Biomedicine & Pharmacotherapy 176 (2024) 116772

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Antioxidant effects of Paeoniflorin and relevant molecular mechanisms as

related to a variety of diseases: A review
Yansong Lu 1, Lu Yin 1, Wei Yang , Ze Wu , Jun Niu *
Department of Dermatology, General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenhe District, Shenyang 110016, China

A R T I C L E I N F O A B S T R A C T

Keywords: Paeoniflorin (PF), which is the main component of the Paeonia lactiflora Pall extract, is one of the traditional
Paeoniflorin Chinese medicines. The pharmacological effects associated with PF include antioxidant, immunomodulatory,
Oxidative stress anti-inflammatory, anticancer, antidepressant-like and neuroprotective effects. Our previous studies had
Antioxidant effect
revealed that PF protected melanocytes and inhibited photodamage through the suppression of oxidative stress
Clinical diseases
(OS). As OS plays a vital role in the progression of a variety of diseases, the capacity for PF to suppress OS may
exert important effects upon them. However, no review exists on these antioxidant effects of PF as related to
various diseases. Therefore, in this review we summarized studies involved with examining the antioxidant ef­
fects and molecular mechanisms of PF. Through its capacity to inhibit OS, PF has been shown to exert beneficial
effects upon several systems including nervous, cardiac/vascular, digestive, and respiratory as well as specific
diseases such as diabetes, autoimmune, pregnancy related, ocular, kidney, dermatology, along with suppression
of distal flap necrosis, postoperative adhesions, and hearing loss. Such findings provide new insights and di­
rections for future research directed at the development of PF as a natural antioxidant for the treatment of
clinical diseases.

1. Introduction a cause of several conditions including neurodegenerative diseases,

Oxidative stress (OS), which is defined as a state of imbalance be­
tween oxidation and antioxidation in the body with the excessive pro­
duction of reactive oxygenated species (ROS), is believed to be a
significant factor contributing to the progression of several diseases
[1–3]. Cells are equipped with complex antioxidant defense networks,
which can cut ROS into less toxic substances, thus maintaining cell redox
homeostasis. The nuclear factor erythroid 2-related factor 2 (Nrf2)
pathway, upregulating antioxidant enzymes such as superoxide dis­
mutase (SOD), NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme
oxygenase-1 (HO-1), plays a key role in maintaining this balance of
redox homeostasis [4–7]. As OS-induced damage has been confirmed as
cardiovascular diseases, emphysema, cataracts, and cancer [8,9], anti­
oxidation represents a crucial process that can be used in the treatment
of such conditions.
In recent years, natural antioxidants have been widely used in clin­
ical therapy, and traditional Chinese medicines with antioxidant effects
have gradually attracted increasing attention [10]. Paeoniflorin (PF) is a
monoterpenoid glycoside extracted from Paeonia lactiflora Pall, a
traditional Chinese herb [11]. PF exerts a variety of pharmacological
effects, including antioxidant [12], immunomodulatory,
anti-inflammatory [13], anticancer [14], antidepressant-like [15], and
neuroprotective effects [16], etc. However, no review exists on the
antioxidant effects of PF as related to different diseases. In this report we

Abbreviations: PF, Paeoniflorin; OS, Oxidative stress; ROS, Reactive oxygenated species; Nrf2, Unclear factor erythroid 2-related factor 2; SOD, Superoxide
dismutase; P, NAD; NQO1, H:quinone oxidoreductase 1; HO-1, Heme oxygenase-1; LDH, Lactate dehydrogenase; MDA, Malondialdehyde; LD, Lactate dehydro­
genase′; SAH, Subarachnoid hemorrhage; GSH-Px, Glutathione peroxidase; CAT, Catalase activity; TLR4, Toll-like receptor 4; JAK2, Januskinase 2; STAT3, Signal
transducer and activator of transcription 3; PD, Parkinson’s disease; AD, Alzheimer’s disease; HIF-1α, Hypoxia inducible factor-1α; VEGF, Vascular endothelial
growth factor; I/R, ischemia/reperfusion; IRS, Insulin receptor substrate; GSK, Glycogen synthase kinase; SIRT1, Sirtuin-1; FOXO1a, Forkhead box O1; IBD, In­
flammatory bowel disease; AGEs, Advanced glycation end products; RPE, Retinal pigment epithelial; CKD, Chronic kidney disease; PGC-1α, Peroxisome proliferator-
activated receptor gamma coactivator-1α; UVA, Ultraviolet A; UVB, Ultraviolet B; SG, Sweat glands; NF-κB, Nuclear factor kappa-B.
* Corresponding author.
E-mail address: niujun06@126.com (J. Niu).
1
These authors contributed equally to this work and should be considered co-first authors.

https://doi.org/10.1016/j.biopha.2024.116772
Received 29 January 2024; Received in revised form 13 May 2024; Accepted 17 May 2024
Available online 28 May 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y. Lu et al.
review and summarize the data on the antioxidant effects (Fig. 1) and
molecular mechanisms (Table 1 and Fig. 2) of PF relating to various
diseases. Such information will be critical for the future development of
PF as a natural antioxidant in the treatment of clinical diseases.
2. Inhibitory effects of PF as an antioxidant in diseases of the
nervous system
Due to the high oxygen consumption, nervous system is particularly
susceptible to OS injury, which could induce irreversible damage to
macromolecules [17]. As an antioxidant, PF may be a promising drug for
the treatment of neurological disorders.
2.1. Brain injury
Previous study has showed that OS is an important cause of tissue
damage after cerebral ischemic injury, such as ischemic stroke [18–20].
Pretreatment of PF significantly attenuated brain ischemic injury via
inhibiting OS through the inhibition of Toll-like receptor 4 (TLR4)/
Nuclear factor kappa-B (NF- κB) and activation of Janus kinase 2
(JAK2)/signal transducer and activator of transcription 3 (STAT3)
signaling pathway [21–23]. In the injured PC12 cells, the treatment of
PF enhanced the levels of p‑JAK2 and p‑STAT3 in a dose-dependent
manner and inhibited phosphorylation of p38MAPK [24]. In a rat
model of acute cerebral infarction, PF reduced the degree of tissue
damage, increased SOD activities, lactate dehydrogenase (LDH) and
Na+-K+-ATPase, while decreasing the contents of malondialdehyde
(MDA) and lactate dehydrogenase (LD) [25]. This effect of PF also
appeared in Subarachnoid hemorrhage (SAH). OS induces the damage of
the neurovascular unit via protein breakdown, lipid peroxidation and
DNA/RNA damage in early brain injury after SAH. Intraperitoneal in­
jection of PF reduced the OS by decreasing expressions of ROS and MDA
and increasing expressions of SOD, glutathione peroxidase (GSH-Px) and
catalase activity (CAT). As a result, the early brain injury after SAH were
Fig. 1. Antioxidant effects of PF in diseases. Through its capacity to inhibit OS, PF has been shown to exert beneficial effects upon several systems including nervous,
psychosis, cardiac/vascular, digestive, and respiratory as well as specific diseases such as diabetes, autoimmune, pregnancy related, ocular, kidney, dermatology,
along with suppression of distal flap necrosis, postoperative adhesions, and hearing loss.
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Biomedicine & Pharmacotherapy 176 (2024) 116772
reduced [16,26].
2.2. Neural degenerative diseases
Different from the brain injury, aging is the major risk factor for the
neural degenerative diseases including Parkinson’s disease (PD) and
Alzheimer’s disease (AD) [27]. Currently, there is no strategy to reverse
these diseases. However, increased expressions of OS markers were
found in the brains of PD patients. Pretreatment of PF significantly
reduced the production of ROS and lipid hydroperoxides, attenuated the
translocation of NF-κB without regulating phosphorylation of ERK1/2,
JNK, and p38, and enhanced the content of GSH in PC12 cells exposed to
the dopamine degenerating drug, 6-hydroxydopamine. In this PD model,
PF exerted these protect effects, in part, by inhibiting the
ROS/PKCd/NF-kB pathway [28]. PF also suppressed OS in
MPP+-challenged SH-SY5Y cells via ERK1/2-mediated Nrf2 activation
[29], and suppressed H2O2 induced OS injury by activating the phos­
phatidylinositol 3 kinase (PI3K)/protein kinase B(Akt-1) pathway in
neural progenitor cell [30]. The phosphorylation of Akt-1 was abolished
by the inhibitor of PI3K upon OS. In an AD model, PF protected SH-SY5Y
cells from Aβ-induced cell injury via inhibiting oxidative injury and
mitochondrial dysfunction, and reversed the learning and memory
deficits induced by streptozotocin [31–34]. In the C. elegans AD model,
PF alleviated the increased levels of ROS that contribute to the in vivo
toxicity of Aβ [35]. Zhai, A., et al. found that PF could reduce HT-22 cells
OS induced by H2O2, which was associated with a decrease in miR-135a
via JAK2/STAT3 and ERK1/2 pathway regulation [36]. PF could sup­
press ferroptosis and then reduce OS by binding to p53, that enhanced
the cognitive and behavioral abilities of AD mice [37].
These studies showing an essential role of PF in the treatment of
neural degenerative diseases. However, there are still limitations need to
resolve in future, such as the low liposolubility of PF, making it difficult
to cross the blood-brain barrier. Enhancing the delivery of PF to the
brain is the key for the future research.
Y. Lu et al. Biomedicine & Pharmacotherapy 176 (2024) 116772

Table 1
Summary of the antioxidant activities of PF. The antioxidant effects of PF in diseases, disease model, the dose of PF, the time points of evaluation, and regulation of
oxidative stress-related mechanisms were concluded.
Disease Disease model Animal and/or cell Dose of PF Time points Regulation of oxidative stress- Ref
of related mechanisms
evaluation

Nervous Ischemic stroke Oxygen‑glucose PC12 cells 25, 50, 100 and 48 h Activating the JAK2/STAT3 [23]
diseases deprivation/ 200 µM pathway
reoxygenation
Brain injuries H2O2 Schwann cells 0, 10, 20, 30, 50, 24 h Inhibiting phosphorylation of [24]
100, 200, and 300 p38MAPK
μmol⋅L− 1
Neonatal hypoxic Hypoxia/ischemia Rat pups ig. 6.25, 12.5, or 11d Inhibiting TLR4/NF-kB [21]
brain injuries 25 mg/kg
Acute Cerebral Middle cerebral artery Rats ig. 60, 120, 240 mg/ 7d Increasing the activities of [25]
Infarction occlusion kg SOD, LDH and Na+-K+-
ATPase, and decreasing the
contents of MDA and LD
Subarachnoid Endovascular perforation Rats/ Cortical i.p.5 mg/kg, twice 3d/24 h Up-regulating the Nrf2/ HO-1 [16]
hemorrhage neuron per day, /30 and pathway
100 µM
Brain injuries Lipopolysaccharide Mice BV-2 microglial 100 and 200 μM 1h Regulating NF-κB pathway [22]
cells
Nerve injuries H2O2 PC12 cells 80 µM 6h Reducing apoptosis and ROS [26]
accumulation
Parkinson’s disease MPP+/MPTP Mice/ SH-SY5Y cells ig. 50 mg/kg/3 µM 2w/24 h Through Nrf2-Dependent [29]
glutathione biosynthesis
mechanisms
Parkinson’s disease 6-hydroxydopamine PC12 cells 3, 10, or 30 µM 24 h Inhibiting ROS/PKCd/NF-kB [28]
pathway
Neural progenitor H2O2 Neural progenitor 200 μg/ml 4h Activating PI3K/Akt-1 [30]
cell injuries cells pathway
Alzheimer’s disease Streptozotocin Mice i.p.10 mg/kg 21d Attenuating mitochondrial [31]
dysfunction
Alzheimer’s disease H2O2 Hippocampal HT-22 100, 150, 200 and 24 h Down-Regulating MicroRNA- [36]
cells 300 µM 135a
Alzheimer’s disease Aβ (1–42) C. elegans strain 500 µM 36 h Regulating oxidative and heat [35]
shock stress responses
Alzheimer’s disease Aβ (25–35) SH-SY5Y cells 2, 10, 50 µM 24 h Preventing Mitochondrial [32]
Dysfunction
Alzheimer’s disease Aβ (1–42) Rats i.p.15 and 30 mg/ 20d Regulating the pathway [33]
(kg day) mediated by nerve growth
factor
Alzheimer’s disease Aβ (1–42) Rats i.p.7.5, 15 and 21d Regulating calcium [34]
30 mg/ (kg day) homeostasis
Alzheimer’s disease APP/PS1 double Mice/ PC12 cells ig.5 and 10 mg/kg/ 5w/4 min Suppressing ferroptosis and [37]
transgenic/ Erastin 2.5 µM and 5 µM then reduce OS by binding to
p53
Psychosis Schizophrenia MK-801 / H2O2 Mice /Primary ig. 10,50,100 mg/kg 6w/27 h Regulating the OS and [40]
cultured / 2 µg/ml and apoptosis pathways
hippocampal 200 ng/ml
neurons
Depression Forced swimming test Rats ig. 10 mg/kg 25 h Elevating plasma SOD and [43]
reducing MDA
Depression Corticosterone PC12 cells 1, 10 and 50 µM 48 h Up-regulating NGF expression [41]
Depression Glutamate 1, 10 and 50 µM 26 h Inhibiting Ca2+ overload [42]
Cardiac and Myocardial injury Lipopolysaccharide Mice i.p.20 mg/kg 3d Inhibiting p38 MAPK/NF-KB [48]
vascular p65
diseases
Myocardial ischemia Operation Rats ig.30 and 60 mg/kg 7d Inhibiting the expression of [49]
reperfusion injury apoptosis-related signaling
pathway
Cardiomyocyte Acrolein H9c2 100 µM 16 h Decreasing ROS production [51]
injury cardiomyocytes and down regulating caspases
cascade reaction
Cardiomyocyte Aconitine H9c2 80 mg/ml 0.5/1 h Decreasing MDA and lactate [50]
injury cardiomyocytes dehydrogenase
Cardiac hypertrophy Angiotensin II H9c2 50, 100, 200 and 24 h Increasing Nrf2/HO-1 and [52]
cardiomyocytes 400 μM PINK1/Parkin expression
Cardiomyocyte Doxorubicin H9c2 100 µmol/L 26 h Downregulating microRNA-1 [53]
injury cardiomyocytes expression
Cardiomyocyte Doxorubicin H9c2 1, 10, or 100 µmol/L 26 h Inhibiting of NOX2, NOX4 [54]
injury cardiomyocytes expression, and NOX activity
Vascular remodeling Platelet derived growth Vascular smooth 50, 100, and 200 µM 13, 25 or Regulating ROS-mediated [56]
diseases factor-BB muscle cells 49 h ERK1/2 and p38 pathways
Coronary disease Advanced oxidation Human umbilical 200 µM 25 h Blocking the ROS-HIF-1α/ [57]
protein products vein endothelial cells VEGF pathway
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Table 1 (continued )
Disease Disease model Animal and/or cell Dose of PF Time points Regulation of oxidative stress- Ref
of related mechanisms
evaluation

Vascular damage H2O2 Human umbilical 10, 62.5, 250, and 26 h Scavenges Intracellular [58]
vein endothelial cells 1000 µmol/L ROS，repressing LDH
leakage, MDA production,
and restoring the activities of
total SOD and GSH-Px
Thrombosis A photo-chemical Human umbilical 10, 50, 250 mg/ml / Inhibiting of arachidonic acid [59]
reaction vein endothelial cells metabolism, the increase of t-
PA activity, and the protective
effect against free radical
Digestive Acute liver injury Lipopolysaccharide Rats i.p.60 mg/kg 7d Regulating the SIRT1/ [70]
system FOXO1a/SOD2 signaling
diseases
Hepatic fibrosis Carbon tetrachloride Mice ig. 100 mg/kg 1w Upregulating of heme [68]
oxygenase-1
Non-alcoholic fatty High-fat diet Rats ig. 20 mg/kg 4w Regulating the insulin [67]
liver disease pathway IRS/Akt/GSK3β
Hyperlipidemia High-fat diet Rats ig. 100, 12w Reducing liver MDA levels, [66]
300,500 mg/kg up-regulating SOD and Nrf2
levels
Hepatic I/Rinjury Operation Mice 5、10、20 mg/kg 24 h Decreasing the e expressions [65]
injected via the tail of apoptosis-associated
vein proteins
Liver inflammation Lipopolysaccharide Rats i.p.2.5, 5, or 10 mg/ 20d Increasing SOD, CAT and GPx [69]
kg levels as well as decreasing
GOT, GPT, LDH and MDA
levels
Cholestasis Alpha- Rats ig.0.2, 0.1 or 0.05 g/ 10d Activating Nrf2 through [72]
naphthylisothiocyanate kg PI3K/Akt-dependent pathway
Cholestasis Alpha- Rats ig.0.1 and 0.2 g/kg 10d Scavenging ROS via [73]
naphthylisothiocyanate inhibiting NADPH oxidase 4
expression
Cholestatic Hepatic Alpha- Mice/ LO2 ig.75, 150, and 10d/24 h Protecting hepatic depending [74]
Injury naphthylisothiocyanate cells 300 mg/kg/ 0, 20, Nrf2
and 100 µM
Inflammatory bowel Lipopolysaccharide Caco-2 cells 10, 50, 100 μM 24 and 48 h Inhibiting NF-κB by activating [77]
disease Nrf2/HO-1 pathway
Intestinal I/R Operation/hypoxic and IEC-6 cells ig.50 and 100 mg/ 3d/3, 6, 12, Decreasing MDA and [76]
reoxygenation kg /6.25, 12.5, 25, and 24 h increasing SOD and GSH
50, 100 and 200 μM
Respiratory Acute lung injury 5% sodium taurocholate Rats ig.40 mg/kg 24 h Activating the Nrf2/ARE [80]
diseases signaling
Asthma Ovalbumin Mice ig.10, 25 or 50 mg/ 4d Affecting glycolysis in asthma [82]
kg
Asthma Ovalbumin Mice ig.50 mg/kg 1w / [81]
Chronic obstructive Cigarette Smoke Rats 12, 24 and 48 mg/ 36w Quenching ROS and [83]
pulmonary disease kg upregulating antioxidant
enzymes via an Nrf2-
dependent mechanism
Radiation-induced γ-rays Human endothelial 50, 100 and 25 h Regulating the Nrf2/HO-1 [79]
lung injury cell lines 200 μg ml− 1 pathway
Diabetes and Diabetic cataracts High glucose Human lens 10 µM 24 h Upregulating SIRT1 [90]
complications epithelial SRA01/04
cells
Diabetic peripheral High glucose RSC96 cells 10 µM 24 h PF decreasing mitochondrial [86]
neuropathy ROS while increasing mtDNA
and mitochondrial membrane
potential
Diabetic peripheral High glucose RSC96 cells 1, 10 and 100 μM 48 h Activating Nrf2/ARE pathway [87]
neuropathy and Bcl-2-related apoptotic
pathway
Diabetic foot ulcer Streptozotocin /high Rats/ Human ig.15 and 30 mg/kg 16d/48 h Accelerating wound healing [88]
glucose immortalized /100 μM through the Nrf2 pathway
keratinocytes cells
Diabetic Streptozotocin/ high Mice/ ig. 20 and 70 mg/ 8w/- Alleviating myocardial [89]
cardiomyopathy glucose cardiomyocytes kg/- damage, resisting OS and
ferroptosis via Nrf2
Vascular Endothelial Streptozotocin /high Rats/Human ig.0.01 g/kg 6w/8d Repressing PKCβ1 protein [94]
Injuries glucose umbilical vein /100 μM level
endothelial cells
Diabetes mellitus Streptozotocin Pancreatic β-cells 20, 40, 80 μM 26 h Inhibiting the p38 MAPK and [85]
JNK signaling pathways
Diabetic osteopathy Methylglyoxal Osteoblastic MC3T3- 0.01, 0.1 and 1 μM 49 h Upregulating glyoxalase [92]
E1 cells system and mitochondrial
function
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Table 1 (continued )
Disease Disease model Animal and/or cell Dose of PF Time points Regulation of oxidative stress- Ref
of related mechanisms
evaluation

Diabetic Advanced glycation end Rat HBZY-1 10− 6, 1 0− 5 and 48 h / [93]

nephropathy products mesangial cell line 10− 4 M
Autoimmune Rheumatoid arthritis Collagen-induced Rats ig.7.5 mg/kg 20d Regulating apoptosis via [96]
disease arthritis AMPK-mediated
mitochondrial fission
Rheumatoid arthritis Freund’s complete Rats i.p.5, 10 and 2 3w Inhibiting inflammation and [97]
adjuvant 0 mg/kg altering to COX-2 expression
Radiation-induced γ-rays Thymocytes 50，100，200 μg/ 24 h Scavenging ROS and [95]
thymocytes injury ml attenuating the activation of
the MAPK
Lymphocytes / Murine T-lineage 500 mg/ml 1–4 h or Reducing mitochondrial [98]
apoptosis cells and human T- 2–6 h membrane potential and
cell leukemia Jurkat increasing ROS
cells
Pregnancy Pregnancy-induced NG-nitro-L-arginine Rats/ human i.p.100 and 300 mg/ 17days/ Upregulating SIRT1 [100]
related hypertension methyl ester / H2O2 umbilical vein kg/ 50, 100 and 24 h
disease endothelial cells 200 μM
Ovarian I/R injury Operation Rats 25, 50 and 100 mg/ 30 min Increasing SOD and GSH [101]
kg levels as well as decreasing
MDA level
In vitro maturation Benzo(a)pyrene Porcine oocytes 0.1 mM / Activating the SHH signaling [102]
of porcine oocytes pathway, inhibiting ROS
production, and increasing
mitochondrial membrane
potential
Prenatal stress Glutamate Rats/ human 15, 30 and 60 mg/ 4w，24 h Regulating Nrf2/HO-1 [103]
neuroblastoma cell kg/ 10− 6, 10− 5, signaling pathway
SH-SY5Y 10− 4 M
Ocular diseases Age-related macular All-trans-retinal Human retinal 50, 100 and 200 μM 18 h Activating AMPK in a Ca2+/ [105]
degeneration pigment epithelium CaMKII-dependent manner
cells
Age-related macular H2O2 Human retinal 50,100 and 200 μg/ 24 h Decreasing ROS production [104]
degeneration pigment epithelium ml and caspase-3 activity, and
cells p38MAPK and ERK
phosphorylation
Hearing loss Cisplatin-induced Cisplatin Mice/ spiral ganglion i.p.30 mg/kg / 30 7d/50 h Decreasing ROS, increasing [107]
ototoxicity neuron μmol/L putative kinase protein 1, and
reducing apoptosis
Hearing loss Neomycin Mice/cochlear i.p.30 mg/kg / 30 7d/26 h Inhibiting ERK signaling [108]
explants μmol/L activation
Kidney diseases Chronic kidney 5/6 nephrectomized/ Rats/ mouse C2C12 ig.25 and 50 mg/ 7w/48 h Regulating AMPK/SIRT1/ [110]
disease induced TNF-α myoblasts kg/ 25 and 50 μM PGC-1α-mediated pathway
skeletal muscle
atrophy
Hypoxia/ COCL2 Human proximal 50, 100 and 200 µM 28 h Inhibiting apoptosis [111]
reoxygenation tubular epithelial and repressing oxidative
injury cells damage via Keap1/
Nrf2/HO-1 pathway
Skin diseases Photodamage Ultraviolet B Human immortalized 25、50 and 100 µM 26 h Inhibiting the ROS-p38-p53 [113]
keratinocytes cells pathway
Photodamage Ultraviolet A Human dermal 200, 400 and 24 h Regulating Nrf2/HO-1/NQ- [114]
Fibroblasts 800 μM O1 signaling pathway or
PLIN2
Vitiligo H2O2 Melanocyte 50 µM 24 h Activating JNK/Nrf2/HO-1 [115]
pathway
Bromhidrosis / Rats/primary human 2.5 mg/kg via foot 6, 24, 48 Associating with ROS [116]
sweat gland cells injection / 9.530 µM and 72 h production, apoptosis, and
/24 h autophagy.
Distal flap Skin flaps surgery Surgery Rats i.p.20 and 50 mg/kg 7d Promoting vascular [119]
necrosis hyperplasia, inhibiting
pyroptosis, and down-
regulating inflammation.
Skin flaps surgery Tert-butyl hydroperoxide Rats/ human ig. 10 mg/kg/ 0, 5, 7d/24 h Regulating Nrf2/HO-1 [118]
umbilical vein 10, and 20 μM Pathway
endothelial cells
Postoperative Postoperative Operation Rats ig.10, 20 and 7d Inhibiting inflammatory [121]
adhesions adhesions 40 mg/kg actions

3. The inhibitory effects of PF as an antioxidant in psychosis
The psychosis is often associated with notable changes in OS markers
[38] and the role of OS in the development of major depressive disorder
is unequivocally established [39]. In MK-801-treated mice, PF increased
SOD and decreased MDA levels, then rescued schizophrenia -like be­
haviors [40]. Mao, Q. Q., et al. reported that PF protected PC12 cells
from corticosterone-induced and glutamate-induced neurotoxicity by
inhibiting OS and Ca2+ overload, while increasing nerve growth factor
expression [41,42]. PF showed this anti-depressive effect by elevating

5
Y. Lu et al.
Fig. 2. The main pathway of PF as an antioxidant. The capacity to inhibit OS serves as the foundation for these beneficial effects of PF, with these effects mainly
being related to the Nrf2 pathway, including Nrf2-KEAP1, Nrf2/HO-1, Nrf2/ARE, Nrf2/HO-1/NQ-O1 and JNK/Nrf2/HO-1. However, the TLR4/NF-kB, JAK2/STAT3,
ROS/PKCd/NF-kB, PI3K/Akt-1, JAK2/STAT3, ERK1/2, NF-KB/p65, and ROS/PLIN2 pathways are also involved in the process of OS inhibition by PF.
plasma SOD and reducing MDA levels in rats subjected to a forced
swimming test [43]. Through antioxidant effects, PF ameliorated the
depressive-like behaviors in depression models.
4. Inhibitory effects of PF as an antioxidant in cardiac and
vascular diseases
Substantial evidence shows that OS is a critical factor in several
cardiac and vascular diseases, such as hypertension [44], myocardial
infarction and atherosclerosis [45]. The effects of PF as an antioxidant in
the treatment of several cardiac and vascular diseases by inhibiting OS
are as follows.
4.1. Myocardial injury
Myocardial oxidative injury can result from a variety of factors
including coronary intervention, thrombolytic therapy, and environ­
mental pollutants, which induced the accumulation of ROS beyond the
cellular threshold that disrupts the normal physiological function of
cardiomyocytes [46,47]. Wang, Jia et al. reported that PF decreased
MDA, GSH and ROS in septic mice, and PF could diminish myocardial
injury via suppressing p38 MAPK/NF-KB p65, and the phosphorylation
activity of p38 MAPK and p65 was inhibited [48]. PF pretreatment
protected rats from myocardial ischemia reperfusion injury by reducing
levels of OS through increasing SOD activity along with decreasing MDA
levels [49]. PF also reverses cardiotoxicity as induced with aconitine and
acrolein via decreasing MDA, LDH and ROS [50,51], and restores the
expression of Nrf2/HO-1 and PINK1/Parkin to alleviate cardiac hyper­
trophy induced by AngII in H9c2 cardiomyocytes [52]. Doxorubicin, a
cardiotoxic anti-tumor drug, could induce cardiomyocyte apoptosis,
which could be inhibited by PF via decreasing the reduction of ROS.
Moreover, these reductions in ROS were closely related to the inhibitory
6
Biomedicine & Pharmacotherapy 176 (2024) 116772
effects of PF on NOX activity and NOX4, NOX2 and miR-1 expressions
[53,54].
4.2. Vascular damage
Increases in ROS within vascular endothelial cells can be due to a
variety of factors [55]. Such increases can induce an abnormal prolif­
eration of vascular smooth muscle cells and vascular remodeling which,
in turn, leads to atherosclerosis and stenosis. Recent evidence indicated
that PF could serve as a possible therapy for vascular reconstruction
diseases by inhibiting vascular smooth muscle cells proliferation
induced by platelet derived growth factor-BB via suppression of ROS
production, an effect which was associated with the reduction of the
phosphorylation of p38 and ERK1/2 [56]. PF protect human umbilical
vein endothelial cells against H2O2 and advanced oxidation protein
products as induced by OS, with the latter being associated with the
down-regulation of hypoxia inducible factor-1α(HIF-1α)/vascular
endothelial growth factor (VEGF) via ROS-NF-κB axis [57,58]. PF also
was shown to decrease free radicals, increase t-PA activity, inhibit
arachidonic acid metabolism, and further prolong thrombosis times and
reduce vascular endothelial damage. These effects are consistent with
the activation of SOD [59].
In conclusion, PF may present a promising alternative drug for the
management of cardiovascular-related disorders.
5. Inhibitory effects of PF as an antioxidant in digestive system
diseases
OS is involved in the pathogenesis of several digestive system dis­
eases, such as liver injury, cholestasis, and intestinal diseases [60]. The
effects of PF as an antioxidant in the treatment of digestive system dis­
eases by inhibiting oxidative stress are as follows.
Y. Lu et al.
5.1. Liver injury
The increase of ROS is related to the pathogenesis of hepatic fibrosis
[61–63] and ischemia/reperfusion (I/R) injury, as well as the elevation
of serum free fatty acids and insulin resistance in the liver [64]. PF has
been shown to exert a protective effect upon hepatic I/R injury by
inhibiting OS and inflammation [65]. PF can reduce MDA and
up-regulate liver SOD and Nrf2 levels which then reduces liver choles­
terol and steatosis as demonstrated in a rat model of hyperlipidemia
[66]. It has also been reported that PF modulates the insulin receptor
substrate (IRS)-1/Akt/glycogen synthase kinase (GSK)3βpathway and
ameliorates high-fat diet-induced non-alcoholic fatty liver disease by
inhibiting OS. PF treatment restored the decreasing phosphorylation of
Akt and GSK3β and the increasing serine phosphorylation of IRS-1 [67].
The capacity for PF to alleviate liver fibrosis is related to the increased
expression of HO-1 and activation of hepatic stellate cells along with an
attenuation of CCl4-induced OS [68]. In vivo, daily administrations of
PF in rats significantly ameliorates the OS as induced by LPS and di­
minishes liver dysfunction [69]. Through its ability to reduce ROS and
MDA levels and increase SOD activity, PF improves liver structure and
function in an acute liver injury model, an effect which was associated
with the sirtuin-1(SIRT1)/forkhead box O1(FOXO1a)/SOD2 pathway
[70]. This suggests that PF protects the liver from OS damage.
5.2. Cholestasis
Cholestasis is characterized by excessive ROS production and an
imbalance of the redox system [71]. Chen, Ma et al. demonstrated an
inhibitory effect of PF on OS as resulting from the capacity for PF to
alleviate alphanaphthylisothiocyanate-induced cholestasis, a mecha­
nism which appears to involve an activation of Nrf2 through the
attenuate phosphorylations of PI3K/Akt pathway [72]. In a rat model of
alphanaphthylisothiocyanate-induced cholestasis, PF attenuated chole­
static liver injury by scavenging ROS through suppressing the expression
of NADPH oxidase 4 [73], and Nrf2 is essential in this process [74].
5.3. Intestinal disease
Excessive OS, inflammatory responses and impaired intestinal bar­
rier function comprise the main features of such intestinal diseases [75],
as inflammatory bowel disease (IBD) and intestinal I/R. In a
dose-dependent manner, PF reversed the increase of MDA and decrease
of SOD and GSH as occurs in I/R-injured rats [76]. PF also inhibited
NF-κB by activating the Nrf2/HO-1 pathway in Caco-2 cells treated with
LPS. This could be blocked by the RNA interference against Nrf2. As a
result, PF inhibited tight junction protein disruption and inflammatory
responses, and regulated barrier function, prevented IBD [77].
The above evidences illustrate the important role of the antioxidative
effect of PF in the digestive system diseases.
6. Inhibitory effects of PF as an antioxidant in respiratory
diseases
Excessive ROS production, as can be induced by radiation in pul­
monary endothelial cells, plays a key role in the pathogenesis of lung
injury [78]. In addition, acute lung injury, as a common complication
associated with the early stages of severe acute pancreatitis, is also
mainly manifested by excessive OS and inflammatory responses. Yu, J.,
et al. reported that PF could protect pulmonary endothelial cells from
radiation-induced oxidative damage via the Nrf2/HO-1 signaling
pathway [79]. In a rat model of acute lung injury resulting from severe
acute pancreatitis, PF down-regulated the levels of LDH and MDA, and
up-regulated SOD levels in lung tissue. Simultaneously, PF increased
Cyt-Nrf2, HO-1 and NQ-O1 expressions, which are related to the
Nrf2/ARE signaling pathway [80]. In addition, transcriptional and
metabolomic databases for asthma have identified some potential target
7
Biomedicine & Pharmacotherapy 176 (2024) 116772
proteins of PF that may play an important role in OS [81]. PF inhibits OS
by modulating glycolysis, which in turn modulates autophagy to
enhance immunity and inflammatory responses in asthmatic mice [82].
What’s similar is that a 40 mg/kg⋅d treatment with PF was effective in
attenuating OS in chronic obstructive pulmonary disease rats by inhib­
iting ROS and increasing antioxidant enzymes through the Nrf2
pathway. In addition, the sooner PF treatment was initiated, the more
pronounced the protective effect of PF was [83]. Overall, PF as an
antioxidant plays a key role in respiratory diseases.
7. Inhibitory effects of PF as an antioxidant in diabetes and
complications
Diabetes is a metabolic disease that poses a major threat to the
human health and well-being. The excessive production of ROS induced
by hyperglycemia is an important pathogenesis of diabetes and com­
plications [84]. It is well known that a close relationship exists between
pancreatic β-cells function and the onset of diabetes. Treatment with PF
ameliorated pancreatic β-cell damage by inhibiting the JNK and
p38MAPK signaling pathways, and in streptozotocin-treated INS-1 cells,
diminished ROS, and MDA reductions along with increasing SOD ac­
tivity. These findings not only indicate that PF improves pancreatic
β-cell function by inhibiting the JNK and p38MAPK pathways but also
by inhibiting OS to maintain blood glucose levels [85]. Yang, Li et al.
reported that PF improved diabetic peripheral neuropathy by upregu­
lating thioredoxin based on 4D Label-free proteomic experiments in
Schwann cells mitochondria. This effect was associated with the ca­
pacity for PF to reduce mitochondrial ROS and enhance mitochondrial
function in a high-glucose environment [86], along with the Nrf2/ARE
and Bcl-2 pathways [87]. Moreover, experiments in vivo and in vitro
have demonstrated that PF inhibited OS through the Nrf2 pathway and
promoted wound healing in diabetic foot [88]. PF resisted OS and fer­
roptosis via Nrf2 to improve cardiac dysfunction in mice with diabetic
cardiomyopathy [89]. Whatmore, PF significantly reduced MDA and
increased SOD and GSH-Px levels in lens epithelial cells subjected to
high levels of glucose, which could be reversed by the inhibition of
SIRT1. Accordingly, it appears that PF inhibited the
epithelial-mesenchymal transition of lens epithelial cells and amelio­
rated diabetic cataracts through a combination of OS suppression and
SIRT1 upregulation [90]. In addition, PF also protected osteoblast
MC3T3-E1 cells from methylglyoxal and antimycin-induced cytotoxic
damage through inhibiting OS and improving mitochondrial function to
relieve diabetic osteopathy [91,92]. There is recent evidence indicating
that an excessive accumulation of advanced glycation end products
(AGEs) leads to an imbalance of oxidant and antioxidant systems that
can then damage kidney tissue and promote the development of
diabetic-induced nephropathy. In the experiment to evaluate the anti­
oxidant capacity of PF, Zhang, Feng et al. found that PF significantly
increased glutathione peroxidase and catalase activities, thereby atten­
uating AGEs-induced OS in mesangial HBZY-1 cells [93]. Through its
ability to inhibit OS, PF has been shown to attenuate the vascular
damage due to fluctuating hyperglycemia as well as diminish inflam­
matory responses and inhibit protein kinase Cβ1 protein levels [94].
Based on these findings, PF may be a promising treatment strategy
for diabetes and complications.
8. Inhibitory effects of PF as an antioxidant in autoimmune
diseases
Disruption of redox balance and mitochondrial dysfunction caused
by excess of ROS is closely related to immune pathogenesis, PF is also an
immunomodulator, it can weaken thymocytes injury induced by
ionizing irradiation through scavenging ROS and activating MAPK [95].
In a rat model of collagen-induced arthritis, PF down-regulated in­
flammatory reactions and regulated apoptosis, while simultaneously
down-regulating MDA and NO levels in serum and synovial tissue and
Y. Lu et al.
up-regulating SOD levels [96]. PF also increased the pain threshold
within this rat model of rheumatoid arthritis and relieved arthritis
symptoms by regulating OS [97]. What’s interesting is that PF has been
shown to activate caspase with the fragmentation of DNA, and in this
way, induces human T-cell leukemia Jurkat cell and murine
T-lymphocyte apoptosis. In contrast to typically observed, PF increased
ROS levels and decreased mitochondrial membrane potential in this
process. Therefore, it appears that PF can exert bidirectional regulatory
effects upon OS [98]. Therefore, PF plays a vital role in regulating im­
munity through antioxidant effects.
9. Inhibitory effects of PF as an antioxidant in pregnancy related
diseases
OS can produce damaging effects within both the mother and fetus,
such as gestational hypertension and delayed fetal brain development
[99]. PF may moderate the development of gestational hypertension by
suppressing OS. In addition, the up-regulation of SIRT1 expression in
gestational hypertensive rats treated with PF, diminishes vascular
endothelial cell injury/dysfunction, and reduces inflammation and OS.
Within human umbilical vein endothelial cells, PF served as a protectant
against H2O2-induced injury [100]. The Increased levels of SOD and
GSH and decreased level of MDA were shown in the treatment of PF in
ovarian ischemia-reperfusion injury [101]. PF enhances porcine oocyte
maturation as demonstrated in vitro through inhibiting ROS production,
increasing mitochondrial membrane potentials, and activating the SHH
pathway [102]. Similarly, in the offspring of prenatal stress rats, PF
decreased intracellular Ca2+ concentrations and apoptosis, down­
regulated ROS and NO levels and regulated mitochondrial membrane
potentials. PF also has been shown to attenuate the injury of SH-SY5Y
cells as induced by glutamate via regulating Nrf2/HO-1 and apoptotic
pathways, increasing the protein levels of Nrf2, HO-1, and NQO-1,
preventing the development of fetal learning and memory lesions
[103]. These results suggest that the antioxidant effects of PF exert a
significant role in the treatment of pregnancy-related disorders. How­
ever, it should be noted that other potential effects of PF in the fetus will
require further investigation.
10. Inhibitory effects of PF as an antioxidant in ocular diseases
Retinal degenerative diseases are characterized by the dysfunction or
death of retinal pigment epithelial (RPE) cells. As RPE cells have a high
metabolic rate they are more susceptible to oxidative damage. In
response to H2O2-induced oxidative damage, PF inhibits the increase of
ROS generation and caspase-3 activity in RPE cells, while inhibiting the
phosphorylation of ERK and p38 MAPK in a dose-dependent manner
[104]. Similarly, in RPE cells treated with all-trans-retinal, PF pre­
treatment activated AMPK in a Ca2+/CaMKII-dependent manner,
thereby inhibiting OS and mitochondrial dysfunction [105]. These re­
sults provide reliable evidence for use of PF in the treatment of ocular
diseases.
11. Inhibitory effects of PF as an antioxidant in hearing loss
Overproduction of ROS, apoptosis, and alterations in mitochondrial
membrane potential lead to spiral ganglion neuronal damage, effects
which may be associated with ototoxicity from the antitumor drug,
cisplatin [106]. Moreover, some antibacterial drugs, such as neomycin,
can produce an excessive production of ROS leading to hear cell damage,
further instigating hearing loss. PF can significantly decrease ROS levels,
increase the expression of putative kinase protein 1 and reduce
apoptosis, thereby counteracting the ototoxicity of cisplatin [107].
Similarly, PF can exert a remarkable effect in reducing neomycin
induced hearing loss, through its capacity to reduce OS and inhibit ERK
signaling activation [108]. These studies suggest that PF may inhibit
hearing damage through antioxidant effects.
8
Biomedicine & Pharmacotherapy 176 (2024) 116772
12. Protective effects of PF as an antioxidant in kidney diseases
The imbalance between protein degradation and synthesis in chronic
kidney disease (CKD), leads to skeletal muscle atrophy [109]. This pa­
thology results from an excessive accumulation of ROS leading to
mitochondrial dysfunction and OS. Li, Wu et al. demonstrated that PF
diminished this skeletal muscle atrophy through inhibiting mitochon­
drial dysfunction and OS in CKD, effects which were abolished by
knocking down peroxisome proliferator-activated receptor gamma
coactivator-1α (PGC-1α) and inhibiting SIRT1and AMPK [110]. In the
model of acute kidney injury induced by H/R, PF promoted Nrf2 nuclear
translocation and then increased the expression of HO-1, which could be
reversed by the Nrf2 inhibitor. This study showed that PF inhibited
apoptosis and decreased OS via the Nrf2/HO-1 pathway [111]. In
summary, the utilization of PF as an antioxidant exhibits promising
therapeutic potential in kidney diseases.
13. Inhibitory effects of PF as an antioxidant in skin diseases
The skin is the largest organ of the human body. Many factors can
lead to skin diseases including inflammation, immunity, OS, etc. The
effects of PF as an antioxidant in the treatment of dermatology diseases
by inhibiting OS are as follows.
Photodamage could be induced by ultraviolet A (UVA) or ultraviolet
B (UVB) radiation, both of which can induce an extensive generation of
ROS [112]. It has been reported that PF protected human keratinocytes
from UVB induced apoptosis through activation of the ROS-p38-p53
pathway [113]. Recent results from our laboratory have indicated that
PF could suppress the OS as induced by UVA via the Nrf2/HO-1/NQ-O1
pathway or by upregulating PLIN2, thereby inhibiting photodamage
[114].The increasing levels of Nrf2, HO-1, and NQ-O1 expression were
observerd. What’s similar is that PF protected melanocytes from
H2O2-induced OS, and the JNK/Nrf2/HO-1 signaling pathway played a
vital role in this process of PF protection. Accordingly, PF may serve as a
potential therapy for vitiligo [115]. In primary human sweat glands (SG)
cells treated with 3‑methyladenine, PF suppressed cell proliferation and
significantly increased autophagy and apoptosis. Interestingly, PF
increased ROS production in SG cells, suggesting that the PF’s role in the
treatment of bromhidrosis involves an increase in OS within these SG
cells [116]. All in all, PF may play a major role in the treatment of
dermatological diseases.
14. Inhibitory effects of PF as an antioxidant in distal flap
necrosis
The most common clinical difficulty associated with wound repair is
distal flap necrosis. It seems likely that the OS generated in injured tissue
can result in endothelial cell injury and decrease skin flap viability
[117]. Recent findings have indicated that PF inhibited endothelial cell
apoptosis through the Nrf2/HO-1 signaling pathway. The protection of
PF was partially abolished by a selective Nrf2 inhibitor [118]. Moreover,
the capacity for PF to increase SOD and decrease MDA activities served
to increase flap survival rates in rats. Hence, PF provides an effective
means for enhancing survival of distal flaps by inhibiting apoptosis,
inflammation, and OS [119].
15. Inhibitory effects of PF as an antioxidant in postoperative
adhesions
There is a high incidence of adhesion formation after abdominal
surgery, which may be related to trauma, infection, or OS of the peri­
toneum [120]. Gao, Wei et al. found that the peritoneal adhesions in rats
subjected to abdominal surgery could be significantly reduced by the
gavage with PF. These beneficial effects of PF appear to involve a down
regulation in the expressions of COX-2, TGF- β1 and IL-6, and an
up-regulation in the expressions of MMP-9 and SOD-2 during the
Y. Lu et al.
postoperative period. Accordingly, the ability for PF to diminish peri­
toneal adhesion involves a suppression of inflammation and OS [121].
PF may become a therapeutic agent for postoperative peritoneal
adhesions.
16. Discussion and conclusion
PF is a safe, effective, and nontoxic compound, whose antioxidative
effects have been extensively investigated both in vitro and in vivo as
related to several diseases. PF has been shown to exert beneficial effects
when applied to disorders involving the nervous, cardiac/vascular,
digestive, and respiratory systems, in diseases such as diabetes, auto­
immune, pregnancy related, ocular, kidney and dermatology as well as
in suppression of distal flap necrosis, postoperative adhesions and
hearing loss. The capacity to inhibit OS serves as the foundation for these
beneficial effects of PF, with these effects mainly being related to the
Nrf2 pathway, including Nrf2-KEAP1, Nrf2/HO-1, Nrf2/ARE, Nrf2/HO-
1/NQ-O1 and JNK/Nrf2/HO-1. However, the TLR4/NF-kB, JAK2/
STAT3, ROS/PKCd/NF-kB, PI3K/Akt-1, JAK2/STAT3, ERK1/2, p38
MAPK/NF-KB p65, IRS/Akt/GSK3β, SIRT1/FOXO1a/SOD2, AMPK/
SIRT1/PGC-1α and ROS-p38-p53 pathways are also involved in the
process of OS inhibition by PF. The main pathway is shown in Fig. 2.
Through these pathways, PF could increase antioxidant enzymes, and
decrease ROS. In addition, through its capacity to inhibit OS, PF can
mitigate the proliferation, apoptosis, ferroptosis and inflammation
associated with several diseases. Interestingly, in the treatment of
bromhidrosis, PF appears to function by increasing OS within SG cells.
Accordingly, the beneficial effects of PF may not only involve an inhi­
bition of OS, but also the promotion OS, within certain diseases. In
addition, PF has anti-tumor effects. However, the underlying molecular
mechanism might be related to the inflammation and apoptosis path­
ways [13,122]. At present, the study on PF against tumors through
regulating OS is limited. [123]. Therefore, as an antioxidant, PF’s
anti-tumor effect has a good prospect and needs further research.
PF exhibits definite antioxidant activity similar other compounds,
such as the antioxidant activity of quercetin in renal I/R injury [124],
resveratrol in atherosclerosis [125], Curcumin in anti-aging [126], and
epigallocatechin gallate in osteoporosis [127]. However, antioxidant
activity of PF is much lower than vitamin C [128]. PF not only has
antioxidant effects, it has a variety of pharmacological activities, such as
immune regulation, anti-inflammatory, and anti-tumor. Thus, PF can
improve disease from multiple ways, which is more extensive than
vitamins.
However, the structural modification, bioavailability, dose adjust­
ment, and toxicity of PF as an antioxidant still need to be further studied.
The low bioavailability of PF due to its hydrolytic degradation in the
intestine and poor penetration has further limited its clinical applica­
tion. Structural modification, such as paeoniflorin-phospholipid com­
plex [129] and paeoniflorin-6′-O-benzene sulfonate, can improve the
bioavailability of PF [130,131]. In addition, the doses and administra­
tions of PF used in different cell or disease model were different. Gavage,
intraperitoneal injection and direct administration, doses were varied
from 0.1μm to 1000μm in cells and 2.5 mg/kg to 1000 mg/kg in animals
for 30 minutes to 36 weeks (see Table 1). What’s more, there has been
little evaluation of toxicity in PF target organs, it is encouraged to design
studies with long-term application of PF to achieve the best possible
level of safety [132]. Therefore, it is crucial to find the best PF con­
centration, administration, and application time to meet different
experimental requirements.
Although a substantial amount of evidence, as presented in this re­
view, indicates that PF may be a promising antioxidant for the treatment
of a variety of diseases, there remains a significant lack of clinical
observation and clinical research regarding the antioxidative effects of
PF. In this regard, to further validate the conclusions of cell and animal
experiments, researchers need to conduct large-scale, randomized,
controlled, double-blind clinical trials to explore the further
9
Biomedicine & Pharmacotherapy 176 (2024) 116772
mechanisms and potential clinical effects of PF. As the main component
of traditional Chinese medicine, PF will provide more and more infor­
mation for clinical solutions and go to the world in the new situation of
China.
CRediT authorship contribution statement
Jun Niu: Writing – review & editing, Validation. Yansong Lu:
Writing – original draft, Data curation. Lu Yin: Data curation. Wei
Yang: Investigation. Ze Wu: Validation.
Declaration of Competing Interest
All co-authors have been seen and agreed with contents of this
research. The authors have declared no conflicts of interest. Neither the
entire research nor any part of its content has been published or has been
accepted elsewhere. It is not being submitted to any other journal.
Data Availability
No data was used for the research described in the article.
Acknowledgments
This work was supported by grants from the Liaoning Province
Technological Innovation Planned Project (Grant number 2022JH2/
101500012), Liaoning Province Doctoral Research Initiation Fund Pro­
gram Project (Grant number 2023-BS-033) and Shenyang Science and
Technology Planned Project (Grant number 22–321–33–34). The lan­
guage was polished by the editorial services of ED-IT.
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