maira Javed
1
, Ammara Saleem
1
*, Anne Xaveria
1
and
Muhammad Furqan Akhtar
2
*
1
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University
Faisalabad, Faisalabad, Pakistan,
2
Riphah Institute of Pharmaceutical Sciences, Riphah International
University, Lahore Campus, Lahore, Pakistan
Daphnetin (DAP), a coumarin derivative extracted from Daphne species, is
biologically active phytochemical with copious bioactivities including anti-
inflammatory, anti-oxidant, neuroprotective, analgesic, anti-pyretic, anti-
malarial, anti-bacterial, anti-arthritic, neuroprotective, hepatoprotective,
nephroprotective, and anti-cancer activities. A wide range of studies have
been conducted exploring the significance and therapeutic potential of DAP.
This study reviewed various databases such as NCBI, PubMed, Web of Science,
Scopus and Google Scholar for published research articles regarding the
sources, synthesis, and various bioactivities of DAP using different key
words, including but not limited to “pharmacological activities,”“sources,”
“neuroprotective effect,”“synthesis,”“cancer,”“anti-inflammatory effect”of
“daphnetin.”Furthermore, this review encompasses both in-vivo and in-vitro
studies on DAP for treating various diseases. A comprehensive review of the
literature revealed that the DAP had a promising pharmacological and safety
profile, and could be employed as a pharmaceutical moiety to treat a variety of
illnesses including microbial infections, cancer, arthritis, hepatic damage,
inflammation and neurological anomalies. The current review intends to
provide an in-depth focus on all pharmacological activities and therapeutic
approaches for the pharmaceutical and biomedical researchers.
KEYWORDS
daphnetin, neuroprotective, anti-inflammatory, anti-bacterial, psoriasis
1 Introduction
Phytochemicals are secondary metabolites that naturally exist in plants. These are
categorized into various groups based on their chemical structure (Martinez et al., 2017).
Coumarin is a naturally occurring secondary metabolite and benzopyrone derivative. This
was one of the first metabolites to be identified in the 1930’s, and found in a variety of
plant species (Archbold et al., 2011;Xu et al., 2011;Amin et al., 2014). A significant
number of researches have been conducted to identify individual compounds, and
develop procedures for their detection, synthesis, effectiveness and toxicity (Sovrlić
and Manojlović, 2017). Since then, over 50 coumarins have been discovered in
OPEN ACCESS
EDITED BY
Mansour Sobeh,
Mohammed VI Polytechnic University,
Morocco
REVIEWED BY
Gabin Bitchagno,
Mohammed VI Polytechnic University,
Morocco
Latifa Bouissane,
Université Sultan Moulay Slimane,
Morocco
*CORRESPONDENCE
Ammara Saleem,
ammarasaleem@gcuf.edu.pk,
amarafurqan786@hotmail.com
Muhammad Furqan Akhtar,
furqan.pharmacist@gmail.com
SPECIALTY SECTION
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
RECEIVED 13 July 2022
ACCEPTED 09 September 2022
PUBLISHED 29 September 2022
CITATION
Javed M, Saleem A, Xaveria A and
Akhtar MF (2022), Daphnetin: A
bioactive natural coumarin with diverse
therapeutic potentials.
Front. Pharmacol. 13:993562.
doi: 10.3389/fphar.2022.993562
COPYRIGHT
© 2022 Javed, Saleem, Xaveria and
Akhtar. This is an open-access article
distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 29 September 2022
DOI 10.3389/fphar.2022.993562
Daphne species. Depending on their structure, there are simple,
dimeric or trimeric coumarins. Daphne contains various
coumarins including: daphnetin, DAP-8-glucoside, daphnin,
esculin, umbelliferone, and acetil-umbelliferon (Manojlović
et al., 2012;Sovrlićet al., 2015). Rutarensin, daphnoretin,
daphneretusin-A, dimethyl-daphnoretin-7-O-glucoside are
categorized among dimeric coumarins while trimeric
coumarin metabolites i.e., daphneretusin B, and triumbellin
were also identified in Daphne species (Mansoor et al., 2013).
This review elaborates sources, pharmacological activities as well
as toxicity of daphnetin (DAP) so as to find and explore its
therapeutic potential and promote the drug development.
DAP i.e., 7, 8-dihydroxycoumarin is generally an odorless
and tasteless white or off-white powder that is freely soluble in
ethanol, methanol and dimethyl-sulfoxide while slightly
soluble in water (Shan et al., 2011). It has a molecular
weight of 178.14 g/mole and melting point 262.0°C(Liao
et al., 2013). It shows high solubility and permeability, and
is metabolized by phase 1 reaction through CYP3A4 with a
short half-life of 15 min. It exhibits poor bioavailability and
absorbs through the intestine by passive diffusion. It is
metabolized to methyl, glucuronide and sulfonate
conjugated metabolites (Yang et al., 1999;Du et al., 2009;
Shan, 2009;Liang et al., 2010;Chen, 2011;Zhang et al., 2014;
Liang et al., 2015;Liang et al., 2017;Xia et al., 2018a). Some
studies on DAP metabolism focused on glucuronidation, but
other studies provided glimpse of other conjugated
metabolites such as sulfonation, and methylation. In
comparison to glucuronidation and sulfonation, the
methylation pathway demonstrated a higher clearance rate
(Liang et al., 2016).
The DAP is derived from different Daphne species. Daphne is
a genus comprising 70 to 95 species of perennial and evergreen
shrubs of Thymelaeaceae family that is indigenous to India,
Europe, and North Africa. These plants are renowned for
their fragrant flowers and brilliantly colored fruit (Riveiro
et al., 2010). DAP-8-glucoside is derived from D. odora in
which it is formed from DAP-7-glucoside (Ueno and Saito,
1976;Halda et al., 1998). Other sources of DAP include D.
gnidium (isolated from the leaves and stems), D. mezereum
(synthesized from shoots), D. giraldii, D. Koreana Nakai,D.
tangutica and D. oleoides. Seventeen compounds including DAP
were isolated from D. oleoides (Brown, 1986;Riaz et al., 2016;
Han et al., 2020;Khouchlaa et al., 2021). D. pedunculata leaves
and stems are also sources of DAP (Moshiashvili et al., 2020)as
shown in Figure 1.E. lathyris Linnaeus, ethnically known as
“Euphorbia semen”in East Asia, is also a source of coumarins
including DAP. Previously, it was reported that simple
coumarins including daphnetin, esculetin, esculin etc. Had
been isolated and identified from the seeds of E. semen
(Masamoto et al., 2003;Zhu et al., 2018). Different sources of
DAP are shown in Figure 1.
This review focusses on the DAP-based treatment and
prevention of diseases which are gradually receiving special
FIGURE 1
Different sources of daphnetin.
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Javed et al. 10.3389/fphar.2022.993562
attention due to underlying exceptional properties of DAP. In
this context, an overview of DAP’s significance as an essential
phytochemical and its intriguing uses have been presented and
addressed. Relevant data were collected using various search
engines such as Google scholar, PubMed, Web of Science,
NCBI and Scopus by using the various search terms such as
“daphnetin,”“Structure activity of daphnetin,”“sources of
daphnetin,”“Synthesis of daphnetin,”“Traditional uses of
Daphne species,”“isolation,”“physical properties,”
“pharmacology of Daphentin”“hepatoprotective,”
“neuroprotective,”“anti-inflammatory,”“anti-arthritic”and
“anti-cancer”and “toxicity of daphnetin,”etc.
2 synthesis of Daphnetin
DAP, naturally occurring or synthesized, has oxygen-
containing heterocycles with a characteristic benzo-α-
pyrone framework (Xia et al., 2018b). It is biosynthesized
from shikimate pathway from L-Tyrosine and
L-Phenylalanine (Norma Francenia, 2019). Previously, it
was synthesized when pyrogallol and malic acid were
heated in concentrated H
2
SO
4
under nitrogen presence. It
is also synthesized from umbelliferone by hydroxylation as
shown in Figure 2 (NDong et al., 2003;Pan et al., 2017;Wang
et al., 2020a).
FIGURE 2
Synthesis of daphnetin.
FIGURE 3
Pharmacological and therapeutic targets of Daphnetin.
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TABLE 1 Pharmacological activities of Daphnetin.
Pharmacological
action
In-vivo/
In -vitro
study
Cell line/
Animal
Method Dose Molecular mechanism Effects/Targets References
Anti-stress In-vivo/in-
vitro
Kunming mice
Cortical neurons
from SD rat brains
Unpredictable stressor 2 and 8 mg/kg ↓GRs ↓in spatial learning and memory improves the
cognitive deficits caused by chronic stress
Liao et al. (2013)
Neuroprotective In-vivo E18 C57BI/6 mice NMDA induced
excitotoxicity
20 and 40 mg/kg × NR2B-containing NMDA
receptors
× apoptosis × calcium overload Yang et al. (2014)
Hepatoprotective In-vivo In-
vitro
male C57BL/6 mice Oxidative stress induced
hepatotoxicity
20, 40 and
80 mg/kg
↑Keap1-Nrf2/ARE-Trx-
1↓ASK1/JNK, P53 protein
↓t-BHP in HepG2 cells ↑Nrf2/Trx-1 ↑GSH, ↓ROS Lv et al. (2020)
Helicobacter Pylori
infection
In-vitro 20 H. pyloristrains
isloted from gastric
antrum
6.25 or
12.5 μg/ML
↑DNA damage,
↑recA ×membrane changes
↓bab A, urel transcription and H. pylori adhesion to
GES-1 cell line
Wang et al. (2019)
Lung protection In-vitro/
In-vivo
Mice Endotoxin induced Lung
injury
5, 10 mg/kg × activation of macrophage and
human alveolar epithelial cells,
induced TNFAIP3 ↓pro-
inflammatory cytokines
NF-Kb related signal pathway, anti-inflammatory
potential
Yu et al. (2014b)
In-vivo C57BL/6 mice L-arginine 2-4 mg/kg i.p ↓IL-6, TNF-α, MPO ↓JAK-2,
STAT-3
↓infiltration and cytokine secretion in inflammatory
cells
Yang et al. (2021c)
Rheumatoid arthritis In-vivo Rats Freund’s complete
adjuvant induced arthritis
2.25 and
4.5 mg/kg
↓IL-1, TNF-αand MIF ↓paw swelling and arthritic scores × inflammatory cells
infiltration and articular cartilage degeneration
(Gao et al., 2008;Yao
et al., 2011;Tu et al.,
2012)
In-vivo Female Wistar rats Collagen induced arthritis 1 and 4 mg/kg ↑Foxp3 ↓Th1/Th2/Th17 Yao et al. (2011)
↓activity of Th17 ↓RORγt, NF-
KB, CD77 ↓IL-10 ↑Tregs
↓paw swelling ×hyperplasia of synovial, destruction
and degeneration of chondrocytes Modulate balance of
Th17 and Tregs
Osteoporosis In-vivo In-
vitro
Sprague Dawley
rats MC3T
3-
E
1
pre
osteoblasts
Dexamethasone induced 1 and 4 mg/kg activate Wnt/GSK-3β/ßcatenin
signaling pathway
↓body weight gain, bone mineral content and
microstructure parameters
Wang et al. (2020b)
↑osteoblast proliferation, differentiation and
mineralization
Hepatoprotective In-vivo Mice Lipopolysaccharide/
D-galactosamine induced
liver failure
20, 40, 80 mg/kg × Inos × COX-2 ↑autophagy ↑
pro-autophagy protein
expression
↓ALT, AST ↓pro-inflammatory cytokines ↓MDA
↓myeloperoxidase ↑GSH, SOD level × MAPK, NF-kβ,
NLRP3
Lv et al. (2018)
Liver cancer In-vivo Huh7 and SK-
HEP-1
0, 5, 10, 50 and
100 µM
↑G1 phase arrest ×cell viability Liu et al. (2022)
×tumorigenesis
↑cell apoptosis
×Wnt/ßcatenin signaling
(Continued on following page)
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TABLE 1 (Continued) Pharmacological activities of Daphnetin.
Pharmacological
action
In-vivo/
In -vitro
study
Cell line/
Animal
Method Dose Molecular mechanism Effects/Targets References
Nephroprotective In-vivo C57BL/6 mice Cisplatin induced
nephrotoxicity
2.5,5,10 mg/kg ↓TNF- α,IL-1β, ROS, MDA ×NF-kB signaling pathway activate Nrf2 pathway Zhang et al. (2018)
↓BUN, creatinine
↓renal injury
↓inflammation, oxidative stress, apoptosis
In-vivo WT and Nrf2 mice Cisplatin induced
nephrotoxicity
20-40 mg/kg ↑SOD, GSH, SIRT1, SIRT6, HO-
1, Nrf2, NQO1 ↓MDA, MPO
↓BUN, creatinine ↓renal injury ↓inflammation,
oxidative stress, apoptosis
Fan et al. (2020)
Diabetic nephropathy In-vivo mesangial cells High Glucose induced 0, 10, 20, 40 μM↑Nrf2 ×p-Akt ×p-p65 ↓ROS, MDA ↓TNF- α,IL-1β↓IL-6, ↓fibronectin
↓collagen IV ↑SOD activity ↓cell proliferation
Xu et al. (2019)
Cerebral Ischemia/
Reperfusion injury
In -vivo C57BL/6mice Middle cerebral artery
occlusion
5, 10, 20 mg/kg ↓TNF- α,IL-1β, IL-6, TLR4 ×TLR4/NF-kβ↓IkBαdegradation ↓neural cell
apoptosis
Liu et al. (2016a)
In-vitro Hippocampal
neuron
Reoxygenation induced
lung injury
10, 20 and 40 µm ↑Nrf2 ↑HO1 × oxidative stress and neuronal apoptosis Zhi et al. (2019)
Ischemic brain injury In-vitro HT22 cells glutamate induced toxicity
in hippocampal HT22 cell
5, 10, 25, 50, 75,
and 100 μM/L
×NF-kB pathway ↑SOD, GSH ×TLR4/NF-kB pathway Du et al. (2014)
Microglial activation In-vivo Murine microglia Intracellular signal
transduction
0–160 µm ×iNOS ×COX-2 ↓TNF-α,IL-1β, IL-6 NO, ×microglial activation
↓Th17 development ×NF-kB × MAPK × IKK /IkB PI-
3K/Akt
Yu et al. (2014a)
Psoriasis In-vitroIn-
vitro
HaCaT human
keratinocytes in
Mice
imiquimod induced
psoriasis like skin lesion
50-100 mg/ cm ↓IL-1β, IL-6, IL-8, IL-17A, TNF-
α, IL23A, MCP-1
pathway ×p65 phosphorylation ×nuclear translocation
↓erythema ↓scaling, epidermal hyperplasia,
inflammatory cells infiltration
Gao et al. (2020)
Cell proliferation and
Estrogenicity
In-vivo In-
vitro
MCF-7 cells Female
mice
17.5, 35, 70,
140 mg/kg
↓Cyclin D1 ↑p27 ↑GO phase ↓G1 phase ↑S phase ↑G2 phase ↑M phase
↓cyclin/CDK2 ↓cyclin D1/CDK4 ×cyclin D1
Jiménez-Orozco et al.
(2011)
Leukemia In-vivo Albino Wistar rats Benzene induced 12.5, 25,
50 mg/kg
↑sphingosine1-phosphate
receptor-1 ↓SGOT ↓Cytochrome
P450 ↓CYP2E1
↓NF-kB ↑Hematological parameter ↑nucleated bone
marrow cells ↑megakaryocyte , SOD, GSH ↓MDA, ↓8-
OhdG ↑albumin, total protein ↓BUN, bilirubin
↓prothrombin time
Pei et al. (2021)
Ovarian cancer In-vitro A2780 5, 10, 20,
40 μg/ml
↓p-Akt ↓p-mTOR ↑p-AMPK,
LC3 II, p62
↑ROS production ×cell proliferation ↑apoptosis,
autophagy, Blood count, Hemoglobin↓
proinflammatory cytokines
Fan et al. (2021a)
Human renal cell
carcinoma
In-vitro A-498 cells 10 and 50 µm ↑p38 MAP kinase ↑cytokeratin
8 and 18
MAPK Signaling pathway ×ERK1/ERK2 pathway ×S
phase transition ×DNA synthesis
Finn et al. (2004)
(Continued on following page)
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TABLE 1 (Continued) Pharmacological activities of Daphnetin.
Pharmacological
action
In-vivo/
In -vitro
study
Cell line/
Animal
Method Dose Molecular mechanism Effects/Targets References
Corneal inflammation and
neovascularization
In-vivo Male ICR mice Alkali burn (10-20 μmol/L)
DAP
eyedrops, q.i.d
↓HUVECs ↑STAT3, ERK, AKT ×corneal inflammation (↑VEGF-A) and
neovascularization (↑TLR4/NLRP3)
Yang et al. (2022)
In various tumors In-vivo Female in bred
BDF1 C57Bl/6
S180 sarcoma, MXT breast
adenocarcino ma,
C26 colon carcinoma
10,20 and
40 mg/kg
↑p38 MAP kinase ↑cytokeratin
8 and 18 ↑pro-apoptotic
caspase-3
×mitogenic pathway ↓Cyclin D1 ×S phase ×Akt/ NF-kβ
pathway ×proliferation
Jiménez-Orozco et al.
(2020)
In-vivo Murine Osteosarcoma LM8 cells 30-60 µm ↓RhoA ↓Cdc
42
↓intracellular stress fibers and filopodia Fukuda et al. (2016)
Mitochondrial
dysfunction and cell death
In-vitro C57Bl/6 mice Tert-butyl hydroperoxide 2.5,5,10 µg/ml ↑HO-1, SOD ↑NADPH, NQO1,
GCLM ↑GCLC, BCl2 ↓Bax,
Caspase 3
×ROS production ×cytochrome c release,
NLRP3 activation ↑Nrf2 pathway activate JNK
and ERK
Lv et al. (2017)
CFA induced
inflammatory pain
In-vivo Murine CFA 4 and 8 mg/kg ↓spinal pro-inflammatory
cytokines
×spinal glial activation × NF-kβpathway
↑Nrf2 pathway/HO-1 signaling pathway
Yang et al. (2021a)
Inflammatory bowel
disease
In-vivo Mice Fecal transplantation 16, 8, 4 mg/kg ↑T reg cells development ↓Th 17 cell differentiation Ji et al. (2019)
Lipid metabolism In-vitro HepG2 cells 5, 20 and 50 µm ↑PNPLA3 ↓TG Liu et al. (2019)
Insulin resistance In-vitro HepG2 cells 20 and 50 µm ↑pAKT/AKT P13K ↑glucose uptake Liu et al. (2019)
Oxidative stress In-vitro HepG2 cells 5, 20, and 50 µm ↓CYP2E1 and CYP4A ↑Nrf2 ↓oxidative stress Liu et al. (2019)
Angiogenesis In-vivo Rat TNF and VEGF induced 9.375–900 µM ↓c-Src, FAK, ERK1/2, Akt,
VEGFR2, iNOS, MMP2
× angiogenesis ×migration ×invasion ×tube
formation × NF-kβpathway ×TNF-αinduced IkBα
degradation ×translocation of the NF- kβp65 protein
↑apoptosis
Kumar et al. (2016b)
Abbreviations: Inhibits; ↑: Upregulates, Increase; ↓: Downregulates, Decrease; CUS, chronic unpredictable stress; GRs: Glucocorticoid receptors; ALF, acute liver failure; APAP, acetaminophen; ASK1, Apoptosis signaling-regulating kinase 1; AREs,
Antioxidant response elements; HO-1, Heme oxygenase-1; JNK, c-Jun N-terminal kinase; NF-κB, Nuclear factor-kappaB; Nrf2, Nuclear factor erythroid 2-related factor; 2NLRP3, Nucleotide-binding domain-like receptor protein 3 ROS, reactive oxygen
species; Trx-1, Thioredoxin-1; Txnip, Thioredoxin-interacting protein; PALI, pancreatic acute lung injury; JAK-2, Janus kinase-2; STAT-3, Signal transducer and activator of transcription 3; VEGFR2, Vascular endothelial growth factor 2; iNOS, inducible
nitric oxide synthase.
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3 Pharmacological activities of
Daphnetin
The DAP has been used to treat coagulation disorders,
various skin diseases, rheumatoid arthritis (RA), cancer,
lumbago, and fever (Tu et al., 2012;Wang et al., 2013). It
exhibited numerous pharmacological activities, including
analgesic, anti-pyretic (Singh et al., 2021a), anti-arthritic, anti-
inflammatory, anti-oxidant (Qi et al., 2016;Lv et al., 2018), anti-
proliferative (Fylaktakidou et al., 2004;Kostova et al., 2011), anti-
bacterial (Cottigli et al., 2001), neuroprotective (Qi et al., 2016),
cardio-protective, nephroprotective, stroke, coagulation
disorders, ischemic brain injury, hepatoprotective and anti-
cancer activities (Pinto and Silva, 2017;Zhang et al., 2018;
Boulebd and Khodja, 2021) as mentioned in Figure 3. It has
been used for treating RA and coagulation disorders for long
duration without significant toxic effects (Du et al., 2014).
Pharmacological actions of DAP are summarized in Table 1.
3.1 Neuroprotective action
Nerve cells interact with one another to carry out various
physiological functions. Any communication breakdown in the
brain, even in a solitary area, can impair the operation of other
brain regions and is the main factor in catastrophic neurological
illnesses or neurodegenerative disorders of the central and peripheral
nervous systems. Progressive neuronal degeneration causes
temporary or permanent sensory loss in a variety of
neurodegenerative disorders. The reactive oxygen species (ROS)
and inflammatory signaling molecules i.e., tumor necrosis factor
alpha (TNF-α), and interleukin (IL)-6 are the key contributors to
neurodegenerative disorders (Qi et al., 2016;Chitnis and Weiner,
2017;Boulebd and Khodja, 2021). For neuroprotective action, DAP
reduces Toll-like receptor-4 (TLR-4), nuclear factor-ĸβ(NF-ĸβ), and
other pro-inflammatory cytokines. It also inhibits JAK/STAT
phosphorylation which is responsible for the increase of pro-
inflammatory cytokines and enzymes, culminating in the
reduction in COX-2 and inducible nitric oxide synthase (iNOS)
levels. It significantly enhances the Nrf-2 expression. DAP is
reported to enhance Heat shock protein (HSP)-70 by
downregulating the expression of NF-ĸβand mitogen-activated
protein kinase (MAPK) at the molecular level, causing the
enzymes to regulate neuronal apoptosis by increasing or
decreasing the phosphorylation of pro-apoptotic proteins (Bax/
Bad) and an anti-apoptotic protein (Bcl-2) (Singh et al., 2021a).
3.1.1 Cognition and memory
DAP has shown significant potential to prevent memory loss
and cognition. It inhibited apoptosis and calcium overload
induced by down-regulating NR2B-containing N-methyl-D-
aspartate (NMDA) receptors as well as calcium accumulation
which was activated by glutamate and caused excitation of
neurons. DAP exhibited neuroprotective properties by
preventing NMDA-induced neuronal cell loss and regulating
the balance of Bcl-2 and Bax expression in cortisol neurons of
mice (Yang et al., 2014).
The neuroprotective effect of DAP has been reported in the
posterior cerebral artery occlusion (MCAO)/reperfusion mice
model. The DAP (1 mg/kg) showed a substantial reduction in
cerebral infarct volume (Du et al., 2014). It has a neuroprotective
effect in stressed mice on microglial activation and its subsequent
inflammatory response. The pre-incubation with DAP
dramatically inhibited TNF-αand IL-1 production in
lipopolysaccharide (LPS) or ß-amyloid activated BV2 cells.
The MAPK and protein kinase B (Akt) pathways play a
negative role in the anti-inflammatory action of DAP.
Furthermore, pre-treatment with Wortmannin, a PI-3 k/Akt
inhibitor, resulted in a significant decrease in LPS-induced
TNF-αand nitric oxide generation in BV2 cells,
demonstrating an opposing role of the MAPK/Akt pathway in
mediating anti-inflammatory effect of DAP. It also reduced the
expression of NF-κB to promote neuroprotection (Yu et al.,
2014a). The neuroprotective action of DAP is presented in
Figure 4.
In another study, the neuroprotective effect in mice was
studied by utilizing the middle cerebral artery occlusion
(MCAO)/R model. It reduced the extent of the MCAO/
R-induced cerebral infarct, neuronal apoptosis, and brain IL-
1β, IL-6, TLR-4/NF-kB, and TNF-αlevels in the cerebral cortex
(Vivier et al., 2016). Lei Shen and his coworkers showed that
DAP had reduced endotoxin lethality in a mouse model of LPS-
induced endotoxemia and suppressed the inflammatory response
to LPS in Raw264.7 cells by inhibiting ROS generation, JAK1 and
JAK2, and enhancing suppression of STAT1 and
STAT3 phosphorylation, and ultimately prevented the
STAT1 and STAT3 transport in the nucleus (Shen et al., 2017).
Several preclinical researches have revealed that DAP had
improved spatial memory and depressed behavior. The chronic
unexpected stress mice model was used to assess the effect of
DAP. It improved the Chronic Unpredictable Stress (CUS)
impaired spatial memory as indicated by mouse performance
in the Morris water maze test. DAP (2 and 8 mg/kg) injection
reduced the immobilization time in a forced swim test compared
to the CUS-treated group, confirming the involvement of DAP in
improving spatial memory and restoring depressive behavior in
mice (Liao et al., 2013).
3.1.2 Stroke
Cerebral ischemia is caused by impaired blood flow and is
accompanied by an inflammatory reaction, release of cytokines,
and inflammatory mediators that play a pivotal role in the
development of stroke (Iadecola and Alexander, 2001). The
TLR4 is highly induced after reperfusion injury. In an earlier
study, DAP was used for treating cerebral ischemia/reperfusion
injury and it was found to exhibit neuroprotective and anti-
inflammatory effect by inhibiting TLR4/NF-kβpathway,
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alleviating the production of inflammatory cytokines and neural
cell apoptosis (Liu et al., 2016a). DAP (at 5, 10, 25, 50, 75, and
100 μM/L) displayed dose-dependent neuroprotective action in
glutamate-induced toxicity in hippocampal HT22 cells and
ischemic brain injury by restoring reduced glutathione (GSH)
and superoxide dismutase (SOD) (Du et al., 2014).
It was further found that DAP suppressed oxidative stress
and cell apoptosis in hippocampal neurons. It increased nuclear
translocation of nuclear factor erythroid 2 (Nrf2) and HO-1
expression in neurons exposed to reoxygenation-induced cell
injury at 10, 20, and 40 µM doses. DAP inhibited oxidative stress
and neuronal apoptosis by activating Nrf2/HO-1 signaling
pathway (Zhi et al., 2019).
3.2 Hepatoprotective action
Excessive generation of ROS causes significant damage to cell
membrane phospholipids, proteins and DNA leading to a variety
of disorders (Blair, 2008;Mendes-Braz and Martins, 2018;Zhao
et al., 2018). DAP reduced hepatotoxicity caused by tert-butyl
hydroperoxide (t-BHP) and acetaminophen through the
modulating Nrf2/Trx-1 pathway. It effectively prevented
t-BHP-induced hepatotoxicity by regulating Nrf2/Trx-
1 pathway in HepG2 cells. Moreover, it inhibited ASK1/JNK
activation and decreased the acute liver failure (ALF),
cytochrome C, and Bax mitochondrial translocation, all of
which concomitantly restored the mitochondrial function. It is
also found that DAP inhibited inflammatory reactions in the liver
by inactivating the thioredoxin-interacting protein (Txnip)/
NLRP3 inflammasome. It also improved the Nrf2 nuclear
translocation and Trx-1 expression (Lv et al., 2020). It
inhibited MAPK, NF-kβ, nucleotide binding domain like
receptor protein 3 (NLRP3) and decreased the pro-
inflammatory cytokines in acute liver failure (ALF) (Lv et al.,
2018). The hepatoprotective mechanism of DAP is given in
Figure 4.
A study reported that the DAP had reduced the lipid
accumulation within the hepatocytes by regulating PI3K
expression and pAKT/AKT levels. Moreover, it decreased
the insulin resistance by promoting the hepatocellular
glucose uptake through upregulating the expression of
Nrf2. In addition, DAP reduced the level of ROS in
hepatocytes by downregulating the expression of
CYP2E1 and CYP4A (Liu et al., 2019). In an earlier study,
DAP improved carbon tetrachloride (CCL4)-induced
biochemical changes. It decreased the CCL4 induced-lipid
peroxidation and boosted the antioxidant defense system.
DAP induced nuclear translocation of Nrf2 related factor 2 to
induce the expression of hydroxyl ion. Thus, DAP prevented
the hepatotoxicity induced by oxidative stress by activating
Nrf2-mediated hydroxyl ion expression (Mohamed et al.,
2014).
FIGURE 4
The molecular interaction of multiple mediators implicated in the neuroprotective effect of daphnetin. TLR-4: toll-like receptor -4; NF-ĸβ:
nuclear factor-ĸβ; Janus kinase: JAK/STAT; COX-2: cyclooxygenase -2; iNOS: inducible nitric oxide; Nrf-2: Nuclear factor erythroid 2-related factor;
MAPK: mitogen activated protein kinase; Bcl-2: pro-apoptotic proteins; Bax/Bad; anti-apoptotic protein; ROS: reactive oxygen species.
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3.3 Effect on heavy metal and endotoxin
induced lung injury
It is found that DAP exhibited a phenomenal anti-oxidant in
arsenic-induced cytotoxicity in human lung epithelial cells. DAP
(at 2.5, 5, 10 g/ml) progressively shielded Beas-2B cells from
NaAsO2-induced apoptosis as well as arsenic cytotoxicity via
Nrf2-dependent pathway and increased GSH level (Lv et al.,
2019).
Endotoxin is an important toxin precipitating lung injury
and is responsible for increased serum concentration of all
cytokines and growth factors (Rojas et al., 2005). DAP at
5 and 10 mg/kg provided considerable protection from
endotoxin-induced acute lung injury in mice by inhibiting
the activation of macrophages and human alveolar epithelial
cells through reducing the production of inflammatory
mediators, induction of TNF-αinduced protein 3
(TNFAIP3) and decreasing the expression of iNOS and
NF-κB to attenuate inflammation. It also downregulated
the phosphorylation of MAPKs including p38, extracellular
signal regulated kinase (ERK), and JNK kinases (Yu et al.,
2014b).
3.5 Anti-bacterial action
DAP was investigated for anti-bacterial activity against
Helicobacter pylori; a Gram-negative bacterium that usually
colonizes stomach causing gastritis and peptic ulcers (Zali,
2011). DAP showed virtuous activity against multidrug
resistant (MDR) H. pylori via enhancing DNA damage,
phosphatidylserine (PS) translocation, and recA expression
while downregulating blood group antigen binding adhesion
(babA) and urease l (urel) with the decrease in the attachment
of H. pylori to GES-1 cells with minimal inhibitory concentration
(MIC) from 25 to 100 μg/ml (Wang et al., 2019); (Walker and
Crabtree, 1998). It also showed antibacterial activity by
destroying cell wall and preventing membrane coherence of
Pseudomonas fluorescens and Shewanella putrefaciens with
MIC of 0.16 and 0.08 mg/ml respectively (Liu et al., 2020). In
another study, the effect of DAP on the Ralstonia solanacearum
was investigated in which it was found that DAP had exhibited
strongest anti-bacterial effect due to the presence of
hydroxylation at C6, C7, or C8 which increased its anti-
bacterial effect by destructing the bio-membrane against R.
solanacearum with the MIC at 64 mg/L (Yang et al., 2016).
DAP (at 10 mg/kg i.p.) was used to treat bacterial
pneumonia caused by methicillin-resistant Staphylococcus
aureus (MRSA) in C57BL/6 mice. It protected against
inflammation, tissue damage, and stimulated the mTOR-
dependent autophagy pathway, which resulted in the
increased bactericidal activity of macrophages by
suppressing ROS production (Zhang et al., 2019).
3.6 Anti-malarial action
Malaria is one of the major fatal diseases, affecting around
1 million people worldwide and leading to death (Hu et al., 2018).
DAP and its two derivatives, DAP78 and DAP79, have
demonstrated anti-malarial activity against Plasmodium
falciparum; nevertheless, DAP functions as an iron chelator,
and its anti-malarial potency decreased significantly with time,
leading its chelating action to be abolished (Huang et al., 2006).
In another investigation, DAP was found to have a high iron
chelating activity when compared to the potent iron-chelator
desferroxamine B at different dosages (Mu et al., 2002). It caused
50% inhibition of
3
H-hypoxanthine incorporation by P.
falciparum at 25 and 40 µM. DAP did not immediately
generate superoxide under in-vitro conditions, therefore it is
not considered an oxidant. However, during in-vivo studies, it
significantly prolonged the survival of mice infected with P. yoelli
(Yang et al., 1992). Wang et al. (2000) reported the schizontocidal
activity of DAP by using P. falciparum FCC1 strain in-vitro. The
in-vivo activity was evaluated against P. berghei in Anka mice at
the dosage of 10–100 mg/kg/day which demonstrated positive
outcome.
3.7 Anti-inflammatory and anti-arthritic
actions
The excess endogenous production of ROS leads to oxidative
stress due to decreased concentration of GSH, SOD, and
increased level of malondialdehyde (MDA). Oxidative stress
also causes activation of the NF-κB pathway. This pathway
controls the release of different cytokines by directing the
expression of number of pro-inflammatory cytokines,
inhibiting the apoptosis proteins (IAPS) and COX-2 which
leads to inflammation. For anti-inflammatory action, DAP
inhibits these pathways.
Adjuvant-induced arthritis is an autoimmune disorder
characterized by chronic inflammation of joints that exhibits
the same pathological response as that of RA (Connor et al.,
1995). Various pro-inflammatory mediators play a significant
role in the pathogenesis of this disorder (Barsante et al., 2005).
DAP significantly attenuated the poly-arthritis by suppressing
the production of pro-inflammatory cytokines (IL-1 and TNF-α)
(Gao et al., 2008).
In another study, DAP alleviated the inflammation and
pathological changes in the joint tissue, synovial hyperplasia,
and chondrocyte degeneration in collagen-induced arthritis
(CIA) in female rats at 1 and 4 mg/kg by restoring the
expression of Th1/Th2/Th17 type cytokines, Foxp3, IL-17, IL-
6, TGF- β, IL-4, and IFN- γ(Tu et al., 2012). In another study, it
inhibited the proliferation of fibroblast-like synoviocytes (FLS) in
rats with CIA and induced apoptosis by suppressing PI3k/AKT/
MTOR signaling pathway at 0-60 μg/ml (Deng et al., 2020). In
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another study, DAP was combined with B cell lymphoma
2 targeted small interfering RNA (si-Bcl2) on fibroblast-like
synoviocytes (FLS) in rats with CIA by downregulation of
Bcl2. When si-Bcl2 was combined with DAP (40 μg/ml), it
increased the effect via promoting apoptosis on RAFLS and
by reducing the expression of Bcl2 and STAT3 (Chen et al.,
2018).
In a previous study, DAP reduced the serum level of Th17,
Th2, and Th1 type cells and upregulated the levels of Tregs in
arthritis rats at 1 and 4 mg/kg. It also decreased RORγt, NF-kB,
and CD77 in joint tissue while increased the expression of Foxp
3
and IL-10. Thus it modulated the balance of Tregs and Th
17
cells
and is considered to be an effective agent in the treatment of CIA
in rats (Yao et al., 2011).
Zhang et al. (2020) reported the chondroprotective effect of
DAP against osteoarthritis. DAP (at 12, 24 and 48 ng/ml)
profoundly protected chondrocytes of rabbits by averting IL-
1β, -6,-12, MMP3,-9, and -13 and decreasing the caspase-3 and
BAX while increasing BCL-2. In another study, DAP exhibited
anti-arthritic action by demethylation of pro-apoptotic genes in
synovial cells (FasL and P53). For this purpose, MTT analysis was
performed on CIA-treated rat synovial cells to determine the
inhibitory effect of DAP and DNA methyltransferase inhibitor
drug (5-aza-dc) in the range of 1.25-40 μg/ml. It inhibited cell
growth in synovial cells in a dose and time dependent manner
(Shu et al., 2014). Zheng et al. reported anti-arthritic action of
DAP using collagen induced FLS. It escalated caspase 3, 8, and 9,
Bax, FasL, and cytochrome c (Cyt-c) with the reduction in Bcl-2
and enhanced the Cyt-c discharge from mitochondria to the
cytosol (Zheng et al., 2020). In another study, DAP at 4 and
8 mg/kg inhibited spinal glial activation in murine mice
provoked by CFA. It also decreased the expression of pro-
inflammatory cytokines. It inhibited the NF-κβ pathway and
activated the Nrf2/HO-
1
signaling pathway (Yang et al., 2021a).
3.8 Osteoporosis
Glucocorticoids are effective agents in treating inflammatory
and autoimmune diseases. While its long-term usage results in
osteoporosis. DAP at 1 and 4 mg/kg exhibited the therapeutic
action against dexamethasone induced osteoporosis in male rats
by restoring bone mineral content, microstructure parameters,
and bone turnover. In-vitro, it promoted osteoblast proliferation,
differentiation, and mineralization in pre-osteoblasts by
activating Wnt/GSK-3β/βcatenin signaling pathway (Wang
et al., 2020b).
3.9 Multiple sclerosis
Multiple sclerosis (MS) is an inflammatory and
neurodegenerative illness that is identified by projected
inflammation, axonal injury, and demyelination. DAP
(8 mg/kg) has exhibited an immune-regulatory role in
autoimmune encephalomyelitis in the murine model used for
MS (Leung et al., 2011). Autoimmune encephalomyelitis is a
demyelinating inflammatory illness of the central nervous system
caused in experimental animals by an immune response to
myelin epitopes (Fletcher et al., 2010). T cells attract
macrophages, microglia, and astrocytes which release
inflammatory mediators such as nitric oxide (NO), and ROS.
DAP therapy lowered the level of pro-inflammatory cytokines,
induced heme oxygenase-1 (HO-1), decreased the level of MDA,
and displayed anti-inflammatory and neuroprotective effects in
mice at 8 mg/kg (Wang et al., 2020c). In a previous study, DAP
administered for 28 days mitigated the encephalomyelitis in mice
via suppressing the activation, maturation, and antigen-
presenting capability of Dendritic cells, and regulated NF-κB
signaling (Wang et al., 2016).
3.10 Systemic lupus erythematosus
Li et al. reported the anti-inflammatory potential of DAP in
the NZB/WF1 systemic lupus erythematosus (SLE) murine
model. In the SLE-prone NZB/W F1 mice, DAP (at 5 mg/kg)
treatment enhanced the survival rates, reduced renal damage and
blood urea nitrogen levels, and lowered the serum autoantibody
production. Furthermore, its therapy significantly reduced the
serum levels of TNF-αand IL-6, inhibited NF-kB activity,
lowered the nuclear factor of activated T-cell protein
production, and increased the A20 protein expression in SLE-
prone NZB/W F1 mice. Finally, DAP reduced the inflammation
in the NZB/WF1 murine SLE model via NF-κB suppression
mediated by A20 overexpression (Li et al., 2017).
3.11 Anti-psoriasis action
Psoriasis is a chronic inflammatory disease of the skin
characterized by excessive proliferation, abnormal
differentiation of keratinocytes, and infiltration of
inflammatory cells into the epidermis and dermis.
Hyperproliferation of keratinocytes and extreme inflammatory
response play a pivotal role in its pathogenesis. Cytokines
secreted by immune cells cause keratinocytes’
hyperproliferation which produces pro-inflammatory
cytokines to potentiate inflammatory response. A previous
study showed the anti-psoriatic activity of DAP in HaCaT
keratinocytes mouse which occurred through the
downregulation of inflammatory cytokines and suppression of
NF-κB signaling pathway (Gao et al., 2020). DAP also decreased
the epidermal hyperplasia and infiltration of inflammatory cells
in imiquimod induced skin lesions in mice. In another research,
DAP above 40 μM caused a decrease in cell viability in human
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HaCaT keratinocytes by upregulation of IL-1, -6, -8, TNF-α, and
IL-23A while inhibiting P65 phosphorylation and nuclear
translocation. Additionally, it improved the inflammation,
erythema, scaling, and epidermal thickness of psoriatic mice
(Gao et al., 2020).
3.12 Anticancer action
DAP is known for anticancer potential against leukemia,
ovary, kidney, colon, and liver cancers. Uncontrolled
proliferation and suppression of apoptosis lead to cancer.
Mitogen pathways are responsible for regulating apoptosis.
DAP is a protein kinase inhibitor; therefore, it significantly
suppresses this pathway and acts as an anti-proliferative
agent. It also acts at different phases of the cell cycle. DAP
inactivates Akt/NF-κB (an anti-apoptotic pathway), JNK,
MAPK, and ERK pathways that are responsible for causing
cancer. DAP activated Keap1-Nrf2 pathway that protected the
cell against oxidative stress by activating transcription of several
cytoprotective genes thus helping to combat cancer (Figure 4)
(Jiménez-Orozco et al., 2020). In a previous study, effect of DAP
(at 2.5, 5, and 10 μg/ml) on tert-butyl hydroperoxide (t-BHP)
induced mitochondrial dysfunction and cell death in C57B1/
6 mice and RAW 264.7 cells revealed that the DAP suppressed
the production of ROS by stimulating various anti-oxidant genes
and activating Nrf2 pathway that protected the body against
oxidative damage. Activation of Nrf2 pathway suppressed
NLRP3 activation, thus inhibiting the activation of caspases
and release of pro-inflammatory cytokines. In this way, DAP
protected the body from cell death and mitochondrial
dysfunction (Lv et al., 2017).
In another study, anti-proliferative properties of DAP in
cancer cells were reported. DAP inhibited migration and
invasion of highly metastatic murine osteosarcoma LM8 cells.
It reduced the intracellular stress fibers and filopodia. It also
decreased the expressions of RhoA and Cdc
42
(Fukuda et al.,
2016).
3.12.1 Kidney cancer
The human renal cell carcinoma (RCC) accounts for up to
90% of kidney cancers due to the alterations of the genes
responsible for controlling cell division (Motzer et al., 1996;
Hsieh et al., 2017). MAPKs pathway causes activation of
transcription factors which in turn regulate gene expression,
thus controlling the cell growth, differentiation, and
proliferation. ERK pathway also controls the proliferation and
differentiation and survival of cells. DAP prevented the RCC
proliferation by inhibiting ERK/MAPK pathway and upregulated
the differentiation mediated by p38 MAP kinase. It also
suppressed the G
1
to S phase transition by inhibiting DNA
synthesis at 10 and 50 µM in AQ-498 cells (Finn et al., 2004).
The anticancer mechanism of DAP is shown in Figure 4.
p38 MAP kinase is intrinsically involved in mediating the
effect of DAP in A-498 cells. Moreover, DAP is involved in
promoting the cellular maturation and is considered to be a new
less toxic approach for treating poorly differentiated RCC (Finn
et al., 2004).
3.12.2 Ovarian cancer
Ovarian cancer is the sixth most common cancer among
European women (Colombo et al., 2006). Autophagy, apoptosis,
and ROS production can trigger cell death and help to treat
cancer. AMPK/Akt/mTOR pathway is associated with autophagy
and apoptosis. In an earlier study, DAP exhibited the anticancer
potential in A2780 xenograft tumor model against ovarian cancer
at 0, 5, 10, 20, and 40 μg/ml in-vitro and 30 mg/kg in-vivo by
inducing cell death, increasing ROS production, inducing
autophagy, and inhibiting the cell proliferation (Fan et al.,
2021a).
3.12.3 Leukemia
Benzene is a chemical present in the atmosphere that can
cause different types of leukemia. Exposure to the vapors of
benzene leads to oxidative damage, inflammatory responses,
changes in cell cycle progression, and DNA damage (Huff,
2007). In a benzene-induced leukemia study, treatment of rats
with DAP at 12.5, 25, and 50 mg/kg caused an increased blood
count, and hemoglobin concentration, reduced the level of
inflammatory mediators, and inhibited ROS production to
retard cancer progression (Pei et al., 2021).
3.12.4 Liver cancer
A previous study reported the therapeutic potential of DAP
against liver cancer. Hepatocellular carcinoma (HCC) was
induced in Wistar rats by diethyl nitrosamine (DEN)
(200 mg/kg) and its effect was enhanced by phenobarbital for
4 weeks. DAP (at 10, 20, and 30 mg/kg) repressed the
biochemical parameters with enhanced levels of GSH,
glutathione S-transferase (GST), SOD and CAT while
decreasing the level of MDA. It also reduced the
inflammatory markers such as COX-2, NF-κB, prostaglandin
(PGE2), IL-1β, IL-6, and TNF-αin treated rats (Li et al., 2022).
In another study, DAP inhibited the progression of
hepatocellular carcinoma in Huh7 and SK-HEP-1 cell lines.
DAP suppressed the cell viability and tumorigenesis,
promoted the apoptosis of cells, and induced the arrest the
cells in G1 phase dose-dependently which were rescued by
SKL 2001, an activator of Wnt/β-catenin signaling. Thus,
DAP exerted an antitumor role through the inactivation of
Wnt/β-catenin signaling (Liu et al., 2022).
3.12.5 Breast cancer
Cell proliferation and estrogenicity lead to the tumor
development in breast. DAP acts at different phases of cell
cycle thus controlling cell proliferation and tumor
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development. Cyclin D1 is a major protein for the initiation of
cell cycle and proliferation of cells. In a previous study, DAP
suppressed cyclin D1, thereby preventing the proliferation in
MCF-7 cells. It is also a protein kinase inhibitor which leads to
the inhibition of proliferation. It did not possess estrogenic
activity (Jiménez-Orozco et al., 2011).
In another study. DAP inhibited p-AKT which reduced NF-
κB in mammary cancer. It was considered to be an effective agent
in the treatment of mammary cancer in rats by suppressing the
Nrf-2-Keap
1
pathway and NF- κB expression (Kumar et al.,
2016a).
3.13 Nephroprotective action
The DAP showed nephroprotective effect against
cisplatin-induced nephrotoxicity by suppressing the NF-κB
signaling pathway and activating the Nrf2 pathway when
C57BL/6miceweretreatedwithDAPat2.5–10 mg/kg. It
decreased the blood urea nitrogen and creatinine levels along
with the reduction of ROS (Zhang et al., 2018). Another study
stated that the DAP (at 40 mg/kg) restored the weight loss,
blood urea, kidney index, and creatinine levels in cisplatin-
induced acute nephrotoxicity. It remarkably increased sirtuins
(SIRT1, SIRT6) and Nrf2 with an increased SOD and GSH
levels, and the reduction in MDA and MPO levels in wild-type
mice (Fan et al., 2020). The nephroprotective mechanism of
DAP is shown in Figure 4. A study also reported the preventive
potential of DAP in diabetic nephropathy in mesangial cells at
10-40 µM by preventing cell proliferation, protection against
oxidative stress and inflammation by targeting Nrf2/keap1,
and Akt/NF-kB inflammatory pathways (Shen et al., 2017;Xu
et al., 2019).
DAP protected the mice from gentamicin-induced
nephrotoxicity at 40 mg/kg by preventing renal injury and
decreasing cell damage. It upregulated the expression of Nrf2,
and antioxidant enzymes such as HO-1, NQ0
1
, GCLC and
GCLM (Fan et al., 2021b).
3.14 Other actions of Daphnetin
Song et al. investigated the potential effect of DAP as
immunosuppressive agent in BALB/c mice using a 100 μl
emulsion comprising of 100 μg OVA as prototype antigen.
DAP (at 5, 10, and 20 mg/kg i.p.) downregulated the OVA-
specific antibody IgG subclasses IgG1 and IgG2b and reduced the
growth of Th1 and Th2 cytokines as well as restrained in-vivo
splenocytes proliferation (Song et al., 2021).
It was reported that the pretreatment with DAP (at 1, 10, 20,
and 40 µM) improved the cell viability in rat insulinoma (INS-1)
cells that were previously exposed to streptozotocin (STZ) as
compared to INS-1 cells (Negative control). It also improved the
insulin secretion in the INS-1 cells. Thus, the antidiabetic effect of
DAP relied on insulin stimulating, and antiapoptotic actions
(Vinayagam and Xu, 2017).
DAP (at 4–16 mg/kg) considerably improved the
experimental colitis by suppressing the colonic inflammation,
improving colonic integrity, and restoring the immune and
metabolic homeostasis. It increased the abundance of short-
chain fatty acid producing microbiota of gut that were
responsible for the increased development of T
reg
cells and
the reduced pro-inflammatory T
h
17 cell differentiation (Ji et al.,
2019).
Previously, it was found that the DAP inhibited melanin
biosynthesis by suppressing the expression of microphthalmia
associated transcription factor responsible for melanogenesis,
and also inhibited melanogenic enzymes such as tyrosine and
tyrosine-related proteins in B16F10 cells. DAP downregulated
the phosphorylation of kinases such as PKA, ERK, mitogen and
stress activated protein kinase (MSK)-1 and cAMP response
element binding protein (CREB). It inhibited the melanin
synthesis, and exhibited the anti-pigmentation activity by
modulating PKA/CREB, and ERK/MSK1/CREB pathways
(Nam et al., 2022).
DAP possesses analgesic action. In a previous study, DAP at
10 mg/kg averted reserpine induced fibromyalgia (chronic pain
syndrome along with depression) in mice. DAP effectively
averted fibromyalgia by downregulating monoamine oxidase-
A (MAO-A), glutamate level, IL-1β, and TNF-αwhile elevating
the GSH, dopamine, serotonin and norepinephrine levels (Singh
et al., 2021b).
A previous study reported that DAP reduced Toll-like
receptor-4 (TLR4) expression and suppressed the activation of
the NF-κB signaling pathway in acute pancreatitis showing its
potential to avert pancreatitis (Liu et al., 2016b). DAP as an
emulsion [locus bean gum (0.5%) and sodium alginate (1.5%)] is
used in the food industry as an additive, preservative and
packaging material. It is used as a preservative because of
antimicrobial and antioxidant properties (Liu et al., 2021;
Cheng, 2022).
Wen et al. investigated the percutaneous absorption of DAP
in rat abdominal skin using various chemical enhancers. The
experiment was performed using isopropyl myristate as a vehicle
while other enhances of O-acylmenthol derivatives were
synthesized from which only M-LA was explored to improve
the DAP permeation. Its effects were also pronounced when DAP
was used with span 80 (Wen et al., 2009).
Yang and his coworkers investigated the effect of DAP on
ischemia repurfusion (I/R) injury. DAP (at 2.5, 5,10, and
20 mg/kg) decreased the myocardial I/R injury with improved
cardiac function in treated cells. It reduced the apoptosis,
oxidative stress, and inflammation both under in-vitro and in-
vivo experiments. It also reduced the risk of ventricular
arrhythmias by downregulation of TLR4, MyD88, and NF-κβ
in I/R mice (Yang et al., 2021b).
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In another study, DAP exhibited anti-angiogenic properties
through inhibition of different stages of angiogenesis such as
migration, invasion, and tube formation. It suppressed the NF-
κB pathway, TNF-αinduced IκBαdegradation and translocation
of the NF- κB-p65 protein. It significantly decreased the
expression of c-Src, FAK, ERK1/2, Akt, VEGFR2, Inos, and
MMP2 as well as induced apoptosis (Kumar et al., 2016b).
DAP also exhibited the protection against LPS induced
inflammatory bone destruction in murine osteolysis model. It
inhibited RANKL-induced osteoclast differentiation, fusion and
bone resorption. It inhibited the activation of ERK and
NFAT
c
1 signaling cascade, so it has the potential to be used
for the treatment of inflammatory osteolysis (Wu et al., 2019).
Zhou and Zhang et al. investigated the in-vitro integration of
DAP-Cu (II) complex with calf thymus DNA (ctDNA). The
findings exhibited that the DAP and Cu
2+
exerted synergistic
pharmacological actions (Zhou et al., 2016).
4 Toxicity studies
A previous study reported the Minimum inhibitory
concentration (MIC of DAP (25 μg/ml) against highly resistant H.
pylori isolated from human gastric antrum. Using the Cell Counting
Kit-8 (CCK-8), the sub-minimum inhibitory concentration (MIC) of
DAP was studied in GES-1 cells. DAP was well tolerated by GES-1
cells, and there was insignificant difference on cytotoxic effect of DAP
by culture media conditions (Wang et al., 2019). Furthermore, the
acute toxicity of DAP was evaluated using the Bacterial reverse
mutation assay (Ames test), which revealed no genetic toxicity.
Bone marrow micronucleus test revealed that DAP) had no effect
on mouse bone marrow cells at various concentrations (0.75, 1.5, and
3 mg/kg). DAP was prepared for an acute skin allergy test at a final
concentration of 4 mg/ml, indicating that it is non-allergenic. A local
mucosa stimulation test was done on the oral mucosa of rabbits which
revealed no oral mucosa ulceration, erosion, erythema and irritation
caused by DAP.
In mice, the maximal oral toxic dose of DAP was greater than
100 mg/kg (Nanzhen et al., 2018). Hippocampal HT-22 cell line was
used with 5 mM glutamate and different concentrations of DAP.
After 12 h of incubation, 100 mΜDAP protected HT-22 cells in
concentration dependent manner against glutamate toxicity (Du
et al., 2014). BV2 microglia were used and treated with 0-160 μM
concentrations of DAP which showed insignificant change in cell
survival rate (Yu et al., 2014a). Indeed, the in-vitro and in-vivo
studies confirmed that DAP was devoid of any significant toxicity at
pharmacologically relevant concentrations.
5 Structure activity relationship
There is a series of DAP derivatives ranging from 1-22 that
showed moderate inhibitory or activating action on GPCRs
resultantly responsible for copious pharmacological activities.
The activity of GPCRs depends on the chemical alteration of
hydroxyl groups at the C-7, C-8, and C-3/C-4 positions of DAP
(Satô and Hasegawa, 1969;Wang et al., 2020a). The C-7 and C-8
substituents were generated through phenolic O-acylation/
O-alkylation (nucleophilic acyl/alkyl substitution), whereas the
C-3 and C-4 substituents were formed using Pechmann
condensation. DAP 2, 3, 4, 5, 15, 16, 18, 19, and 20 cause
moderate activation on GPCRs while 3-5, and 19 exhibit
profound activation with EC50 of 1.18–1.91 nM (Wang et al.,
2020a).
Substitution at C-3 or C-4 of DAP produces different
derivatives. The anti-oxidant activities of different DAP
derivatives were evaluated. The catechol group was considered
a key pharmacophore for the anti-oxidant activity. The
introduction of electron-withdrawing hydrophilic group at the
C-4 position increased the anti-oxidant potential but it was not
observed with C-3 substitution. Introduction of the hydrophobic
phenyl group produced negative effect on the anti-oxidant
activity at C-3 and C-4. The 4-carboxymethyl DAP exerted
the most powerful anti-oxidant activity. It also displayed
strong metabolic stability (Dar et al., 2015;Xia et al., 2018b).
6 Discussion
The inclusion of multiple research investigations on
pharmacological mechanisms of DAP in treating numerous
chronic conditions was a main emphasis of the current study.
Consequently, the review offers a comprehensive outline of the
prospective medicinal uses of this phytochemical. The current study
uncovered the pharmacological and therapeutic benefits of DAP for
human health. Several medicinal plants are rich source of bioactive
compounds which exhibit numerous pharmacological activities,
minimal side effects, and the potential source of novel drugs for
the treatment of diseases. Many drugs currently available in the
market have either been directly or indirectly derived from the
traditional plants. By reviewing the available information, it was
determined that DAP was a bioactive constituent with a variety of
effects against bacterial microorganisms, inflammation, malarial
parasite, viral infections, cardiovascular diseases, rheumatoid
arthritis, kidney disorders, cerebral disorders, various cancers,
lung infections, melanogenesis, bowel diseases, oxidative stress,
diabetes mellitus, and others. However, its impact against
different cancer types are particularly important in the therapy of
numerous malignant diseases.
DAP is a simple coumarin derivative with a variety of
therapeutic benefits in preclinical research and mostly isolated
from the Daphne genus.Thus, there are areas to work on the
isolation from other genus and synthesis in laboratory.
Furthermore, identification of various intermediate metabolites
may broaden the range of biologically active compounds to be
tested for various ailments.
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In numerous preclinical researches, DAP’s neuroprotective
effects have been thoroughly documented. Studies have
demonstrated the protective effect of DAP against ischemic/
reperfusion injury, and spatial memory impairment caused by
CUS, NMDA-induced excitotoxicity, glutamate-excited HT-22
cells, as well as cerebral ischemia (Liao et al., 2013;Du et al., 2014;
Yang et al., 2014;Liu et al., 2016a;Berman and Bayati, 2018). The
neuroprotective effect can be significantly achieved by the
modification of the TLR-4/NF-κB, HSP70, JAK/STAT, and
Nrf-2/HO
−1
downstream pathways (Figure 4). DAP’s potential
as a neuroprotective compound could further be supported in
preclinical research by examining its impact on the Aβamyloid,
tau, Parkinson’s, and Huntingtin proteins.
In cancer, cells divide uncontrollably and metastasize other
tissues. The findings of current review indicated that the DAP
was pharmacologically effective against different type of cancers
including cancers of kidney, liver, ovary and leukemia via
inhibiting the proliferation and promotion of apoptosis
making it a viable adjuvant in the treatment of cancer.
The inflammation and oxidative stress are increased in severe
joint inflammatory conditions such as osteoarthritis and RA. The
upsurge of pro-inflammatory cytokines, NF-κB,
myeloperoxidase, iNOS, NOS, COX-2, and other mediators
worsen the disease (Prasad et al., 2021). Thus, the analysis of
previous studies indicated that the DAP was effective in retarding
the progression of RA and other inflammatory diseases even at
low doses via inhibiting the pro-inflammatory cytokines, NF-κB
and MMP levels, and restored the protein expressions.
The DAP and derivatives were effective against several
bacterial infections as well as different malarial parasites via
suppressing the metabolic functions of these microbes as
demonstrated by diverse in-vitro and in-vivo studies. Such
studies are need to be extended to antibiotic resistant
microbes so as to treat and prevent drug resistant infections.
The hepatoxicity could be due to infections, malignant diseases
and drug therapy. Previous investigations indicated that the DAP
had antioxidant potential and inhibited lipid and protein
oxidation, decreased ROS, and pro-inflammatory cytokines to
prevent and treat hepatotoxicity (Khan et al., 2019).
Several intriguing pharmacological investigations on DAP
against different diseases have outlined the mechanisms
supporting the use of DAP as supplementary therapy. Further
research is needed on long-term toxicity, information on
potential medication interactions and its effect as adjuvant
therapy against chronic diseases. To further support the
clinical value in medical practice, supplementary clinical trials
are also required. Previous studies show that DAP is a suitable
candidate for the drug development.
7 Conclusion and future perspectives
This review provides pertinent information regarding the
pharmacological aspects of DAP to explore its hidden potential
as it targets various molecular and cellular pathways to combat
numerous inflammatory disorders, infectious diseases,
neurological disorders, hepatotoxicity, nephrotoxicity,
psoriasis, diabetic nephropathy, leukemia, and other cancers.
DAP exhibited no mutagenic effect, allergenic action,
sensitization, mucosal irritation, erythema, and mortality in
toxicity studies. The information summarized above will be
used for the development of an effective formulation for the
treatment of various ailments without significant adverse/toxic
effects.
On the basis of literature reviewed, it has been found that
DAP exhibited remarkable pharmacological profile and it could
be used as a treatment or adjuvant for the treatment of different
disorders. Thus, still its biosynthesis and structure activity
relationship should be critically analyzed. The effect of DAP
on H. pylori was investigated but other microorganisms causing
gastrointestinal infections should be investigated to reduce their
impact on human and animal health. The development of
nanoformulations of DAP need attention to enhance its
therapeutic effect and half-life. The synergistic effect of DAP
with commercially available drugs should be studied to
enhancing their effects in treating various diseases. As DAP
attenuates the activation of microglia that plays a crucial role
in the pathogenesis of multiple neurodegenerative diseases, this
evidence suggests the possibility of DAP as treatment option for
Huntington and Parkinson’s disease. Further research should be
implicated to explore its various bioactivities and mechanisms.
Toxicity study of DAP and its derivatives should be conducted in
detail to assure their safety in human and animals (Lu et al.,
2021).
Author contributions
AS and MA: Conceptualization, visualization, review,
supervision, analysis, review, and editing. MJ, AX: Literature
search, collection of data, writing original draft.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Frontiers in Pharmacology frontiersin.org14
Javed et al. 10.3389/fphar.2022.993562
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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