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Chinese Medicine
Plant-derived extracts orcompounds
forHelicobacter-associated gastritis:
asystematic review oftheir anti-Helicobacter
activity andanti-inammatory eect inanimal
experiments
Danni Chen2†, Wenlai Wang4†, Xiangyun Chen2†, Ning Liang5, Jiawang Li2, Wei Ding2, Hongrui Zhang1,3,
Zhen Yang2*, Hongxia Zhao4* and Zhenhong Liu1,3*
Abstract
Background Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become com-
mon worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-
associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy
of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop.
Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies
of alternative natural medicines.
Purpose This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-
Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal
experiments. We intended to provide detailed preclinical-research foundation including plant and compound infor-
mation, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter
infection, gastritis and neoplasms for future study.
Methods The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO
(CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web
of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP),
the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023.
Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity
†Danni Chen, Wenlai Wang and Xiangyun Chen contributed equally to this
work as co-first authors.
*Correspondence:
Zhen Yang
for3000yz@aliyun.com
Hongxia Zhao
zhaohongxia7000@163.com
Zhenhong Liu
lzhh0399@163.com
Full list of author information is available at the end of the article
Page 2 of 44
Chenetal. Chinese Medicine (2025) 20:53
was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias
tool to evaluate the risk of bias of each study included.
Results Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibit-
ing Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation.
Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phe-
nols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-
base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control
groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/
MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG.
Conclusion Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms
and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further
researches to apply these treatments in humans are needed, which will provide direction for the future development
of therapeutic drugs to increase eradication rate and alleviate gastritis.
Keywords Helicobacter-associated gastritis, Phytotherapy, Compound, Plant extract, Inflammation, Helicobacter
Introduction
Helicobacter infection causes progressive damage to the
gastric mucosa, which can cause numerous diseases,
including Helicobacter-associated gastritis (HAG), gas-
tric or duodenal peptic ulcer disease (PUD), gastric
cancer, and gastric mucosa-associated lymphoid tis-
sue (MALT) lymphoma [1]. Helicobacter infection is
the most prevalent cause of chronic gastritis (so-called
HAG). Helicobacter initiates gastric endothelial and
myelocyte cell responses, resulting in oxidative stress,
an inflammatory response, and abnormal cell apoptosis,
cell growth, and differentiation. In addition, Helicobac-
ter-induced gastritis and subsequent disease progres-
sion, such as precancerous lesions and neoplasms due
to failed bacterial eradication and poor inflammatory
control, are important issues.e International Agency
for Research on Cancer (IARC) has defined Helico-
bacter as a class I carcinogen, and either eradication of
Helicobacter or attenuation of mutagenic inflammation
can prevent gastritis from developing into gastric can-
cer [2]. HAG is a representative type of “inflammation-
carcinogenesis," which means that chronic gastritis will
develop into gastric cancer through different regulatory
mechanisms if efficacy measures are absent. As described
by the Correa cascade, the human model of gastric car-
cinogenesisslowly progresses from the following series of
pathologic changes: superficial gastritis, chronic gastritis,
atrophy, intestinal metaplasia (IM), dysplasia, and can-
cer [3–5]. Helicobacter is a risk factor for gastric tumor
development, and anti-Helicobacter therapy is compul-
soryfor preventing or treating malignant and precancer-
ous lesions in the stomach.
PPI-based triple therapies (PPI-TTs) are predomi-
nantly therapeutic approaches for Helicobacter infection.
e PPI-TTs comprise a proton pump inhibitor (such as
omeprazole or pantoprazole) and two antibiotics. With
the wide application of PPI-TTs, antibiotic resistance
problems appear, which lead to eradication failure. e
resistance of the first-line antibiotics clarithromycin and
metronidazole is the greatest challenge. Clarithromycin
resistance has increased to 15–30% [6] worldwide, and
clarithromycin, metronidazole, and levofloxacin have
resistance rates of 25%, 30%, and 20%, respectively, in
2,852 Helicobacter-treatment-initial patients in Europe
[7]. e recommended empirical first-line therapy, bis-
muth-based quadruple therapy (BiQT), combines anti-
biotics with bismuth, which diminishes resistance to
clarithromycin and metronidazole.
Owing to the decreased effectiveness of antibiotics
against Helicobacter, many researchers are focusing on
discovering and developing potent plant-derived drugs
that favor complete eradication or are advantageous for
eradication. Many medicinal plants and isolated bioac-
tive compounds have been validated for their antibac-
terial, anti-inflammatory activity, and preventive effect
on abnormal cell growth and development both invitro
and invivo. To date, no systematic review has been con-
ducted on the utilization of phytopharmaceuticals in
HAG treatment. Our objective is to perform a compre-
hensive analysis that highlights the in vivo efficacy of
phytopharmaceuticals on HAG and elucidates the mech-
anisms by which these plant-derived substances inhibit
the progression of infection, gastritis, and neoplasms.
is systematic review is distinct from traditional reviews
in that we adhere to a controlled research strategy, which
minimizes potential sources of bias throughout the entire
review process. is includes the objective, literature
search, discovery of relevant literature, evaluation of the
quality of relevant research, data summaries or analyses,
and conclusions [8]. e dependability and correctness
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Chenetal. Chinese Medicine (2025) 20:53
of conclusions are enhanced by the clear methodologies
employed in systematic reviews, which serve to reduce
bias [9]. ese will provide a better understanding of
HAG and serve as a reference for further drug research
on this field.
e Correa cascade describes the disease process,
which begins with Helicobacter infection and ends with
gastric carcinogenesis. Atrophic gastritis, intestinal
metaplasia, and dysplasia are three precancerous lesions
that indicate disease severity and an increased risk of car-
cinogenicity [8]. Plant-derived extracts and compounds
from different species fulfil a role at different stages of
this process. We included 61 studies treating HAG and
assigned a number from 001 to 061 for them. (Table1, 2).
Materials andmethods
e present investigation was conducted in accordance
with the guidelines outlined in the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement. e study protocol has been regis-
tered on the PROSPERO website (CRD42024527889).
Search strategy
To collect relevant data, an extensive search was per-
formed across multiple databases, including PubMed,
Scopus, Web of Science, Embase, China National Knowl-
edge Infrastructure (CNKI), the Chinese Scientific
Journal database (VIP), the Wanfang database, and the
China biomedical literature service system (SinoMed),
up until November 2023. Using the retrieval of the Pub-
Med database as an example, Medical subject headings
(MeSH) terms and Free-text phrases from the PubMed
database were used. e text terms included: (“Helico-
bacter Infections” [Mesh] OR “Infections, Helicobacter”
OR “Helicobacter Infection” OR “Infection, Helicobac-
ter”) AND (“Plants” [Mesh] OR “Plants” OR “Plant” OR
“Plants, Medicinal” [Mesh] OR “Medicinal Plant” OR
“Plant, Medicinal” OR “Medicinal Plants” OR “Herbs,
Medicinal” OR “Medicinal Herbs” OR “Herb, Medicinal”
OR “Medicinal Herb” OR “Pharmaceutical Plants” OR
“Pharmaceutical Plant” OR “Plant, Pharmaceutical” OR
“Plants, Pharmaceutical” OR “Healing Plants” OR “Heal-
ing Plant” OR “Plant, Healing” OR “Plants, Healing”).
Only publications in Chinese and English were included.
e detailed search strategies of the above databases are
attached in the Additional file1.
Eligibility criteria
e inclusion criteria for relevant articles are listed
below: (1) Studies that meet the PICOS condition are
included: P (Animals) refers to “Helicobacter-infected
animals," and I (Interventions) refers to “Plant-derived
compounds or plant extracts," C (Comparators) refers
to “Comparative control group," O (Outcomes) refers to
“Outcomes of anti-Helicobacter and anti-inflammatory
activities," and S (Study designs) refers to “Controlled
studies with separate treatment groups." (2) e primary
outcomes of the study include anti-Helicobacter and
anti-inflammatory effect simultaneously.
Studies that met the following criteria were excluded:
(1) Editorials, reviews, clinical studies, theoretical
researches, case reports, conferences, book chapters,
and letters. (2) Articles that did not meet the PICOS cri-
teria. (3) Treatment was not a single extract or a mono-
mer compound. (4) Papers solely focused on invitro or
exvivo studies.
Study selection
Endnote X9 software was utilized to arrange the search
results. Reviewers (including W. W. and X. C.) evaluated
the literature separately after eliminating duplicates, tak-
ing into account the abstract and title. e whole texts of
the studies would be retrieved, and their eligibility would
be assessed using the established inclusion and exclu-
sion criteria, if deemed pertinent. e study authors were
contacted if more information was required. All disputes
or disagreements among study selection were settled
with the third (Z. L.).
Data extraction
Two reviewers (N. L. and J. L.) independently extracted
relevant data of the eligible studies using a standard
Excel, respectively. Any controversy or disagreement
among data extraction was reconciled with the third (Z.
Y.). e relevant data was abstracted from eligible arti-
cles: the first author’s name, publication year, extraction
solvent, part of the plant for extraction, plant species,
family, compound name, anti-Helicobacter potency out-
come, gastric histopathology, characteristic parameters
of HAG, indicators of further exacerbations of HAG.
Meta‑analysis
e reviewer (D. C.) performed quantitative analysis by
meta-analysis on Review Manager software (RevMan
5.4), considering anti-Helicobacter and anti-inflamma-
tory activity, including CLO and RUT positive rates,
IL-1β, and TNF-α protein levels. e WebPlotDigitizer
software was used to extract data from images. Forest
plots present data including events and total number of
groups, mean, standard deviation, and effect size as study
weight, risk ratio, or standardized mean difference with
95% confidence intervals(95% CI). Due to the heteroge-
neity across studies, we chose a random effect model for
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Chenetal. Chinese Medicine (2025) 20:53
Table 1 Plant extract intervention for HAG
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
002 Lee JY et al.
2023 [10]Ethanol (Leaf) Maclura tricuspi-
data
Moraceae M C57BL/6 mice;
Hp (4 × 109 CFU/
mL),
100 μL orally, 3
times/w, for 2w
10, 20 mg/kg; 6w 1. Gastric CLO↓
2. Stool Hp anti-
gen△
3. Serum anti-Hp
IgG↓
003 Wu H et al.
2023 [11]Chloroform (Dried
tuber) Corydalis yanhusuo
(Y. H. Chou & Chun
C. Hsu)
Papaveraceae M mice;
Hp (108 CFU/mL),
0.2 mL orally, tri-
weekly,
for 4w
100, 200, 400
mg/kg; 2w 1. Gastric RUT↓
2. Serum anti-Hp
IgG↓
004 Yuan Y et al.
2023 [12]UN (UN) Persicaria capitata
(Buch. -Ham. ex D.
Don) H. Gross
Polygonaceae Sprague–Dawley
rats;
pre-treated with
(2 g/L sodium
bicarbonate),
Hp (1011 CFU/L),
1.5 mL orally, 5
times at 1d-inter-
val
1.58 g/kg/d; 2w 1. Gastric Hp density
(CFU)↓
005 Jin Z et al.
2022 [13]Water, Ethanol
(UN) Parnassia palustris
LCelastraceae M Kunming mice;
Hp (1.2 × 109 CFU/
mL),
200 μL orally, 6
times at 1d-inter-
val
20 mg/d; 5d 1. Gastric RUT↓
006 Lee TH et al
2022 [14]Salt baked in bam-
boo barrel (Bamboo) UN M C57BL/6 mice;
Hp (108 CFU),
200 μL orally, daily,
for 8w
83.3, 166.6,
333.2 mg/kg; 5d 1. Gastric mRNA
of CagA gene: T, ST,
BST score 0; BS↓
007 Song MY et al
2022 [15]Ethanol (Korean
Propolis) (Korean Propolis) UN M C57BL/6 mice;
pre-treated
with 0.2 mL
(5% sodium bicar-
bonate) 3d,
Hp (5 × 109 CFU/
mL),
orally, 4
times at 2d-inter-
val, for 1w
0.2 mL/kg of 200 mg/kg, 3-times/w; 4w 1. Serum IgG↓
2. Gastric CLO↓
3. Gastric gene
expression of Hp
16S rRNA, Ss1 strain,
SsA strain, UreA,
NapA↓
4.Gastric CagA
protein↓
Page 5 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 1 (continued)
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
008 Mayyas A et al.
2021 [16]Ethanol (Peel) Punica granatum L Lythraceae F Wistar rats;
pre-treated
with streptomycin
(5 mg/mL) 3d,
Hp (2.7 × 109 CFU/
mL),
orally, twice/d
at 4 h-interval,
for 8d
50 mg/kg,
twice daily; 8d 1. Urease activity↓
2. Hp positive rats
(HE-stained sec-
tions)↓
009 Park JM et al.
2021 [17]No extract solvent.
Shelled kernels
pellet
(Shelled kernels)
Juglans regia L Juglandaceae M C57BL/6 mice;
pre-treated
with pantoprazole
(20 mg/kg) 3
times/w,
Hp (108 CFU/mL),
0.1 mL orally, then
[CAG and cancer
model: AIN-46A
containing 7.5%
NaCl pellet diet
for 24w, 36w
respectively]
100, 200 mg/kg;
24w or 36w UN
011 Tripathi A et al.
2021 [18]Ethanol (Leaf) Capparis zeylanica
LCapparaceae M Wistar rats;
pre-treated
with naproxen
(30 mg/kg),
Hp (108 CFU/mL),
orally 1 mL/d,
for 7d
120, 240, 360, 480
O.D. mg/kg; 8w 1. Gastric RUT: 360, 480 mg/kg eradicated Hp
2. Gastric Hp HrgA, 16S rRNA gene: 360, 480 mg/kg eradicated
014 Park JU et al.
2020 [19]Ethanol (Unripe
fruit) Rubus crataegifo-
lius Bunge Rosaceae M Balb/c mice;
Hp (2 × 108 CFU),
0.5 mL orally
100 mg/kg BW/d;
8w 1. Average number of the viable bacteria in gastric (CFU)↓
014 Park JU et al.
2020 [19]Ethanol (Stem
bark) Ulmus macrocarpa
Hance Ulmaceae M Balb/c mice;
Hp (2 × 108 CFU),
0.5 mL orally
100 mg/kg BW/d;
8w 1. Average number of the viable bacteria in gastric (CFU)↓
016 Lee HA et al.
2018 [20]Ethanol (Root) Allium hookeri Amaryllidaceae M C57BL/6 mice;
Hp (109 CFU),
orally,
3 times at 3d-inter-
val
25, 50, 100 mg/
kg/d; 4w 1. CLO score, CLO positive rate dose dependently↓
Page 6 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 1 (continued)
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
017 Sandhya S
et al. 2018 [21]Methanol,
Chloroform (Root) Tephrosia maxima.
LFabaceae Albino Swiss mice;
Pre-treated
with Naproxen
(30 mg/kg) 3d,
Hp (108 CFU/mL),
1 mL orally, for 7d
120 mg/kg/d;
4, 7, 10w 1. Gastric CFU↓, RUT↓, 16S rRNA of Hp△
020 Ik LY et al.
2019 [22]Ethanol/Hot water
(Unripe ruit) Rubus crataegifo-
lius Bunge Rosaceae M C57BL/6 mice;
Hp (2 × 108 CFU),
orally,
3 times
150 mg/kg; 4w 1. Log10CFU/stomach↓,
no significance
020 Ik LY et al.
2019 [22]Ethanol/Hot water
(Stem bark) Ulmus macrocarpa
Hance Ulmaceae M C57BL/6 mice;
Hp (2 × 108 CFU),
orally,
3 times
150 mg/kg; 4w 1. Log10CFU/stomach↓,
no significance
020 Ik LY et al.
2019 [22]Ethanol/Hot water
(Ripe ruit) Gardenia jasmi-
noides J. Ellis Rubiaceae M C57BL/6 mice;
Hp (2 × 108 CFU),
orally,
3 times
150 mg/kg; 4w 1. Log10CFU/stomach↓,
no significance
024 Kim A et al.
2016 [23]Dried powder (UN) Angelica keiskei Apiaceae C57BL/6 mice;
Hp (109 /mL)
orally,
thrice for a 3-day
period,
for 7w, AIN-76A
diet for 7w
3% NAC, 8% AK;
7w 1. Gastric Hp 16S rRNA↓
025 Kim AY et al.
2016 [24]A. Freeze-dried
powder (Root);
B. L-ascorbic
acid catalyze
a myrosinase reac-
tion to get a new
powder (Root)
Brassica rapa L Brassicaceae F C57BL/6 mice;
Hp (1109 CFU),
orally,
3 times at 2d-inter-
val, for 1w
A: 200 mg/kg/d,
B: 100, 200 mg/
kg/d; 4w
1. CFU/g stomach↓
2. Gastric mucosa IHC for Hp colonization↓
3. Gastric urease activity↓
4. Serum anti-Hp IgG: only high dose of HY3↑
026 Ye H et al.
2015 [25]Volatile oil of plant
(UN) Chenopodium
ambrosioides L. /
Dysphania ambro-
sioides (L.)
Amaranthaceae M Kunming mice;
Hp (1.2 × 109 CFU/
mL),
0.4 mL orally,
5 times at 1d-inter-
val
49.32 mg/kg; 4w 1. Gastric RUT↓
Page 7 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 1 (continued)
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
027 Zhang S et al.
2015 [26]Ethanol (Whole
plant) Polygonum capi-
tatum
Polygonaceae M/F (1:1) C57BL/6
mice;
Hp (108 CFU/mL),
0.1 mL orally, 3
alternate days,
for 9d
32, 64, 128 μg;
2w 1. Eradication rate of gastric Hp (CFU): (CLA + AMX + OMZ)- 100%; PCE-
89%; PCE + AMX- 93%
2. Gastric mRNA of CagA△
029 Park JM et al.
2014 [27]Ethanol (UN) (Licorice) Fabaceae M B6.129P2-
IL10tm1Cgn/J;
Hp (109 CFU/mL),
0.1 mL orally, 4
times, for 1w then
[cancer model:
pellet diet AIN76
(7.5% NaCl)
for 28w]
25, 50, 100 mg/
kg; 24w UN
030 Yamada T et al.
2014 [28]Freeze-dried
products
A. RB1 (gluc-
oraphanin +
glucoraphenin)
B. RB2
(glucoraphanin)
× Raphanobrassica
karpechenkoi
UN M Mongolian
gerbils;
Hp (108 CFU),
1 mL orally
2%; 11w
(week2—12) UN
031 Brown JC et al.
2011 [29]Powder (Skin) Vitis rotundifolia
Michx Vitaceae F C57BL/6 mice;
Pre-treated
with MGS powder,
Hp (107–108 CFU/
mouse),
0.25 mL orally, 3
times at 2-d-inter-
val, for 5d
5%, 10%, 0.5 mg/
mouse, daily; 1w 1. Gastric log CFU /g↓ but no significant difference with infected
untreated mice
033 Pastene E et al.
2010 [30]Absorber resin
Sepabeads SP-850
(Ripe fruits Peel)
Malus domestica
cv
Granny Smith
/Malus domestica
(Suckow) Borkh
Rosaceae C57BL6/J mice;
Hp (109 CFU/mL),
0.3 mL orally, 4
times at
2-d-interval
200 μL of 150,
300 mg/kg/d;
20d
1. Gastric Hp 16S rRNA
(lg Hp g/stomach): 0
034 Gu L et al.
2007 [31]Freeze-dried pow-
der (Garlic bulb) (Garlic) UN M Gerbillinae;
Hp (109 CFU/mL),
0.4 mL/4d orally, 5
times
1 mL/100 g/d;
4w UN
Page 8 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 1 (continued)
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
035 Paraschos S
et al. 2007 [32]Ethylacetate
+ Methanol
(Resin/gum)
Pistacia lentiscus
var. chia Poir
/Pistacia lentiscus L
Anacardiaceae F C57BL/6 mice;
Hp (108 CFU),
100 μL orally, 3
times within a
week
0.75 mg/d; 3 m,
[an extra group
pre-treated]
1. Serum anti-Hp IgG: -
2. Gastric tissue Hp (log CFU/g)↓
3. Gastric tissue Hp colonization grades (Histopathology)↓
036 Murakami M
et al. 2005 [33]Special process
(Rice) (Aqueous rice) UN M Mongolian
gerbils;
Hp (109 CFU/mL),
0.8 mL orally
UN; 10w 1. Gastric CFU of Hp↓ no significant difference with infected untreated
mice
2. Serum anti-Hp IgG↓
037 Otsuka T et al.
2005[34]Water (Fruit) Prunus mume Sieb.
et Zucc Rosaceae M Mongolian
gerbils;
Hp (108 CFU/mL),
orally
1%, 3%; 9w 1. Stomach Hp ureaseA gene↓
2. Serum anti-Hp IgG△
038 Souza Mdo
et al. 2009 [35]Hydro-Ethanolic
(Stem bark),
Dichloromethanic
fraction (Stem
bark)
Calophyllum brasil-
iense Cambess Calophyllaceae M Wistar albino
rats/
Swiss-Webster
Mice;
Pre-treated
with acetic acid
(0.03 mL, 20%),
Hp (6 × 108 CFU/
mL),
1 mL orally
50, 100, 200
mg/kg HEECb,
100, 200 mg/kg
DCMF; UN
1. Negative rate of RUT↑
039 Ruggiero P
et al. 2009 [36]Fermentation
process (UN) (Grape) UN BALB/c mice;
Hp 10, 50 μg,
two oral each
other day
5 mL/d; UN 1. CFU/stomach↓ no significant difference with untreated infected mice
2. Gastric Hp or VacA localization (IHC): (Red Wine + Green Tea)↓
039 Ruggiero P
et al. 2009 [36]Distilled
Water (Leaf) (Green tea) UN BALB/c mice;
Hp 10, 50 μg,
two oral each
other day
5 mL/d; UN 1. CFU/stomach↓ no significant difference with untreated infected mice
2. Gastric Hp or VacA localization (IHC): (Red Wine + Green Tea)↓
041 Jeong M et al.
2015 [37]Water, Ethanol
(UN) Artemisia capillaris
Thunb Asteraceae F C57BL/6 mice;
Pre-treated
with Pantoprazole
(20 mg/kg), 3
times,
Hp (109 CFU/mL),
0.1 mL orally, 4
times, for 1w, then
[cancer model:
pellet diet AIN76
(7.5% NaCl) for 24,
36w]
75 mg/kg, UN UN
Page 9 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 1 (continued)
Refs. Extraction
solvent (Part) Plant species Family Male/Female
Animal; Model Dose; Duration Anti‑Hecilobater
activity
041 Jeong M et al.
2015 [37]Water, Ethanol
(Leaf) Camellia sinensis L
/Inversodicraea
tanzaniensis Cheek
Podostemaceae Same as the previ-
ous line 75 mg/kg, UN UN
042 Stoicov C et al.
2009 [38]Ethanol (Leaf) (Green tea) UN M C57BL/6 J mice;
Hp (5 × 107 CFU),
500μL orally, 3
times at 2d-inter-
val
①pre-treated GT/
infection
/GT ②infection/
GT.1%; 8w
1. Stomach H.felis flaB gene: A, B score 0, C↓
043 Limuro M et al.
2002 [39]Water- ethanol
mixture (Clove) Allium sativum L Amaryllidaceae M Mongolian
gerbils;
Hp (2:0 £ 108 CFU),
0.5 mL orally
1%, 2%, 4%; 6w
Or 4%; 4w 1. Stomach colonies of Hp (CFU): -
054 Ishizone S
et al. 2007 [40]Distilled water,
enzyme-catalyzed
reaction (Rice)
Oryza sativa L Poaceae M Mongolian
gerbils;
Hp (10 CFU),
0.8 mL orally
12w 1. Gastric Hp ( +) incidence (IHC)↓; CFU△
2. Serum anti-Hp IgG↓
3. Gastric immunostainging slice of Hp↓
058 Ma X et al.
2020 [41]Ethylacetate
(Rhizome) Alpinia officinarum
Hance Zingiberaceae M BALB/c mice;
Pretreated
with mixed antibi-
otic solution
(0.3 mL/d, for 3d),
Hp (109 CFU/mL),
orally 0.3 mL/2d,
for 14d
0.09, 0.18, 0.36
g/kg/d; 3w 1. RUT↓
2. Gastric juice PH↓
059 Zhao X 2006
[42]Ethanol
(Resin /Gum) (Mastic) UN Gerbillinae;
Hp (109 CFU),
0.5 mL orally, 2
times at 6 h-inter-
val
3.75, 7.5, 15
mg/200μL;
0.2 mL/d, 2w
1. Hp clearance rate (Hp 16S rDNA)↑
Page 10 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 2 Plant-derived compound intervention for HAG
Refs Compound Origin species Alternative name Family Male/Female Animal;
Model Dose; Duration Anti‑Hecilobater
activity
001 [43]
Gobert AP et al.
2023
2-hydroxybenzylamine (Buckwheat) Buckwheat Polygonaceae FVB/N INS-GAS mice;
Hp (109) ,
0.2 mL orally, 2 times/2d
1, 3 mg/mL; 7w 1. Stomach CFU -
010 [44]
Shi M et al.
2021
Chaenomeles
speciosa total triterpe-
noids
Chaenomeles speciosa
(Sweet) Nakai Mugua, Quince Rosaceae M C57BL/6J mice;
Pretreated with mixed
antibiotic solution (0.3
mL/d, for 7d),
Hp (109CFU/mL),
0.30 mL orally,
at 1d-interval,
for 14d
20 mL/kg of 50, 100
mg/kg,
1 times/d; 4w
1. Gastric CLO↓
012 [45]
Jung DH et al.
2020
H-002119-00-001/β-
caryophyllene Syzygium aromaticum Cloves Myrtaceae M C57BL/6 mice;
Hp (5x109CFU/mL),
200 μL orally, 3
times at 2d-interval
5 mL/kg of 100, 200, 500
mg/kg; 2w or 4w 1. Gastric CLO ↓
2. Gastric Hp 16S rRNA↓
013 [46]
Kim SE et al.
2020
Phytoncide Pinus koraiensis Pinecones Pinaceae M C57BL/6 mice;
Pre-treated with 5%
NaHCO3
(0.2 mL, for 3d),
Hp (5x109CFU/mL),
0.2 mL orally, 3
times at 12 h-interval,
for 2d
100, 200, 400 mg/kg/d;
2w 1. Blood anti-Hp IgG↓
2. CLO↓
3. CagA gene expression↓
015 [47]
Chen ME et al.
2018
①Baicalin, ②Baicalein Scutellaria baicalensis
Georgi Huangqin Lamiaceae M C57BL/6 mice;
Hp (109CFU/mL),
orally, totally 3 doses,
on alternate days
0.2 mL of 80 μM [or+ 0.2
mL/d of LR-JB3 (2.5x107
CFU/mL)]
1. Gastric Hp numbers↓
2. Gastric VacA mRNA↓
3. Serum IgA , IgM of Hp↓
018 [48]
Yang JS et al.
2018
Eudesmin Fatsia polycarpa Hayata Araliaceae M C57BL/6 mice;
Hp (109CFU),
orally, totally 3 doses,
on alternate days
5, 10, 20, 40 μM, 0.2
mL/d;
3d
1. Stomach Hp 16S rRNA↓
019 [49]
Chang C et al.
2017
①Geniposide, ②Geni-
pin Gardenia jasminoides
J. Ellis Zhizi Rubiaceae M C57BL/6 mice;
Hp (109CFU),
orally, totally 3 doses,
on alternate days
①0.2 mL/d
of 31, 62
mg/kg/d; 3d
②0.2 mL/d
of 18, 36 mg/kg/d; 3d
1. Gastric Hp VacA
mRNA↓, Hp CagA mRNA -
021 [50]
Yanaka A et al.
2017
Sulforaphane Brassica oleracea L. Broccoli Brassicaceae Nrf2(+/+), Nrf2(-/-)
F C57BL/6 mice;
Hp (5x107CFU),
high-salt diet (7.5%
NaCl) for 2m
3 μmol/d of SGS
[or+ homogenized
Broccoli Sprouts]
1. Gastric Hp CFU ↓
Page 11 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 2 (continued)
Refs Compound Origin species Alternative name Family Male/Female Animal;
Model Dose; Duration Anti‑Hecilobater
activity
022 [51]
Zhang S et al.
2017
Quercetin Polygonum capitatum Polygonaceae M Kunming mice;
Hp (3x108CFU/mL),
diet mixed with Hp
at 1mL/kg concentra-
tion fed for 1d
64 mg/kg; 3d UN
023 [52]
Cao D et al.
2016
18β-Glycyrrhetinic Acid
(GRA) Glycyrrhiza glabra L. Liquorice,
Gancao Fabaceae M Mongolian gerbils;
Hp (108CFU),
0.8 mL orally, 3
times at 2d-interval
0.1%; 10w 1. Gastric pH Value
caused by Hp infection↓
2. Gastric Hp colonization
rate -
028 [53]
Liu C et al.
2019
Epimedium polysac-
charide
(EPS), Trollius chinen-
sispolysaccharide
(TCPS), Siberian
solomonseal rhizome
polysaccharide
(SSRPS), Astragalus
polysaccharides
(APS)
UN Berberidaceae,
Ranunculaceae,
Liliaceae,
Fabaceae
F BALB/c mice;
Hp antigen
(10 μg OVA or 5
μg rUreB), immu-
nized intranasally, 3
times at 2w-interval
50 ug/mouse Immunization with rUreB
alone or (rUreB+PPSs)
before Hp challenged
orally: 1. Stomach 16S
rDNA of Hp: PPSs+ rUreB↓
2. Serum IgG antibodies:
PPSs+ rUreB no difference
with rUreB alone
3. Stomach homogenate
IgA: rUreB + SRPS/APS↑
4. Intestinal lavage fluid
IgA: rUreB+ TCPS/APS↑
031 [29]
Brown JC et al.
2011
Quercetin
/3, 3′, 4′, 5, 6- pentahy-
droxyflavone
Vitis rotundifolia Michx. Muscadine grape Vitaceae F C57BL/6 mice;
Pre-treated
with NaHCO3(0.1 mL
of 0.5 mol),
Hp (107-8CFU),
0.25 mL orally, 3
times at 2d-interval,
for 5d
5%, 10% MGS powder
Or
0.5 mg of 25 mg/kg
quercetin;
11w (all fed 1w
before infection)
1. Gastric log CFU /g↓
no significant difference
with infected untreated
mice
032 [54]
Suk KT et al.
2011
2-4 polymer urushiol Rhus verniciflua Stokes/
Toxicodendron ver-
nicifluum (Stokes) F. A.
Barkley
Lacquer Tree Anacardiaceae F C57BL/6 mice;
Pre-treated with
NaHCO3(200 μL of 0.2
N),
Hp (109CFU),
500 μL/d orally, a total
of 19 inoculations (3
times a week), for 1w
0.128 mg/mL/d; 1w 1. Hp eradication rate:
urushiol 33%, Triple ther-
apy 75%, (Triple therapy
+ urushiol) 100%
040 [55]
Toyoda T et al.
2007
Nordihydroguaiaretic
acid (NDGA) Larrea tridentata DC
Coville Creosote Bush Zygophyllaceae M Mongolian gerbils;
Hp (108CFU/mL),
0.8 mL, 1 mL orally,
[chemical carcinogen,
N-methyl-N-nitrosourea,
20w]
0.01%, 0.05%, 0.25%; +
AIN93G diet;
44w
1. Stomach
Urease A gene△
2. Serum anti-Hp IgG-
Page 12 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 2 (continued)
Refs Compound Origin species Alternative name Family Male/Female Animal;
Model Dose; Duration Anti‑Hecilobater
activity
040 [55]
Toyoda T et al.
2007
Arctigenin Arctium
lappa LNiubangzi Asteraceae M Mongolian gerbils;
Hp (108CFU/mL),
0.8 mL, 1mL orally,
[chemical carcinogen,
N-methyl-N-nitrosourea]
0.1%;
+ AIN93G diet; 44w 1. Stomach
Urease A gene△
2. Serum anti-Hp IgG-
044 [56]
Wu HM et al.
2024
Epiberberine (EPI) Coptis chinensis Franch. Huanglian Ranunculaceae F C57BL/6J mice;
Hp (1010CFU),
0.4 mL orally, totally 4
times every 2 days
50, 100, 200
mg/kg; 2w 1. Stool antigen test
and RUT: Hp clearance
rates: (OMZ+CLA+AMX)
-100%; low, medium
and high-dose of EPI
33.3%, 50%, 66.7%
045 [57]
Li G et al.
2023
Neutral corn protein
hydrolysate (CPN) Zea mays L. Corn gluten meal Poaceae M KunMing mice;
Hp (109CFU/mL),
0.4 mL orally,
on alternate days, 7
times in total
200, 400, 600
mg/kg·bw;
Pre-treated for 2w
before infection
1. Gastric CFU/g ↓
046 [58]
Tang Q et al.
2023
Coptisine Coptis chinensis Franch. Huanglian Ranunculaceae F C57BL/6J mice;
Hp (109CFU),
0.2 mL orally, 4
times at 2d-interval
50, 100, 150
mg/kg/d; 2w Clearance rate:
1. Hp Stool Antigen:
quadruple therapy (QT),
Cop-M, Cop-H 83.33%,
83.33%, 100%
2. Stomach tissue CFU:
QT, Cop-M, Cop-H all
100%
3. Stomach tissue stain-
ing: QT, Cop-M, Cop-H
100%, 83.33%, 100%
047 [59]
Dai YY et al.
2022
Linolenic Acid-
Metronidazole (Lla-MTZ) UN Flax, Soybeans,
Rapeseed UN C57BL/6 mice;
Hp (109CFU),
0.5 mL orally, every
other day on 5 times
24 mg/kg; 1 times/d
for 3d 1. Gastric mucosa of Hp
CFU: OMZ+ Lla-MTZ did
best
048 [60]
Su T et al.
2019
①Artemisinin (ART)
②Artesunate(ARTS)
③Dihydroartemisinin
(DHA)
Artemisia annua L Artemisiae Annuae,
Qinghao Asteraceae C57BL/6 mice;
Pre-treated with MNU
(240 ppm), 3 times/w
for 6 cycles,
Hp (109CFU),
0.2 mL orally, 3 times/w
for 3w
60 mg/kg; 36w UN
049 [61]
Toyoda T et al.
2016
Curcumin Curcuma longa L. Turmeric Zingiberaceae M Mongolian gerbils;
Hp (108CFU/mL),
1mL orally
5000 ppm 1. UreA mRNA△
Capsaicin Capsicum spp. Chili peppers Solanaceae 100 ppm
Piperine Piper nigrum L. Black peppers Piperaceae 100 ppm
Page 13 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 2 (continued)
Refs Compound Origin species Alternative name Family Male/Female Animal;
Model Dose; Duration Anti‑Hecilobater
activity
050 [62]
Zhang X et al.
2015
Resveratrol UN Berries, Nuts, Peanuts,
Grape skin UN M Kunming mice;
Hp (108CFU) orally, 3
times
100 mg/kg/d;
6w 1. Gastric Hp CFU -
051 [63]
Kundu P et al.
2011
Curcumin
/Diferuloylmethane Curcuma longa L. Turmeric,
Jianghuang Zingiberaceae C57BL/6 mice;
Hp (108CFU) orally,
twice during 3d
25, 50 mg/kg;
7d 1. Urease test: gastric Hp
colonization all score 0
2. Gastric Hp gene UreB,
NapA: all score 0
052 [64]
De R et al.
2009
Curcumin
/Diferuloylmethane Curcuma longa L. Turmeric,
Jianghuang Zingiberaceae C57BL/6 mice;
Hp (108CFU) orally,
twice during 3d
25 mg/kg; 7d 1. Gastric Hp VacA△
053 [65]
Toyoda T et al.
2009
Caffeic Acid Phenethyl
Ester (CAPE) UN Propolis UN M C57BL/6 mice;
Hp (108CFU),
1mL orally
0.01%, 0.03%, 0.1%; 10w 1. Serum Anti-Hp IgG△
055 [66]
Takeda K et al.
2007
Auraptene (AUR) Citrus × aurantium f.
aurantium
Natsumikan
/Citrus × natsudaidai
Hayata
Rutaceae M Mongolian gerbils;
Hp (2x108CFU),
orally, twice during 2w
100, 500 ppm 1. Serum Anti-Hp IgG-
2. Gastric Hp coloniza-
tion-
3. Stomach urease A gene:
high dose group↓
056 [67]
Liu B et al.
2003
Total secondary carot-
enoids Chlorococcum
Sp(microalgae) Chlorococ-
caceae F BALB/c mice;
Hp (109CFU),
0.15 mL orally,
3 times at 2d-interval
100 mg/kg/d;
2w 1. Gastric Hp CFU△
057 [68]
Takagi A et al.
2000
Plaunotol Croton stellatopilosus
H. Ohba Plaunoi Euphorbiaceae M BALB/c mice;
Hp (109CFU),
orally, 3d
25-100 mg/kg/d; 4w 1. Serum Anti-Hp IgG↓
060 [69]
Tian A et al.
2014
Sophora alopecuroides L.
total alkaloids (TASA)
[sophoridine (SR),
matrine (MA), sophocar-
pine (SC), and leman-
nine (LMN)]
Sophora alopecuroides L. 555 Fabaceae F BALB/c mice;
Pre-treated with ome-
prazole (0.4 mg),
Hp (2x108CFU),
0.4 mL orally, twice
in a day
2, 4, 5 mg/d 1. Gastric mucosa Hp 16S
rDNA↓
061 [70]
Chen X et al. 2020 Palmatine Coptis chinensis Franch. Huanglian Ranunculaceae M Sprague-Dawley rats;
Hp (1.5x108CFU/mL),
orally, at 1d-interval
10, 20, 40 mg/kg/ d UN
*Tables1 and 2 “↓ or ↑” indicates that the value is statistically signicant compared to the control group; “△” indicates that there is an upward or downward change compared to the control group but is not statistically
signicant; “-” indicates that there is no change in the indicator or that the value presented is abnormal. “UN” means that the information is not described in the article
Page 14 of 44
Chenetal. Chinese Medicine (2025) 20:53
all the analysis. e funnel plots reflected the publication
bias.
Methodological quality assessment
Two reviewers (W. D. and H. Z.) independently assessed
the methodological quality of the included studies using
the Systematic Review Center for Laboratory Animal
Experimentation (SYRCLE) risk of bias tool [9]. is
tool includes ten items,each with a high, unclear, or low
risk of bias. Any discrepancies were resolved by a senior
member of the research (Z. L.).
Results
Study inclusion
After screening 2503 records, we identified 61 publica-
tions satisfying the inclusion criteria. Figure1 presents
the comprehensive and well-structured PRISMA flow-
chart. All 61 investigations that were implemented on
mice or rats were conducted between 2003 and 2023.
irteen animal strains were utilized to create the HAG
models and treated with plant extracts or plant-derived
compounds. e most frequently used strain was
C57BL/6 mice (36 studies), and the top 2 and top 3 were
BALB/c mice (12 studies) and Mongolian gerbils (12
studies), respectively(Figs.1, 2).
Assessment ofrisk ofbias
One study used a random number table to randomize
the animals into groups, and sixty studies did not
report their randomization methods and were thus
marked "unclear." Fifty-one included studies reported
random animal placement,and the remaining studies
did not mention such placement. Six studies provided
elaborate “blinding of outcome assessment” informa-
tion, whereas other studies were not known. One study
incompletely reported outcome data, and the remain-
ing studies did not have sufficient information to deter-
mine whether there was any loss of outcome data. Two
studies did not fully report the expected results, three
studies were uncertain, and the remaining studies fully
reported the expected outcomes. In all included stud-
ies, information about “baseline characteristics," “allo-
cation concealment," “blinding of participants and
personnel," “random evaluation of result,” and “incom-
plete outcome data”was not available. Other causes,
such as differences in modeling methodology, hetero-
geneity of the interventions, and variations in animal
characteristics, may lead to evidence that is non-gener-
alizable (Figs.3, 4).
Meta‑analysis ofanti‑Helicobacter andanti‑inammatory
eects
In order to examine phytomedicines’ curative effects of
anti-Helicobacter and anti-inflammatory, meta-analysis
were conducted, and the results supported our per-
spective. Among the 61 studies, three studies gave the
Helicobacter positive events data after plant extracts
or compounds treatment by the Campylobacter-Like
Organism (CLO) test, and six studies gave the relevant
data by the Rapid Urease Test (RUT). e study results
presented in Fig. 5 demonstrate experiment groups in
which gavaged animals plant extracts or compounds sig-
nificantly reduced the Helicobacter positive rate of CLO
(RR = 0.31, 95% CI 0.16 to 0.59, I2 = 0%, p = 0.0003) and
RUT (RR = 0.46, 95% CI 0.32 to 0.66, I2 = 0%, p < 0.0001)
(Fig.5).
Interleukin-1β (IL-1β) and tumor necrosis factor-α
(TNF-α) are major inflammatory mediators on HAG.
Among the analyzed studies in Fig. 6, five substances
significantly decreased IL-1β protein level (pg/mL)
(SMD = − 2.32, 95% CI − 3.66 to − 0.97, I2 = 59%,
p = 0.0007), four elements also declined IL-1β production
(pg/ug) (SMD = −1.15, 95% CI −1.69 to −0.60, I2 = 0%,
p < 0.0001). e forest plots also reveal that plant origin
substances groups have good potency on refraining TNF-
α, and the data manifest TNF-α (pg/mL) (SMD = −3.13,
95% CI − 4.06 to − 2.20, I2 = 29%, p < 0.00001), TNF-α
(pg/ug) (SMD = −1.38, 95% CI −1.93 to −0.84, I2 = 16%,
p < 0.00001) (Fig.6).
We obtained funnel plots by including studies that
employed parameters using the same unity. Outcomes
reveal a mild asymmetrical distribution, which suggests
there may existpublicationbias (Fig.7).
Anti‑Helicobacter activity ofplant extracts andcompounds
In this systematic review, plant-derived extracts or
compounds that have good efficiency on HAG are
summarized by tabling. Tables1, 2, 3, 4 and5 present
fundamental knowledge and pharmacological facts on
the anti-Helicobacter and anti-inflammatory activity of
plant extracts and compounds in the treatment of HAG.
CLO or RUT are test kits that could determine Helico-
bacter infection score by color. ree extracts of Maclura
tricuspidata, Korean Propolis, Allium hookeri; and three
compounds, Chaenomeles speciosa total triterpenoids,
β-caryophyllene, and Phytoncide decreased CLO score.
Seven extracts of Corydalis yanhusuo (Y.H.Chou & Chun
C.Hsu), Parnassia palustris L., Capparis zeylanica L.,
Tephrosia maxima. L., Chenopodium ambrosioides L.,
Calophyllum brasiliense Cambess., and Alpinia offici-
narum Hance; and one compound Epiberberine declined
score of RUT.
Page 15 of 44
Chenetal. Chinese Medicine (2025) 20:53
Helicobacter Colony-Forming Unit (CFU) is a com-
mon way to quantitatively measure the severity of infec-
tion using stomach tissue. Seven extracts of Persicaria
capitata, Rubus crataegifolius Bunge, Ulmus macrocarpa
Hance, Tephrosia maxima. L., Brassica rapa L., Polygo-
num capitatum, and Pistacia lentiscus L.; and five com-
pounds, Baicalin, Sulforaphane, Neutral corn protein
hydrolysate, Coptisine, and Linolenic Acid-Metronida-
zole significantly reduced the number value of CFU in
experiment groups.
Urease is an important virulence factor that is essential
for bacterial survival. ree extracts of Punica granatum
L., Brassica rapa L., and Prunus mume Sieb. et Zucc. and
Fig. 1 PRISMA flow diagram for the systematic review
Page 16 of 44
Chenetal. Chinese Medicine (2025) 20:53
two componds, Curcumin and Auraptene made urease
levels decrease, thereby ameliorating infection.
Multiple plants improved infection conditions because
they relieved Helicobacter gene expression in the host
body. Two extracts of Bamboo salt, and Korean Propo-
lis and one compound Phytoncide markedly down-reg-
ulated gene expression of the cytotoxin-associated gene
A (CagA), which is the representative pathogenic fac-
tor. Two extracts of Red Wine, and Green Tea and two
compounds, Baicalin and Geniposide, declined another
key virulence gene vacuolating cytotoxin A (VacA)
expression. Further, Korean Propolis extracted by etha-
nol attenuated gene expression of several Helicobacter
pathogenic agents in tissues including 16S rRNA, Sydney
strain 1 (Ss1), encoding urease A subunit (UreA), surface
antigen gene (SsA), and neutrophil-activating protein A
(NapA). e gastric neuregulin 1 (HrgA) and 16S rRNA
gene expression were dampened by Capparis zeylanica
L.. Curcumin could remove gastric tissue encoding ure-
ase B subunit (UreB) and NapA gene expression. Mastic
extraction and Sophora alopecuroides L. total alkaloids
significant reduced Helicobacter 16S rDNA expression.
In addition, Angelica keiskei, Malus domestica cv. Granny
Smith; two compounds, β-caryophyllene and Eudesmin
decreased Helicobacter 16S rRNA.
Anti-Helicobacter antibodies such as IgG, IgA, and
IgM, whose concentrations changed in animal tissue
samples, also indicated the therapeutic effects of plants.
Extracts of Maclura tricuspidata, Corydalis yanhusuo
(Y.H.Chou & Chun C.Hsu), Korean Propolis, Aqueous
rice, and Oryza sativa L., as well as compounds Phyton-
cide, Baicalin, and Plaunotol, lead to a reduction in anti-
Helicobacter antibodies (Tables1, 2, 3).
A few studies did not report results for Helicobacter
eradication (“UN” on the right-most column), although
they indeed treated animals with Helicobacter suspen-
sion and verified infection and gastritis. While these
studies have drawbacks, they have irreplaceable research
value because they concentrate on dredging the "inflam-
mation‒cancer transition" mechanism. e correspond-
ing mechanisms are shown in Tables4 and 5.
Anti‑inammatory activity ofplant extracts
andcompounds
Interleukin level is an important indicator against gastric
inflammation. Overall, seven extracts derived from Per-
sicaria capitata, Bamboo salt, Korean Propolis, Licorice,
Vitis rotundifolia Michx., Artemisia capillaris unb.,
and Alpinia officinarum Hance; and sixteen compounds,
2-hydroxybenzylamine, Chaenomeles speciosa total trit-
erpenoids, Phytoncide, Baicalin, Baicalein, Eudesmin,
Fig. 2 Mouse or rat models used in different studies
Fig. 3 Risk of bias graph
Page 17 of 44
Chenetal. Chinese Medicine (2025) 20:53
Geniposide, Genipin, 18β-Glycyrrhetinic Acid, Querce-
tin, 2–4 polymer urushiol, Neutral corn protein hydro-
lysate, Artemisinin, Artesunate, Dihydroartemisinin, and
Piperine all reduced IL-1β. Juglans regia L., Licorice,
Artemisia capillaris unb., Chaenomeles speciosa total
triterpenoids, Neutral corn protein hydrolysate, Cop-
tisine, Artemisinin, Artesunate, Dihydroartemisinin,
Piperine, and Caffeic Acid Phenethyl Ester alleviated
the generation of IL-6. Maclura tricuspidata, Parnassia
palustris L., Korean Propolis, Licorice, Chaenomeles spe-
ciosa total triterpenoids, Quercetin, Neutral corn protein
hydrolysate, Curcumin, Capsaicin, Piperine, Resveratrol,
Caffeic Acid Phenethyl Ester, Sophora alopecuroides L.
total alkaloids, and Palmatine revealed their capability
of IL-8 reduction invivo. Alpinia officinarum Hance and
2-hydroxybenzylamine ameliorated the generation of IL-
17, while Persicaria capitata and Chaenomeles speciosa
total triterpenoids mitigated IL-18 production. Some
substances boosted IL levels, for example Polygonum
capitatum, Chaenomeles speciosa total triterpenoids and
Total secondary carotenoids upgraded IL-4 levels invivo.
Parnassia palustris L. elevated IL-2 content, whereas
Coptisine and Caffeic Acid Phenethyl Ester reduced it.
Chaenomeles speciosa total triterpenoids enhanced IL-10
level, but Curcumin and Piperine significantly declined
the production.
Seven plant-based extracts of Parnassia palustris L.,
Bamboo salt, Korean Propolis, Licorice, Vitis rotundifolia
Michx., Artemisia capillaris unb., and Alpinia offici-
narum Hance, and eleven compounds Chaenomeles spe-
ciosa total triterpenoids, Phytoncide, 18β-Glycyrrhetinic
Acid, Quercetin, Neutral corn protein hydrolysate, Arte-
misinin, Artesunate, Dihydroartemisinin, Capsaicin,
Piperine, and Caffeic Acid Phenethyl Ester markedly
diminished the levels of TNF-α. Moreover, research-
ers found that the following three extracts and six
compounds decreased the interferon-gamma (IFN-γ)
concentration invivo: Angelica keiskei, Polygonum capi-
tatum, Vitis rotundifolia Michx., 2-hydroxybenzylamine,
Geniposide, Genipin, Piperine, Caffeic Acid Phenethyl
Ester, and Total secondary carotenoids.
Multiple plant-derived medicines reduced iso-
form of nitric oxide synthase (iNOS)/NO containing
Korean Propolis, Rubus crataegifolius Bunge, Ulmus
macrocarpa Hance, Gardenia jasminoides J. Ellis,
Angelica keiskei, Licorice, 2-hydroxybenzylamine,
18β-Glycyrrhetinic Acid, Piperine, Resveratrol, and
Caffeic Acid Phenethyl Ester. As for another group of
key inflammation-associated enzymes, cyclooxyge-
nase-2/prostaglandin E2 (COX-2/PGE2), a variety of
elements involving extracts of Juglans regiaL., Rubus
Fig. 4 Risk of bias summary
Page 18 of 44
Chenetal. Chinese Medicine (2025) 20:53
crataegifolius Bunge, Ulmus macrocarpa Hance, Gar-
denia jasminoides J. Ellis, Angelica keiskei, Licorice,
Artemisia capillaris Thunb., Geniposide, Genipin,
18β-Glycyrrhetinic Acid, Artemisinin, Artesunate,
Dihydroartemisinin, and Sophora alopecuroides L.
total alkaloids have good efficacy on restraining COX-
2/PGE2 generation in animal models. (Table4, 5).
Table 4 and 5 summarize the mechanisms of plant
products regulating HAG from four aspects: anti-
inflammatory, anti-oxidative, anti-apoptosis and an-
tiproliferation effects.
Other ndinds
Major pathways regulating the HAG process have been
exhibited on Fig. 8. e seven main signaling path-
ways regulating HAG are the nuclear factor kappaB
(NF-κB), janus kinase-signal transducer and activa-
tor of transcription 3 (JAK-STAT3), mitogen-activated
protein kinase (MAPK), toll-like receptor 4-myeloid
differentiation factor 88 (TLR4-MyD88), NOD-, LRR-
and pyrin domain-containing protein 3-caspase 1
(NLRP3-Caspase1), nuclear factor erythroid-2-related
factor 2-heme oxygenase 1 (NRF2-HO-1), and phos-
phoinositide 3-kinase-protein kinase B (PI3K-AKT)
pathways, which are critical mechanisms of these plant-
derived substances. e NF-κB signaling pathway (16
elements) is the most thoroughly researched pathway
and may be the most relevant one in HAG. (Fig.8).
In addition, several studies poked into the subsequent
progress of HAG. As shown in Fig.9, three extracts [17,
28, 42] and six compounds [44, 46, 55, 64, 65] effec-
tively inhibit precancerous lesions. Ten extracts [17, 27,
28, 31, 33, 34, 37, 39, 40] and eleven compounds [43, 55,
60, 61, 65, 69] are significantly efficacious in suppress-
ing stomach cancer. ese plants or compounds unfold
promising research prospects for treating advanced
HAG lesions (Fig.9).
Aside from that, we discover that many of the plant
medicines from the included literature are recorded in
the Chinese Pharmacopoeia. Table6 reveals their com-
pound name, plant species, Chinese Pinyin, and the
traditional function of Traditional Chinese Medicine
(TCM) (Fig.10 and Table6).
Many plant extracts or compounds belong to sixteen
main families. e top three families with the highest
frequency (five quantities) are Asteraceae, Fabaceae
and Rosaceae (Fig.11).
In addition, many plant-derived compounds from the
same classes, such as Terpenoids and Flavonoids. Fig-
ure12.displays the frequency of each important class
and their ranking. e compounds mainly attribute to
nine classes, with Terpenoids being the largest class,
which contains nine compounds, Alkaloids, and Phe-
nols, each comprising six and fivecompounds, respec-
tively (Fig.12).
Fig. 5 Forest plots of anti-Helicobacter activity. [A Positive events of CLO; B Positive events of RUT]
Page 19 of 44
Chenetal. Chinese Medicine (2025) 20:53
Discussion
e meta-analysis shows that plant-derived extracts
and compounds possess anti-Helicobacter and anti-
inflammatory efficacy to treat HAG. Animal experiments
illustrate that phytomedicine decreased Helicobacter
positive rates of CLOand RUT while reducing levels of
IL-1β and TNF-α. ese phytomedicines improve HAG
and block disease progression by regulating several
mechanisms, including anti-Helicobacter, anti-inflam-
matory, anti-oxidative, anti-apoptotic, and anti-prolif-
erative, through multiple signaling pathways including
NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT,
NLRP3/Caspase-1, and NRF2/HO-1. We also found
that TCM demonstrates enormous potential for treating
HAG because of its comprehensive and many-sided ther-
apeutic effects on HAG, including anti-inflammatory,
Fig. 6 Forest plots of anti-inflammatory activity. [A IL-1β protein level (pg/mL), B IL-1β protein level (pg/ug), C TNF-α protein level (pg/mL), D TNF-α
protein level (pg/ug)]
Page 20 of 44
Chenetal. Chinese Medicine (2025) 20:53
antibacterial, anti-atrophy, anti-intestinal metaplasia,
hemostasis or ulcer improvement, digestion improve-
ment, gastrointestinal function improvement, and stom-
ach alleviation.
Mechanisms ofHelicobacter pathogenicity inHAG
e pathogenic mechanisms of Helicobacter are related
to its colonization, survival, and virulence factors, which
cause an inflammatory response, oxidative stress, and
progressive epithelial lesions of the stomach.
Motility, urease, and adhesion are three common
Helicobacter pathogenic mechanisms. Helicobacter
colonization ability relies on motility, urease activity,
and adhesion. e motility of Helicobacter, owing to
bacterial-sheathed flagella with filaments consisting of
two flagellin subunits [71](FlaA and FlaB), which pre-
vent the activation of the host innate immune system
via escape recognition by TLR5 [72, 73], is indispen-
sable for bacterial entry into the mucus. e ability of
bacteria to adapt chemotactically relies on the pH of
thegastric mucus [74]. Urease is essential for Helico-
bacter colonization; it decomposes urea into ammonia
and carbon dioxide, which enables bacteria to survive
at very low pH values. e large amount of urease
that Helicobacter produces is aided by Urel, which is
an acid-stimulated inner membrane protein. Adhe-
sion ability is inseparable from adhesins, proteins
anchored on the bacterial outer membrane, which are
encoded by members of the large hop superfamily of
outer membrane protein-encoding genes. SabA [75],
Hop family adhesin BabA (BabA) [76], Hop family
adhesin AlpA (HopC), Hop family adhesin AlpB (HopB)
[77], and Hop family adhesin HopQ (HopQ) are cru-
cial gene for adhesins of Helicobacter. HopQ is a key
adhesin that combines with human carcinoembryonic
antigen-related cell adhesion molecules (CEACAMs),
thereby translocating the major pathogenicity factor
CagA into cells [78, 79]. Pathogenic feature genes of
Helicobacter major are present in pathogenic island.
e cytotoxin-associated gene A protein (CagA) and
vacuolating cytotoxin A protein (VacA) are responsi-
ble for stomach tissue inflammation and damage by
activating NF-κB [80, 81]. Helicobacter susceptibility
and widespread prevalence are due to the acquisition
Fig. 7 Funnel plots of different studies. [(A Positive events of CLO; B Positive events of RUT; C IL-1β and TNF-α protein levels (pg/mL); D IL-1β
and TNF-α protein levels (pg/ug)]
Page 21 of 44
Chenetal. Chinese Medicine (2025) 20:53
of cytotoxin-associated gene pathogenicity island
(cagPAI), which encodes the type IV secretion sys-
tem (T4SS). e T4SS, a protein complex spanning
the bacterial cell envelope, can directly deliver vari-
ous effector molecules, including the proinflammatory
and oncogenic protein CagA [82], HBP (heptose-1,
7-bisphosphate, an essential intermediate metabolite
of the lipopolysaccharide inner heptose core) [83, 84],
peptidoglycan fragments [85], and bacterial DNA [86],
into host cells after bacterial adherence. ese bacte-
rial substances interact with intracellular target mol-
ecules and have substantial effects on processes such
as intracellular signaling, cell function, and even malig-
nant transformation in the host [87, 88]. Multiple stud-
ies have confirmed that cagPAI-positive strains trigger
more inflammation than negative strains do [78, 83,
89]. In addition, the CagA protein, transcribed by the
CagA gene, which includes two critical motifs, EPIYA
and CRPIA, accounts for the high expression of proin-
flammatory cytokines (IFN-γ, IL-1β [90], and IL-8 [91]),
DNA damage [92], gastric epithelial cell apoptosis, and
gastric adenocarcinoma. VacA is released via the type V
secretion system (T5SS) and enters host cells through
endocytosis. Its transport to mitochondria results in
cell apoptosis via mitochondrial transmembrane poten-
tial (ΔΨm) dissipation, cytochrome c release, and Bcl-
2-associated X protein (Bax) activation [93]. (Fig. 13
and Table1, 2).
Mechanisms ofinammatory regulation inHAG
Host inflammation is the primary and most vital aspect
of HAG. Once monocytes, macrophages, and epithe-
lial cells identify damage-associated molecular patterns
(DAMPs) or microbial-associated molecular patterns
(MAMPs), inflammation ensues. ese cells secrete pro-
inflammatory cytokines and chemokines. e network
that builds connections between cells and cytokines in
the immune system facilitates responses to Helicobacter
infection. e hostinflammatory factors ILs-1β, −2, −4,
−6, −8, −10, −17, and −18,IFN-γ, and TNF-α are closely
associated with HAG and, even later, GC.
e F4/80 protein content in stomach tissue slices
indicates the extent of macrophage infiltration. Artemi-
sia capillaris unb. and β-caryophyllene decreased
the levels of F4/80.In addition, myeloperoxidase(MPO)
is a heme proteinthat neutrophils aggregate and release
if stimulated. MPO content can indicate the activation
and infiltration of neutrophils. In included studies, one
extract (Angelica keiskei) and three compounds (Chae-
nomeles speciosa total triterpenoids, Neutral corn
protein hydrolysate, and Resveratrol) decreased MPO
levels.
Pro‑inammatory cytokines inHAG
Lipopolysaccharide (LPS) of Helicobacter induces
IL-1β[94]. Comparing to Il-1β (+ / +) mice, Il-1β (-/-
) mice exhibited attenuated inflammatory cell recruit-
ment, proliferation excess, and apoptotic deficiency to
inhibit gastritis and carcinogenesis [95]. ILs-6,−8,−11,
and−17are cytokines strongly linked with HAG-to-can-
cer progression. Strains expressing CagA strongly acti-
vate extracellular signal-regulated kinase 1/2 (ERK1/2),
STAT3, and increase IL-6 and −11 levels, which results
in the aggravating ofHAG and gastric cancer [96]. IL-6
significantly elevates in GC patients and is positively cor-
related with C-reactive protein (CRP) level, tumor size,
stage [97], invasion, lymph node, and hepatic metas-
tasis [98], and survival time [99]. Il-8is the most selec-
tive and consistent gene in HAG patients [100], and it is
the most up-regulatedgene according to whole-genome
profiling of Helicobacter-exposed gastric epithelial
cells [101]. Helicobacter induces epithelial gastric cells
Table 3 Method of Helicobacter detection inanimals
Name Abbreviation Method
Campylobacter-Like Organism test
OR
Rapid Urease Test
CLO
OR
RUT
1. Test stomach tissue by CLO/RUT kit
2. Rationale: Helicobacter urease
3. Score by color change
Helicobacter urease activity / 1. Mixes stomach tissue with urease activity test solution and read the absorbance
2. Rationale: Helicobacter urease
Helicobacter Stool Antigen HPSA 1. Test animals’ stool antigen of Helicobacter
Helicobacter Colony-Forming-Unit CFU 1. Homogenize stomach tissue and plate onto Medium after dilution, incubate
at 37℃ for 48 h under microaerophilic conditions, finally count the colonies
Anti-Helicobacter IgG/A/M
(Helicobacter IgG/A/M antibodies) IgG, IgA, IgM 1. Test serum, blood samples from eye, tail vein by ELISA assay kit
Helicobacter
gene detection CagA, VacA, Ss1, UreA, SsA,
NapA, 16S DNA and so on 1. Collect gastric tissue and test by qRT-PCR
2. Rationale: Extract Helicobacter gene for PCR test
Histopathological analysis / 1. Giemsa stain of stomach paraffin slices, and confirm Helicobacter density or count
bacteria under microscope
Page 22 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 4 HAG-related regulatory mechanism of plant extract
Refs. Plant species Gastric
Histopathology Infammatory
Biomarkers Oxidative
Stress
Biomarkers
Apoptosis
OR
Proliferation
Biomarkers
Pathway Signature
Molecule
[10]Maclura tricuspidata ulcers,
erosion,
inflammation↓
IL-8↓
[11]Corydalis yanhusuo
(Y.H.Chou & Chun
C.Hsu)
hyperemia,
epithelial cell loss↓
[12]Persicaria capitata
(Buch.-Ham. ex D.Don)
H.Gross
inflammatory cell, dis-
ordered arrangement
of glands↓
IL-1β, IL-18, pro-IL-1β↓,
NLRP3, pro-caspase-1↓NF-kB↓,
AKT, p-AKT↑
[13]Parnassia palustris L erosion, ulceration,
hemorrhage, conges-
tion↓;
mucosa thickness
repairability↑
IL-8, TNF-α↓,
IL-2↑
[14] (Bamboo salt) gastric damage
and inflammation ↓IL-1β, TNF-α↓
[15] (Korean Propolis) gastric epithelium
damage, inflamma-
tory cell, sub-mucosal
edema↓; PAS + cells↑
IL-1β, IL-8, TNF-α↓,
NO, iNOS↓,
A20, A1a, c-Myc↓
, p-IκBα, p-p65↓
[17]Juglans regia L 24w:
gastric edema,
erythema, inflamma-
tion, erosions, ulcer,
atrophy↓
36w:
gastric tumor, ulcer,
pale and thin mucosa,
edema↓
IL-6↓,
COX-2/COX-1, PGE2↓,
c-Fos, c-Jun↓,
SOCS-1↑,
15-PGDH↑
Keap1↓,
NRF2, HO-1↑c-Myc↓,
Ki-67↓NF-κB, p-p65↓,
STAT3, pSTAT3↓
[18]Capparis zeylanica L gastric ulcer, petechial
marks, hemorrhages,
erosion, inflammation↓
[19]Rubus crataegifolius
Bunge,
Ulmus macrocarpa
Hance
gastric inflammation↓
[20]Allium hookeri gastric lesions score↓
[22]Rubus crataegifolius
Bunge,
Ulmus macrocarpa
Hance,
Gardenia jasminoides
J. Ellis
gastric inflammation↓iNOS, COX-2↓
[23]Angelica keiskei gastric inflammatory
lesions↓MPO, IFN-γ↓,
iNOS, COX-2↓LPO↓NF-κB activated B cells↓,
IκBα↑
[24]Brassica rapa L gastric infiltration
of eosinophils↓
[25]Chenopodium ambro-
sioides L gastric
inflammation↓
[26]Polygonum capitatum pathological score↓IFN-γ↓,
IL-4↑G cells, D cells
in MALT↓
[27] (Licorice) gastric erosion/ulcer,
inflammation↓;
dysplasia, tumor/
adenoma↓
IL-1β, IL-6, IL-8, TNF-α↓,
iNOS, COX-2, PGE2↓,
bFGF, FcrRIIB, ICAM-1,
Lungkine, Thymus-CK1,
TRANCE, TROY↓
MDA↓BrdU + cells↓p-STAT3, pJAK2↓
Page 23 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 4 (continued)
Refs. Plant species Gastric
Histopathology Infammatory
Biomarkers Oxidative
Stress
Biomarkers
Apoptosis
OR
Proliferation
Biomarkers
Pathway Signature
Molecule
[28] × Raphanobrassica
karpechenkoi
gastric mononuclear
cells, heterotopic prolif-
eration glands,
intestinal metaplasia↓
8-OHdG↓Ki-67 + cells↓
[29]Vitis rotundifolia Michx gastric
inflammation↓IL-1β, TNF-α, IFN-γ↓
[30]Malus domestica cv
Granny Smith gastritis score↓MDA↓
[31] (Garlic) chronic atrophic gastri-
tis, low-grade dysplasia,
gastric intraepithelial
neoplasia↓
[32]Pistacia lentiscus var.
chia Poir activity of chronic gas-
tritis: gastric neutrophil
infiltration, Sydney
system score ↓
[33] (Aqueous rice) stomach neutrophils,
mucosa thickness↓BrdU labeling index↓
[34]Prunus mume Sieb. et
Zucc stomach inflamma-
tory cells, hemorrhagic
erosion, mucosa
hyperplasia↓
[35]Calophyllum brasiliense
Cambess stomach ulcer area,
gastric inflammation,
erosion↓
[36] (Grape, Green tea) gastritis score↓
[37]Artemisia capillaris
Thunb 24w:
1.gastric erosions,
erythematous gastric
mucosa, nodular
mucosal changes,
protuberant foci↓
2.pathology score
of CAG (loss of pari-
etal cells, monocytes,
lymphocytes, mac-
rophages replacing
gastric glands, and ero-
sive mucosal changes)↓
36 weeks:
1.gastric nodular
mucosal changes,
thinned gastric
mucosa, adenomatous
polyps, tumorous
lesion with central
ulcerations↓
2.severe CAG, gastric
ulcer, gastritis cystica
profunda, adenoma,
gastric adenocarci-
noma↓
IL-1β, IL-6, TNF-α↓,
COX-2, PGE2↓,
Gastric F4/80 protein↓,
15-PGDH↑,
HSP70↑
MDA↓p-p65↓,
pSTAT3↓
[38] (Green tea) inflammation, hyper-
plasia, dysplasia↓
[39]Allium sativum L gastric edema, hemor-
rhage, hemorrhagic
spots,
gastric mucosa thicken-
ing↓
Page 24 of 44
Chenetal. Chinese Medicine (2025) 20:53
or cancer-derived cell lines to generate elevated lev-
els of IL-8 via the activation of activatorprotein 1(AP-
1),NF-κB [102, 103], or STAT3 [104]. Additionally, a high
level of IL-8 is strongly relatedto venous and lymphatic
invasion and invasion depth [105]. Keratoconus (KC) is
a rodent homolog of human IL-8. Likewise, Helicobac-
ter stimulates IL-17 and IFN-γ in mice and increases
IL-23 andIL-12 in macrophages. Anti-IL-17 Ab-treated
Il-17 (-/-)mice have a reduced bacterial load and gastric
inflammation, whereas recombinant adenovirus, which
encodes mouse IL-17, exacerbatesgastritis [106].
e T-helper 1 (1)-mediated factor IFN-γ, which is
secreted mainly by CD4 + and C D8 + T cells [107, 108],
is closely correlated with the severity of Helicobacter-
induced inflammation in the stomach [108–110]. After
eradication therapy, the level of IFN-γ decreased to the
same level as that in the uninfected group [111]. e level
of TNF-α is always significantly increased with IFN-γ and
IL-12 in HAG patients [112], mice and invitro.
Anti‑inammatory cytokines inHAG
Some protective cytokines in HAG have anti-inflamma-
tory functions. e tissue isolated from infected human
stomach mucosa and mice showed a prevalence of IFN-
γ-producing T cells, whereas IL-4-producing T cells were
rare or absent [109, 112–114]. Infected Il-4 (-/-) mice had
increased IFN-γ level and more severe gastritis. On the
other hand, Ifn-γ (-/-) mice showed no inflammation but
high IL-4.
Tiny amounts of IL-10 were detected when the T cells
were stimulated with Helicobacter urease invitro [107].
Another study revealed that live Helicobacter induced
IL-12 and IFN-γ tens of times, whereas IL-10 slightly
increased. Interestingly, compared with live Helicobac-
ter, killed Helicobacter induced significantly more IL-10.
It demonstrated that live Helicobacter induced 1 cells,
which produced IL-12 and IFN-γ, whereas oral vaccines
may induce more IL-10 [115]. erefore, IL-4 and IL-10
function as protective factors in gastritis.
In the included studies, three studies reported a sig-
nificant increase in IL-4 level: Polygonum capitatum,
Chaenomeles speciosa total triterpenoids, and Total
secondary carotenoids of Chlorococcum Sp. However,
only one study showed a significant increase in IL-10:
Chaenomeles speciosa total triterpenoids. IL-10 had
no significant decrease change comparing to model
groups after the following treatments: × Raphanobras-
sica karpechenkoi (↓no sig), Calophyllum brasiliense
Cambess. (↓no sig), Caffeic acid phenethyl ester (↓no
sig). Curcumin and Piperine decreased the concentra-
tion of IL-10 significantly due to a decrease in monocytes
in the lamina propria during inflammatory rehabilitation.
Inammation‑related enzymes inHAG
Nitric oxide synthase (NOS), which is created by
L-arginine in response to Helicobacter infection, con-
sists of three distinct NOS isoforms. One of the iso-
forms, iNOS, a calcium-independent isoform, responds
to bacterial LPS and proinflammatory cytokines. iNOS
creates a significant amount of NO when injurious
stimuli occur in cells. TNF-α, IFN-γ, IL-1β, and LPS
attach to receptors on the cell membrane, activating
NF-κB and STAT, which translocate into the nucleus
and finally start iNOS gene transcription [116]. e lev-
els of iNOS, COX-2, and NO [100] are greater in Hel-
icobacter-positive gastritis patients, especially in the
bacterial density of the gastric antrum [117].
iNOS and COX-2 are associated with GC [118].
Tumor-associated macrophages (TAMs) with high
COX-2 accumulate near GC tumor nests. COX-2 and
iNOS catalyze the increase in PGE2 and NO, respec-
tively, in gastric cancer. e long-lasting effects of NO
and PGE2 lead to oxidative stress, DNA damage, and
the overexpression of DNA methyltransferases [119].
e tumor suppressor enzyme 15-prostaglandin
dehydrogenase (15-PGDH) is a critical PG catabolic
enzyme. Early inactivation of 15-PGDH causes COX-2
activation and contributes to PGE2 overproduction,
Table 4 (continued)
Refs. Plant species Gastric
Histopathology Infammatory
Biomarkers Oxidative
Stress
Biomarkers
Apoptosis
OR
Proliferation
Biomarkers
Pathway Signature
Molecule
[40]Oryza sativa L gastric neutrophils,
mono cell↓BrdU + cells↓
[41]Alpinia officinarum
Hance gastric inflammatory
cell↓IL-1β, IL-17, TNF-α↓p-ERK1/2,
p-JNK, p-p38↓
[42] (Mastic) gastric neutrophils,
atropy↓
Page 25 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 5 HAG-related regulatory mechanism of compound
Refs. Bioactive
Compound Plant species Gastric
Histopathology Infammatory
Biomarkers Oxidative
Stress
Biomarkers
Apoptosis
OR
Proliferation
Biomarkers
Pathway
Signature
Molecule
[43] 2-hydroxyben-
zylamine (Buckwheat) acute and chronic
inflammation,
intramucosal
carcinoma,
dysplasia and carci-
noma↓
IL-1β, IL-17, TNF,
INF-γ,
CXCL1↓,
NOS2↓
pH2AX + x↓
[44]Chaenomeles
speciosa total
triterpenoids
Chaenomeles
speciosa (Sweet)
Nakai
gastric mucosal
damage, inflamma-
tory cell infiltration,
glandular atrophy↓
MPO, IL-1β, IL-6,
IL-18,
KC,
TNF-α, MCP-1↓,
pro-ILs-1β, −18↓,
TXNIP, NLRP3, pro-
caspase-1,
caspase-1↓,
IL-4, IL-10↑
ROS,
LDH,
MDA↓,
SOD,
GSH-Px,
CAT ↑
Bax, Bad↓,
Bcl-2, Bcl-xl↑,
Bcl-2/Bax,
Bcl-xl /Bad↑,
cytochrome C,
Apaf-1,
PARP-1,
cleaved-PARP-1,
cleaved-
caspases-3, −9↓,
pro-caspases-3,
−9↑
p-IKKβ, p-IκBα, p65,
p-IKKβ/IKKβ,
p-IκBα/IκBα↓,
TLR4, MyD88↓
[45] β-caryophyllene Syzygium aromati-
cum
damage of the sur-
face epithelium,
inflammatory
cell, submucosal
edema↓
Gastric F4/80
protein↓
[46] Phytoncide Pinus koraiensis inflammation,
atrophic score↓IL-1β, TNF-α↓
[47] Baicalin, Baicalein Scutellaria baicalen-
sis Georgi IL-1β↓
[48] Eudesmin Fatsia polycarpa
Hayata IL-1β, IgM↓
[49] Geniposide,
Genipin Gardenia jasmi-
noides J. Ellis IL-1β, IFN-γ↓,
COX-2↓,
IgA, IgM↓
[50] Sulforaphane Brassica oleracea L gastric inflamma-
tion↓
[51] Quercetin Polygonum capi-
tatum
IL-8↓G0/G1, G2/M
phase cells↓,
S-phase cells↑,
Bax↓, Bcl-2↑
p38 MAPK↓
[52] 18β-
Glycyrrhetinic Acid Glycyrrhiza glabra L gastric neutrophils,
mononuclear cells,
hyperplasia, peptic
ulcer↓
IL-1β, TNF-α↓,
COX-2, iNOS↓
[29] Quercetin Vitis rotundifolia
Michx gastric inflamma-
tion↓IL-1β, TNF-α,
IFN-γ↓
[54] 2–4 polymer
urushiol Rhus verniciflua
Stokes gastritis mitiga-
tion↓IL-1β↓,
TNF-α↑
[55] Arctigenin Arctium lappa L gastric intestinal
metaplasia,
heterotopic prolif-
erative glands,
incidences of glan-
dular stomach
adenocarcinoma↓
8-OHdG↓
Nordihy-
droguaiaretic acid Larrea tridentata
DC Coville
[56] Epiberberine Coptis chinensis
Franch gastric tissue
disturbances,
cellular gaps,
inflammatory cell↓
Page 26 of 44
Chenetal. Chinese Medicine (2025) 20:53
which leads to colon carcinogenesis. Hence, the loss of
15-PGDH increases PGE2 in gastric-intestine cancer
[120, 121]. Juglans regia L. and Artemisia capilla-
ris unb. effectively preserved 15-PGDH in infected
mice with a decrease in COX-2/COX-1 and PGE2,
which restrained the tumor on stomach. It explains
how it blocks the “inflammation‒carcinoma” process.
(Tables4, 5).
Antioxidative eects andmechanisms inHAG
e Helicobacter colonizing mucosa undergoes remark-
able neutrophil infiltration and oxyradical formation,
which cause damage, including erythema, ulcers, and
hemorrhage. When the body’s oxidative stress and anti-
oxidant processes are out of balance, inflammation, over-
apoptosis, and overproliferation are promoted.
Reactive oxygen species (ROS), which produce oxygen
with electrons, are crucial factors for polyunsaturated
Table 5 (continued)
Refs. Bioactive
Compound Plant species Gastric
Histopathology Infammatory
Biomarkers Oxidative
Stress
Biomarkers
Apoptosis
OR
Proliferation
Biomarkers
Pathway
Signature
Molecule
[57] Neutral corn pro-
tein hydrolysate Zea mays L gastric neutro-
phil, cell damage
and swelling↓
MPO, IL-1β, IL-6, KC,
TNF-α, MCP-1↓MDA,
LDH↓;
SOD,
GSH-Px↑
NF-κB↓,
TLR4, MyD88↓
[58] Coptisine Coptis chinensis
Franch IL-2, IL-6↓
[59] Linolenic Acid-
Metronidazole (Flax, Soybeans,
Rapeseed) inflammatory cell
infiltration↓
[60] Artemisinin,
Artesunate,
Dihydroartemisinin
Artemisia annua L incidence and size
of tumor nodules↓IL-1β, IL-6, TNF-α↓,
COX-2↓p-IκBα ↓,
IκBα↑
[61] Curcumin Curcuma longa L gastric neutrophils,
mononuclear cells,
heterotopic prolif-
erative glands↓
KC, IL-10↓p-IκBα↓
Capsaicin Capsicum spp. KC, TNF-α↓
Piperine Pipernigrum L IL-1β, IL-6, IL-10, KC,
IFN-γ, TNF-α↓,
iNOS↓
[62] Resveratrol (Berries, Nuts, Pea-
nuts, Grape skin) gastric inflamma-
tion score↓MPO, IL-8↓,
iNOS↓LPO↓
[64] Curcumin Curcuma longa L epithelial, submu-
cosal and muscu-
laris mucosal layers
damage, inflam-
mation, glandular
atrophy↓
[65] Caffeic Acid Phene-
thyl Ester (Propolis) gastric neutrophils,
mononuclear cells↓
intestinal meta-
plasia, heterotopic
proliferative glands,
hyperplasia↓
IL-2, IL-6, KC, TNF-α,
IFN-γ↓,
iNOS↓
BrdU + cells↓p50, p-IκBα↓
[67] Total secondary
carotenoids Chlorococcum
Sp (microalgae) gastric inflamma-
tion↓IFN-γ↓,
IL-4↑
[68] Plaunotol Croton stellatopilo-
sus H.Ohba gastric inflamma-
tion↓
[69]Sophora alope-
curoides L. total
alkaloids
Sophora alopecu-
roides L gastric inflamma-
tory cell and prolif-
erated glands↓
IL-8↓,
COX-2↓NF-κB↓
[70] Palmatine Coptis chinensis
Franch gastric inflamma-
tion↓IL-8,
ADAM17, HB-EGF,
p-EGFR/EGFR,
MMP-10, CXCL16,
CD8 + T↓, Reg3a↑
*Table4 and 5 “↓ or ↑” indicates that the value is statistically signicant compared with the control group
Page 27 of 44
Chenetal. Chinese Medicine (2025) 20:53
fatty acidperoxidation of the cell membrane. When inju-
ries occur, ROS and reactive nitrogen species (RNS),
which are generated by Helicobacterand activated neu-
trophils, serve as chemoattractants that attract more
neutrophils and monocytes. Additionally, ROS and
RNS cause DNA damage that fuels tumor growth
[122].Chaenomeles speciosatotal triterpenoids signifi-
cantly reduced ROS level in infected group.
Lipid peroxide (LPO) radicals are converted from
lipid-free radicals generated by ROS-oxidizing poly-
unsaturated fatty acids. Hence, LPO is considered an
index of oxidative membrane damage [23]. Super-
oxide dismutase (SOD), catalase (C AT ), glutathione
Fig. 8 Signaling pathways regulating HAG
Fig. 9 Phytomedicines act on Correa cascade. ( Created in BioRender. https:// BioRe nder. com/ daegq 0t. Agreement number: YF2826GU41.)
Page 28 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 6 Traditional Chinese Medicine treating HAG
Refs Compound
OR
Extract
Plant Species Family Chinese Pharmacopoeia
Pinyin Traditional Ecacy (TCM)
[26] Extract Polygonum capitatum Polygonaceae Huzhang (POLYGONI CUSPIDATI RHIZOMA
ET RADIX) Drain dampness and subdue yellowing, Clear heat
and remove toxins, Transform stasis and alleviate
pain, Stop coughing and transform phlegm
[51] Quercetin
[62] Resveratrol
[56] Epiberberine Coptis chinensis Franch Ranunculaceae Huanglian (COPTIDIS RHIZOMA) Clear heat and drain dampness,
Reduce fire and remove toxins
[58] Coptisine
[70] Palmatine
[22] Extract Gardenia jasminoides J. Ellis Rubiaceae Zhizi (GARDENIAE FRUCTUS) Reduce fire and alleviate vexation, Clear heat
and drain dampness, Cool blood and remove toxins
[49] Geniposide, Genipin
[27] Extract (Licorice) Fabaceae Gancao (GLYCYRRHIZAE RADIX ET RHIZOMA) Tonify lung and supplement qi, Clear heat
and remove toxins, Resolving phlegm and stop
coughing, Resolving convulsion and alleviate pain
[52] 18β-Glycyrrhetinic Acid Glycyrrhiza glabra L Fabaceae
[31] Freeze-dried powder (Garlic) Amaryllidaceae Dasuan (ALLII SATIVI BULBUS) Remove toxins and resolve swelling, Kill parasites,
Stop diarrhoea
[39] Extract Allium sativum L
[61] [63] [64] Curcumin Curcuma longa L Zingiberaceae Jianghuang (CURCUMAE LONGAE RHIZOM) Circulate blood and qi, Unblock meridians and relieve
pain
[60] Artemisinin, Artesunate,
Dihydroartemisinin Artemisia annua L Asteraceae Qinghao (ARTEMISIAE ANNUAE HERBA) Clear deficiency heat, Clear bone-steaming tidal fever,
Clear summer heat, Stop Malaria, Relieve yellowing
[47] Baicalin, Baicalein Scutellaria baicalensis Georgi Lamiaceae Huangqin (SCUTELLARIAE RADIX) Clear heat and drain dampness,
Reduce fire and remove toxins,
Stop bleeding, Quiet the fetus
[55] Arctigenin Arctium lappa L Asteraceae Niubangzi (ARCTII FRUCTUS) Release the exterior with pungent-cool, Disperse
the lung and promote skin eruption, Remove toxins
and clear the throat
[11] Extract Corydalis yanhusuo Papaveraceae Yanhusuo (CORYDALIS RHIZOMA) Circulate blood, Resolve stagnation, Alleviate pain
[16] Extract Punica granatum L Lythraceae Shiliupi (GRANATI PERICARPIUM) Astringe the intestine and stop diarrhoea, Stop bleed-
ing, Repel parasitic worms
[17] Shelled kernels pellet Juglans regia L Juglandaceae Hetaoren (JUGLANDIS SEMEN) Tonify the kidney, Warm the lung, Moisten the intes-
tine
[34] Extract Prunus mume Sieb.et Zucc Rosaceae Wumei (MUME FRUCTUS) Astringing lung and intestine, Generate fluids, Repel
roundworms
[37] Extract Artemisia capillaris Thunb Asteraceae Yinchen (ARTEMISIAE SCOPARIAE HERBA) Relieve dampness and heat, Promote bile flow
and relieve yellowing
[40] Distilled and enzyme-
catalyzed product Oryza sativa L Poaceae Daoya (ORYZAE FRUCTUS GERMINATUS) Promote digestion and harmonize the middle jiao,
Strengthen the spleen
[41] Extract Alpinia officinarum Hance Zingiberaceae Gaoliangjiang (ALPINIAE OFFICINARUM RHIZOMA) Warm the stomach and stop vomiting, Dissipate cold
and alleviate pain
[44]Chaenomeles
speciosa total triterpenoids Chaenomeles speciosa
(Sweet) Nakai Rosaceae Mugua (CHAENOMELIS FRUCTUS) Relax tendons and harmonize meridians, Harmonize
the middle jiao and transform dampness
Page 29 of 44
Chenetal. Chinese Medicine (2025) 20:53
Table 6 (continued)
Refs Compound
OR
Extract
Plant Species Family Chinese Pharmacopoeia
Pinyin Traditional Ecacy (TCM)
[53] Epimedium polysaccharide UN Berberi-
daceae Yinyanghuo (EPIMEDII FOLIUM) Warm kidney yang, Strengthen tendons and bones,
Eliminate wind and resolve dampness
[53] Astragalus polysaccharides UN Fabaceae Huangqi (ASTRAGALI RADIX) Tonify qi and promote yang energy, Secure the exte-
rior and stop sweating, Induce urination and resolve
oedema, Generate fluids and nourish blood, Resolve
stagnation and unblock impediment, Remove toxin
and drain the pus, Astringe wound and regenerate
new tissues
[54] 2–4 polymer urushiol Toxicodendron vernicifluum
(Stokes) F. A. Barkley Anacardiaceae Ganqi ( TOXICODENDRI RESINA) Transform stasis and unblock meridians, Alleviate
malnutrition and kill parasitic worms
[61] Capsaicin Capsicum annuum L Solanaceae Lajiao (CAPSICI FRUCTUS) Warm the middle jiao and remove cold, Promote
digestion
[61] Piperine Piper nigrum L Piperaceae Hujiao (PIPERIS FRUC TUS) Warm the middle jiao and remove cold, Regulate qi,
Transform phlegm
[65] Caffeic Acid Phenethyl Ester UN UN Fengjiao (PROPOLIS) Invigorate the weak, Transform turbidity, Relieve
wasting thirst disorder
[66] Auraptene Citrus × aurantium f. aurantium Rutaceae Zhishi (AURANTII FRUCTUS IMMATURUS);
Zhiqiao (AURANTII FRUCTUS) Zhishi: Circulate qi and resolve masses, Transform
phlegm and resolve masses; Zhiqiao: Circulate qi
and harmonize the stomach, Resolve stagnation
and promote digestion
Page 30 of 44
Chenetal. Chinese Medicine (2025) 20:53
Fig. 10 Various effects of traditional Chinese medicine in treating HAG
Fig. 11 Plants or compounds from a same family
Fig. 12 Compounds from a same class
Page 31 of 44
Chenetal. Chinese Medicine (2025) 20:53
peroxidase (GSH-Px), glutathione (GSH), and Vit C/E
can effectively eliminate ROS. ese antioxidants guard
the gastric mucosa against superoxide anion damage.
e level of ROS is increased in the mucosa of HAG
patients, resulting in GSH depletion [123]; however, the
level of ROS decreases after anti-Helicobacter treatment
[124]. Angelica keiskei and Resveratrol ameliorated the
generation of LPO. Neutral corn protein hydrolysate
elevated the production of SOD and GSH-Px, and Chae-
nomeles speciosa total triterpenoids increased SOD,
GSH-Px and CAT.
Lactatedehydrogenase (LDH) releases whenHelicobac-
terstimulates intracellular NADPH oxidase to generate
endogenous stress factors that assault the cell membrane
and cause lipid peroxidation, thereby destroying the
membrane [57]. Chaenomeles speciosatotal triterpe-
noids and Neutral corn protein hydrolysate alleviated
the up-regulation of LDH.
Malondialdehyde (MDA) is a biomarker of oxidative
stress [125], the excessive accumulation of which causes
cell membrane dysfunction. MDA increased whereas
SOD decreased in a gastric mucosal damage model [126,
127]. ree plant extracts: Licorice, Malus domestica
cv. Granny Smith, and Artemisia capillaris unb.,
and two compounds, Chaenomeles speciosa total
Fig. 13 Mechanisms of HAG injuries. (Created in BioRender. https:// BioRe nder. com/ o86q7 08. Agreement number: GD27RQB2OM.) Helicobacter
infects and survives in the stomach via various pathogenic factors. Helicobacter causes damage to the host and ultimately causes tumors
via oxidative stress, inflammation, DNA damage, apoptosis, and proliferation ways. The order in which mechanisms are listed in the figure does
not represent their order of occurrence in diseases. HopQ, Hop family adhesin HopQ; cagPAI, cytotoxin-associated gene pathogenicity island;
T4SS, type IV secretion system; CagA, cytotoxin-associated gene A protein; HBP, heptose-1, 7-bisphosphate; T5SS, type V secretion system;
VacA, vacuolating cytotoxin A; iNOS, isoform of nitric oxide synthase; COX-2, cyclooxygenase-2; MPO, myeloperoxidase; IL, interleukin; IFN-γ,
interferon-gamma; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; Bax, Bcl-2-associated X protein; Bad, Bcl-2-associated
agonist of cell death; Apaf-1, apoptotic protease activating factor-1; Bcl-2, B-cell lymphoma-2 protein; Bcl-xl, Bcl-2-like protein-1; ROS, reactive
oxygen species; LPO, lipid peroxide; MDA, malondialdehyde; LDH, lactatedehydrogenase; Keap1, kelch-like ECH-associated protein 1; NRF2, nuclear
factor erythroid-2-related factor 2; HO-1, heme oxygenase-1; pH2AX, phospho-histone H2A. X; 8-OHdG, 8-hydroxydeoxyguanosine; Mcl-1, myeloid
cell leukemia protein 1; EGFR, epidermal growth factor receptor; ADAM, a disintegrin and metalloproteinase; BrdU, 5’-bromodeoxyuridine; Ki-67,
antigen identified by monoclonal antibody Ki-67.
Page 32 of 44
Chenetal. Chinese Medicine (2025) 20:53
triterpenoids and Neutral corn protein hydrolysate,
significantly declined the production of MDA.
Phospho-histone H2A. X (pH2AX) marker, which
is linked to the generation of reactive aldehydes and
DNA damage, increases the number of nuclei in gas-
tric epithelial cells in Helicobacter-infected mice. e
2-hydroxybenzylamine decreased the number of
pH2AX-positive cells in the mice. e 8-hydroxydeoxy-
guanosine (8-OHdG) is a marker of oxidative DNA dam-
age. × Raphanobrassica karpechenkoireduced the level
of 8-OHdG in the gastric mucosa, and two compounds
Nordihydroguaiaretic acid and Arctigenin, decreased
the level of 8-OHdG in the serum (Tables4, 5).
Anti‑apoptotic eects andmechanisms inHAG
Helicobacter colonization can destroy gastric mucosal
barrier function, causing apparent cell apoptosis. Some
plant substances decrease the occurrence of cell apop-
tosis, which can cause gastric lesions or peptic ulcer
diseases. Zhang S et al. [51] found that Helicobac-
terinfection elicited cell cycle arrest at the G1/S transi-
tion. e number of G0/G1-phase (DNA/DNA synthesis)
cells significantly increased, but the number of S-phase
(DNA synthesis) cells decreased. Quercetin[51] reduced
the number of G0/G1-phase cells and increased the
number of S-phase cells, therefore protecting the gastric
mucosa and maintaining the balance between the loss
and regeneration of epithelial cells.
e B-cell lymphoma gene 2 (Bcl-2) family consists
of two subfamilies: proliferation agonists (Bcl-xl, Bcl-
2, Bcl-w, Brag-1, Bfl-1, and Mcl-1) and apoptosis ago-
nists(Bcl-xs, Bax, Bad, Bid, Bak, andHrk) [128]. Bcl-2,
BH3 interacting domain death agonist (Bid), and Bax
increased in Helicobacter-infected gastric adenocar-
cinoma [129]. Bax increased during gastric epithelial
barrier injury [130]. Bax/Bcl-2, which belongs to the
mitochondrial apoptotic pathway, is a crucial ratio that
modulates the balance between apoptosis and prolifera-
tion. Helicobacter-associated apoptosis may contribute
to cell proliferation or gastric atrophy, resulting in GC
[131]. Helicobacter colonization activated the p38 MAPK
pathway to induce apoptosis, but Quercetin reversed
this harmful effect by attenuating p38, IL-8 production,
and the declining Bax/Bcl-2 ratio. Chaenomeles speci-
osatotal triterpenoidsexhibited anti-apoptotic potency,
increasing Bcl-2-like 1 (Bcl-xl), Bcl-2, Bcl-xl/Bad, and
Bcl-2/Bax while decreasing Bad, Bax.
Pro-apoptotic proteins Bax and Bad and inflamma-
tory stimulation disrupt the integrity of the mitochon-
drial membrane, causing a decrease in the mitochondrial
membrane potential, leading to the release of cytochrome
C from the mitochondria into the cytoplasm and the
activation of Apoptotic protease activating factor-1
(Apaf-1). Apaf-1, cytochrome C and pro-caspase-9 form
apoptotic vesicles. e apoptotic vesicles cleave pro-
caspase-3 and pro-caspase-9 into cleaved caspase-3 and
−9 and ultimately cause apoptotic cell death. In addi-
tion, the superoxide produced by Helicobacter infection
in the gastric mucosa causes poly ADP‒ribose polymer-
ase-1 (PARP-1) activation and promotes the release and
development of mitochondrial apoptosis-inducing factor
(AIF). Chaenomeles speciosa total triterpenoids act as
anti-apoptotic agents by the manner mentioned above
that relieved levels of cytochrome C, Apaf-1, pro-cas-
pase-9, and cleaved caspase-3 and −9, as well as PARP-1.
(Table4, 5).
Anti‑proliferative eects andmechanisms inHAG
CagA up-regulates the pro-survival factors phospho-ERK
and Myeloid cell leukemia protein-1 (Mcl-1)in infected
mice, interfering with host cell survival and anti-apop-
totic processes that overcome epithelial self-renewal and
help sustain Helicobacter infection [132]. Helicobacter-
associated GC is associated with Bcl-2 up-regulation and
Bax decline, which induces overproliferation [118].Epi-
dermal growth factor receptor (EGFR), which regulates
epithelial cell differentiation, proliferation, and apop-
tosis [133], plays a crucial role in gastric cancer [134].
Palmatine reduced Heparin-binding epidermal growth
factor-like growth factor (HB-EGF) and p-EGFR/EGFR
levels, suppressing HAG progression.
Myc proto-oncogene (Myc/c-Myc) is an active tran-
scription factor that functions via transcriptional ampli-
fication of target genes to regulate cell differentiation and
proliferation. Helicobacter-positive patients [135] and
human gastric adenocarcinoma samples [136] have
increased Mycexpression. Two extracts of Korean Prop-
olis and Juglans regia L. significantly decreased c-Myc
among the included studies.
e cells that undergo DNA synthesis (in the S-phase
of the cell cycle) during exposure to BrdU (5’-bromod-
eoxyuridine) in the stomach glands will be labeled with
BrdU and counted. BrdU incorporation signifies that cel-
lular proliferation occurs at positions such as the base of
the gastric gland and the apoical portion. Four studies
among the included studies revealed that Caffeic acid
phenethyl ester, Licorice, Aqueous rice, and Oryza
sativa L. alleviated inflammation and decreased the
hyperplasia score (BrdU-positive cells) in animals. More-
over, Ki-67-positive cells, which aredetected across the
hyperplastic mucosa in Helicobacter-infected mice, area
marker of the proliferative index. × Raphanobrassica
karpechenkoiandJuglans regiaL.reduced the number
of Ki-67-positive cells. (Table4, 5).
Page 33 of 44
Chenetal. Chinese Medicine (2025) 20:53
Signaling pathways modulate HAG
NF‑κB
e NF-κB family members p50, p65 combine to form
homodimers and heterodimers which are retained in
the cytosol by interacting with inhibitors (IκBs). When
stimuli such as oxidative stress and inflammation are pre-
sent, IκB is phosphorylated by the IκB kinase(IKK) com-
plex, which results in the IκB/p50/p65 complex isolating
from IκB to translocate to the nucleus, bind to specific
genes, and subsequently lead to the release of inflam-
matory factors. Peptidoglycan, which is encoded by
cagPAIand recognized by nucleotide-binding oligomeri-
zation domain-containing protein 1(NOD1), enters host
cells via the T4SS and activates NF-κB [85]. e virulence
factors CagA [90, 137]and VacA induce NF-κB activa-
tion, causing the release of proinflammatory cytokines
[93]. Aside from the NOD1 sensor, HBP, ADP-heptose/
ALPK1-TIFA/NF-κB initiates initial inflammation, which
occurs even earlier than NOD1activation [138].
Persicaria capitata alleviated inflammatory cell
infestation and improved the gland arrangement with
IL-1β, IL-18, pro-IL-1, NLRP3, andpro-caspase-1reduc-
tion through elevating PI3K/AKT but suppressing
NF-κB. Korean propolis reduced p-IκBα and p-p65
levels, which decreasedthe levels of IL-1β, IL-8, TNF-
α, iNOS, and NO. Korean propolis decreased tumor
necrosis factor α-induced protein 3 (TNFAIP3 or A20),
A1a,and c-Myc, which have a noticeable positive corre-
lation with NF-κB[139, 140]andaggravate gastrointes-
tinal inflammation. Juglans regiaL. obviously improved
HAG condition (edema, erythema, inflammation,
ulcer) and subsequent disease deterioration(ulcer, atro-
phy,tumor, pale and thin mucosa), which accompanied
lower production of IL-6, COX-2/COX-1, PGE2, c-Fos,
c-Jun, c-Myc, p-p65, and pSTAT3. Angelica keiskei,
which has good anti-HAG ability, inhibits LPO, iNOS,
COX-2, MPO, IFN-γ, and NF-κB. Artemisia capilla-
ris unb.from Asteraceae revealed remarkable early-
stageanti-gastritisability andanti-chronic gastritis and
anti-precancerous lesion capacity by down-regulating
IL-1β, IL-6, TNF-α, COX-2, PGE2, gastric F4/80 protein,
and MDA with low p-p65 and pSTAT3 expression. e
nine compounds Chaenomeles speciosatotal triterpe-
noids, Neutral corn protein hydrolysate, Artemisinin,
Artesunate, Dihydroartemisinin (all from Artemisia
annua L.), Capsaicin, Piperine, Caffeic Acid Phene-
thyl Ester and Sophora alopecuroides L. total alka-
loids down-regulated NF-κB signaling because of their
low expression in p-IKK, p-IκBα, p65, and p50, which
always accompany down-regulation of cytokines such
as ILs-1β, −6, and −8, TNF-α, IFN-γ, the enzymes iNOS
and COX-2, and NO, PGE2, MPO, and MCP-1. (Fig.14
and Table4, 5, 7).
STAT3
e CagA is an apparent substance that activates
STAT3 signaling [141]. Activated JAK phosphorylated
the receptor’s cytoplasmic domain to create a docking
site for Src homology 2 domain tyrosine phosphatase
(SHP2)-containing signaling protein. e phosphoryla-
tion of a critical tyrosine residue (Tyr705) triggers STAT3
dimerization by contacting the phosphotyrosine-SH2
domain, thus mediating activation of STAT3, which
binds to DNA sequences to stimulate target genes.JAK1/
STAT3 is upstream of IL-8 and NF-κB in Helicobacter-
infected gastric epithelial cells [104], and p-STAT3 level
is related to poor survival in gastric adenocarcinoma
patients [142]. Dysregulated STAT3 activation leads to
VEGF overproduction and increased angiogenic phe-
notype in GC [143].c-Myc, which is overexpressed after
Helicobacter infection, is a STAT3 target gene and can
compensate for the role of STAT3,contributingto gastric
epithelial cell proliferation[144].
Helicobacter infection promoted ROS generation,
which elevated IL-6 production and subsequent STAT3
phosphorylation in AGS cells [145]. STAT3 activation
and subsequent tumor development do not occur with-
out the Glycoprotein 130 (gp130) receptor, which is a
signaling element of the IL-6R‒gp130 complex, and
theIL-6 family member IL-11 is a promotion element
of GC by activating STAT3 to overexpress proliferative
genes in mice [146, 147]. e gp130F759/F759 mice
extended gp130-induced STAT3 activation, whereas
indicated a negative regulation for SHP2 [148]. Another
study also found phosphorylated CagA boosted SHP2/
ERK1/2 activity, whereas unphosphorylated CagA was
inclined to activate STAT3 [149]. erefore, stomach
epithelial STAT3 targeting or IL-6R-gp130 blocking
may be therapeutic ways to prevent gastric carcinogen-
esis [150].
Helicobacter-induced and high salt diet WT mice
were sacrificed after 24 weeks (a time to establish a
CAG model) and 36 weeks (a time to establish a GC
model), respectively, after which NF-κB (p-p65) and
STAT3 (pSTAT3) were activated and inflammatory bio-
markers IL-6, COX-2, and PGE2 were overexpressed.
Juglans regiaL.treatmentalleviated pathological dam-
age to the gastric mucosa, including inflammation,
ulcers, atrophy, and adenoma, and ameliorated NF-κB,
p-p65, STAT3, pSTAT3, IL-6, COX-2/COX-1, PGE2,
c-Myc,and Ki-67, whereas increasing the levels of the
defensive protein15-PGDHand the JAK/STAT regula-
tor suppressor of cytokine signaling 1 (SOCS-1) [17].
Jeong M etal. [37]generatedCAG and GC mousemod-
els in the same wayand fed themArtemisia capillaris
unb.or Camellia sinensis L.. e two plant-derived
extractsdecreased p-p65, pSTAT3,IL-1β, IL-6, TNF-α,
Page 34 of 44
Chenetal. Chinese Medicine (2025) 20:53
COX-2, PGE2, and gastric F4/80 protein but preserved the
protective protein 15-PGDH. Park JM etal. [27]treated
Il-10(− / −)mice with a high salt diet for 24 weeks and
reported intense gastric inflammation and nodular
lesions with granular gastric mucosa. Licoriceattenuated
inflammation and tumorigenesis by suppressing p-JAK2
and p-STAT3 production, reducing ILs-1β, −6, and −8,
TNF-α, iNOS, COX-2, PGE2,and other cytokine arrays
for inflammation and tumorigenesis, including bFGFand
FcrRIIB. e anti-HAG and GC potencies of Juglans
regiaL., Licorice, Artemisia capillaris unb., and
Camellia sinensis Lmay share the same mechanism: the
IL-6R/gp130/JAK/STAT3 pathway. (Fig.14 and Table4,
5, 7).
MAPK
MAPKK and MAPKKK are key kinases involved
in MAPK signaling, which regulates inflammatory
Fig. 14 Signaling pathways regulating the HAG. (Created in BioRender. https:// BioRe nder. com/ m32b2 29. Agreement number: RT27ZDTNZS.)
LPS, peptidoglycan, VacA, and CagA are bacterial fragments from Helicobacter, and these fragments cause the release of multiple factors that take
part in inflammation, apoptosis, overproliferation, and tumors through different signaling pathways including NF-κB, JAK/STAT3, MAPK, TLR4/
MyD88, PI3K/AKT, NLRP3/Caspase-1, and NRF2/HO-1. ROS, reactive oxygen species; IL-6R, interleukin 6 receptor; gp130, glycoprotein 130; JAK,
janus kinase; STAT3, signal transducer and activator of transcription 3; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; TLR4, toll-like receptor
4; MyD88, myeloid differentiation primary response gene 88; TRAF6, tumor necrosis factor receptor-associated factor 6; IKK, IκB kinase; IκBα,
inhibitor of kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; ASC, apoptosis associated speck-like protein containing a CARD;
AP-1, activator protein 1; Keap1, kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid-2-related factor 2; HO-1, heme oxygenase-1;
MKK, mitogen-activated protein kinase kinase; MEK, mitogen-activated extracellular signal-regulated kinase; MAPKK, MAP Kinase Kinase;
MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, jun N-terminal kinase; LPS, lipopolysaccharides;
CagA, cytotoxin-associated gene A protein; VacA, vacuolating cytotoxin A; NOD1, nucleotide-binding oligomerization domain-containing protein
1; HB-EGF, heparin-binding epidermal growth factor-like growth factor; ADAM17, a disintegrin and metalloproteinase 17; EGFR, epidermal growth
factor receptor; MMP10, matrix metalloproteinase 10; Apaf-1, apoptotic protease activating factor-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8,
interleukin-8; IL-17, interleukin-17; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; iNOS, inducible nitric oxide synthase; NO, nitric oxide; COX-2,
cyclooxygenase-2; PGE2, prostaglandin E2.
Page 35 of 44
Chenetal. Chinese Medicine (2025) 20:53
response, cell growth, differentiation, proliferation, and
apoptosis [151]. MAPKs include three primary mem-
bers: extracellular-signal-regulated kinases (ERK), c-jun
N-terminal kinases (JNK), and MAPK14 (p38α). IL-8 and
IL-17 are the dominant cytokines that induce inflamma-
tion and carcinoma. IL-17 can induce cytokines such as
TNF-α, IL-1β, and IL-8 [152]. ERK1/2, p38 MAPK, and
AP-1 mediate IL-8 secretion during Helicobacter infec-
tion [153–155]. For example, peptidoglycan injected
via the T4SS is recognized by NOD1, thereby eliciting
NF-κB, MAPK, and AP-1 activation, which initiate the
production of cytokines. LPS from Helicobactercauses
monocytic lineage cells to release IL-8 through NF-κB
and MAPK pathways [155]. ERK1/2 and NF-κB signal-
ingare two ways in which IL-17 can increaseIL-8 expres-
sion [156, 157]. In addition, c-Fos and c-Jun proteins,
which are essential for cell proliferation, combine to form
AP-1, which produces IL-8 with the help of activating
NF-κB. Likewise, CagA interacts with ERK1/2 [158]and
p38 MAPK. CagA translocates into human B lymphoid
cells, where it interacts with SHP2, which is indispensa-
ble in p38 MAPK pathway activation, causing the up-reg-
ulation of Bcl-2 and Bcl-x[159].
Alpinia officinarum Hance has good efficiency in
suppressing gastric inflammation response by reducing
p-ERK1/2, p-JNK, and p-p38 and ameliorating down-
stream production of IL-1β, IL-17, and TNF-α. Querce-
tinfrom the plant Polygonum capitatum restrained the
MAPK pathway by reducing p38 MAPK and IL-8 levels.
Quercetin presented remarkable capacity on regulat-
ing the equilibrium between apoptosis and proliferation
that declined G0/G1, G2/M phase cells, and Bax but
enhanced S-phase cells and Bcl-2.
It has been confirmed that Palmatine, a botanical iso-
quinoline alkaloid, was initially isolated from Coptis
chinensis Franch., suppressed ADAM17/EGFR sign-
aling to inhibit MMP10 generation, thereby elevating
the anti-inflammatory effect. On the other hand, Pal-
matine increased Reg3a levels but decreased CXCL16
production, therefore ameliorating pathological dam-
age and improving the host’s defensive ability. EGFR is
responsible for the increase in MMP10. EGFR interacts
with EGFR ligands such as HB-EGF, whose extracellular
domain should be shed with the aid of ADAM17. Pal-
matinehampered the cleavage of HB-EGF by ADAM17
in Helicobacter infection rats. MMP10, which has a sig-
nificant correlation with CagA-positive Helicobacter
infection, can control cytokine-associated chemotaxis,
which causes leukocytes to migrate to the infected site
and aids in the evolution of inflammation. ismight be
a way by which Helicobacter infection induces hyperplas-
tic polyps and gastric cancer [160]. Inhibitors targeting
ERK1/2 and JNK impeded such MMP10 secretion, which
indicated MAPK may be upstream of MMP10 [161].
(ADAM17-HB-EGF/EGFR/MMP10, MAPK/MMP10)
(Fig.14 and Table4, 5, 7).
Table 7 Signaling pathway of phytomedicine for HAG
Serial Number Signaling Pathway Plant extract OR Compound
1
(16 types) NF-κB Persicaria capitata, Korean Propolis, Juglans regia L., Angelica keiskei,
Artemisia capillaris Thunb., Camellia sinensis L., Chaenomeles speciosa total
triterpenoids, Neutral corn protein hydrolysate, Artemisinin, Artesunate,
Dihydroartemisinin, Curcumin, Capsaicin, Piperine, Caffeic Acid Phenethyl
Ester, Sophora alopecuroides L. total alkaloids
2
(4 types) JAK/STAT3 Juglans regia L., Licorice, Artemisia capillaris Thunb.,
Camellia sinensis L
3
(3 types) MAPK Alpinia officinarum Hance, Quercetin, Palmatine
4
(2 types) TLR4/MyD88 Chaenomeles speciosa total triterpenoids,
Neutral corn protein hydrolysate
5
(2 types) NLRP3/Caspase-1 Persicaria capitata, Chaenomeles speciosa total triterpenoids
6
(1 type) PI3K/AKT Persicaria capitata
7
(1 type) NRF2/HO-1 Juglans regia L
1
(3 pathways) NF-κB, PI3K/AKT, NLRP3/Caspase-1 Persicaria capitata
NF-κB, JAK/STAT3, NRF2/HO-1 Juglans regia L
NF-κB, TLR4/MyD88, NLRP3/Caspase-1 Chaenomeles speciosa total triterpenoids
2
(2 pathways) NF-κB, JAK/STAT3 Artemisia capillaris Thunb.,
Camellia sinensis L
NF-κB, TLR4/MyD88 Neutral corn protein hydrolysate
Page 36 of 44
Chenetal. Chinese Medicine (2025) 20:53
TLR4/MyD88
TLR4, a key Toll-like receptor in the HAG process,
induced inflammation on the stomach through the com-
plex of MyD88, IL-1R-associated protein kinase (IRAK),
and tumor necrosis factor receptor-associated fac-
tor 6 (TRAF6), resulting in the upregulation of NF-κB,
ERK, JNK, and p38 and the activation of proinflam-
matory cytokines such as IL-6. IL-1 and LPS induced
the TLR4/MyD88 signaling pathway activation [162].
Two compounds from included studies, Chaenomeles
speciosa total triterpenoids and Neutral corn pro-
tein hydrolysate, dampened TLR4 and MyD88 expres-
sion, which restrained NF-κB signaling as well and
relieved mucosal damage, including swelling and inflam-
matory infiltration. Chaenomeles speciosa total triter-
penoids significantly relieved inflammation by declining
levels of MPO, NLRP3, and multiple cytokines (IL-1β,
IL-6, IL-18, KC, TNF-α, and MCP-1). Neutralcorn pro-
tein hydrolysate attenuated gastritis through reduction
of MPO, IL-1β, IL-6, KC, TNF-α, and MCP-1.
TLR4/MyD88/NF-κB could regulate the cell balance
between apoptosis and proliferation as well. Silenc-
ing high-mobility group protein B1 (HMGB1)/TLR4/
MyD88 signaling, which inhibited the downstream
NF-κB pathway, prevented overproliferation. e same
study revealed that inhibiting HMGB1 down-regulated
Bcl-2 and MMP-2 but up-regulated Bax in gastric can-
cer cells [163]. Chaenomeles speciosa total triterpe-
noidsincreased the levels of the pro-proliferative factors
Bcl-2 and Bcl-xl but decreased the levels of the pro-apop-
totic factor Bax, which inhibits over-apoptosis, possibly
via the NF-κB pathway. is compound derived from
Chaenomeles speciosa (Sweet) Nakaideclined the for-
mation of apoptotic vesicle, which is composedof Apaf-
1, cytochrome C, and pro-caspase-9. (TLR4/MyD88/
NF-κB) (Fig.14 and Tables4, 5, 7).
Others
Persicaria capitata, a plant from Polygonaceae, regu-
lated NF-κB, PI3K/AKT, and NLRP3/Caspase-1 simul-
taneously to reduce Helicobacter density and relieve
inflammatory cell infiltration and disordered arrange-
ment of glands in SD rats gastric. Persicaria capitata
is an inhibitor of NF-κB that alleviated HAG by reduc-
ing production of pro-IL-1β, IL-1β, IL-18, NLRP3, and
pro-caspase-1,but elevating AKTand p-AKT levels. e
interaction of CagA with activated Hepatocyte Growth
Factor Receptor (Met) via its CRPIA motif is vital for
downstream PI3K/AKT signaling stimulation and pleio-
tropic transcriptional responses, such as those involving
β-catenin and NF-κB [164]. Inhibiting AKT helps NF-κB
dissociate from IκB, further regulating downstream tar-
get gene expression, such as triggering the release of
inflammatory factors. GES-1 cells and Helicobacter
infection in vivo aggravate the inflammatory response
by down-regulating AKT and increasing NF-κB, which
induce NLRP3, pro-IL-1β, IL-1β, and IL-18. Further-
more, NLRP3 further induces increased levels of IL-1β
and IL-18 [12]. (PI3K/AKT/NF-κB).
e NLRP3 inflammasome is a notable factor in host
response to microbes and tissue lesions, which elicits
inflammatory and apoptotic action. Helicobacter viru-
lence factors such as T4SS and FlaA stimulate NF-κB
and AP-1 by pattern-recognition receptors (PRRs), and
subsequently NLRP3 oligomerizes and capsase-1 acti-
vates, which will cleave pro-IL-1β [165]. Persicaria
capitata decreased IL-1β, IL-18, pro-IL-1β, NLRP3,
and pro-caspase-1. CAG mice infected with Helico-
bacter were given Chaenomeles speciosatotal triter-
penoids, and their chronic gastritis and atrophy glands
were improved by the reduction of thioredoxin-inter-
acting protein (TXNIP), NLRP3, pro-caspase-1, and
caspase-1 levels. (NLRP3/Caspase-1).
Nuclear factor erythroid-2-related factor 2 (NRF2)
plays a vital role in cell autophagy in order to con-
flict oxidative stress and inflammation in Helicobac-
ter infection cells and mice [166]. einducible host
defensive enzyme Heme Oxygenase-1 (HO-1), whose
generation requires NRF2, regulates antioxidative
stress processes to suppress CagA action [167]. Jug-
lans regia L.lowered Kelch-like ECH-associated pro-
tein 1(Keap1) levels while increasing NRF2 and HO-1
expression to prevent inflammation and oxidative stress
in gastric mucosa. (NRF2/HO-1) (Fig.14 and Table4,
5, 7).
Traditional Chinese Medicine treating HAG
TCM has rich experience in treating gastrointesti-
nal diseases. Nine plants, including Zhizi (Ripe ruit
extract, Geniposide, Genipin), Gancao (plant extract,
18β-Glycyrrhetinic Acid), Dasuan (Clove extract),
Huzhang (whole plant extract, Quercetin), Huangqin
(Baicalin, Baicalein), Huanglian (Epiberberine, Copti-
sine, Palmatine), Qinghao (Artemisinin, Artesunate,
Dihydroartemisinin), Niubangzi (Arctigenin), Jian-
ghuang (Curcumin) from TCM are promising plant
medicines because these botanical medicines extracts
or compounds derived from them are most frequently
administrated in rats or mice for HAG of the included
literatures and are expected for more in-depth stud-
ies. As Table6 shows, 25 plants for HAG are commonly
used medicines in TCM. Among these TCM medicines,
four plants have notable anti-bacterial activities (Shiliupi,
Dasuan, Wumei, and Ganqi) and fifteen plants have sig-
nificant anti-inflammatory effects (Zhizi, Huzhang, Gan-
cao, Dasuan, Yinchen, Mugua, Huangqin, Yinyanghuo,
Page 37 of 44
Chenetal. Chinese Medicine (2025) 20:53
Huangqi, Niubangzi, Huanglian, Qinghao, Hujiao, Zhishi,
and Zhiqiao), which indicate TCM has good advantages
and prospects in the discovery of anti-HAG drugs. To
discuss further, we found seven plants are conducive for
stomachache (Yanhusuo, Huzhang, Gancao, Gaoliangji-
ang, Mugua, Yinyanghuo, Jianghuang), nine for flatulence
(Yanhusuo, Daoya, Mugua, Ganqi, Jianghuang, Lajiao,
Hujiao, Zhishi, Zhiqiao), and seven for gastrointestinal
function improvement (Gancao, Daoya, Gaoliangjiang,
Huangqi, Lajiao, Hujiao, Fengjiao). In addition, nine
plants are beneficial for hyperemia, erythema, and hem-
orrhage in mucous membrane, ulcer, and are labeled “huo
xue hua yu, po xue tong jing, yang xue zhi xue” (Chinese
pinyin) in TCM (Yanhusuo, Shiliupi, Zhizi, Huzhang,
Dasuan, Huangqin, Huangqi, Ganqi, Jianghuang), which
deserved to investigate their potency for precancerous
conditions such as atrophy, intestinal metaplasia, and
carcinoma. (Fig.10 and Table6).
Numerous TCM formulas are commonly used in clinics
for their more effective and versatile efficacy than a sin-
gle plant medicine. Banxia Xiexin decoction, which con-
tains berberine, palmatine, baicalein, and glycyrrhizin, is
more instructive to HAG, gastric atrophy, and IM than
control group patients [168]. Multiple classical ancient
formulas from TCM, including Banxia Xiexin decoction
[169], Qingwei San, Huanglian Wendan decoction [170],
and Zuojin pill [171], which all contain Huanglian (Cop-
tis chinensis Franch.) have superior anti-inflammatory
activities and higher Helicobacter eradication rates. Jian-
ghuang (Curcuma longa L.) and Gaoliangjiang (Alpinia
officinarum Hance) and Shengjiang/Ganjiang (Zingiber
officinale Roscoe) are three noteworthy herbs from
Zingiberaceae curing inflammation, pain, and diges-
tion disease on stomach in TCM, and they are common
medicine used in decoctions for HAG, such as Banxia
Xiexin decoction, Huangqi Jianzhong decoction, and
Gancao Ganjiang decoction. Furthermore, several plants,
including Panax ginseng C. A. Mey (Renshen), Rhei
Radix Et Rhizoma (Dahuang), Poria cocos (Schw.) Wolf
(Fuling), Panax notoginseng (Burk.) F. H. Chen (Sanqi),
and Pineilia ternata (unb.) Breit (Banxia), are highly
potential herbal medicines as well [170], though there are
not detailed studies for their anti-HAG potency in animal
models. (Fig.10 and Table6).
Clinical studies ofphytomedicine used inHAG
Among the phytomedicines we included, several well-
studied plant extractsor plant-derived compoundshave
progressed to clinical trials. For example, randomized,
double-blind, controlled trials have demonstrated that
broccoli can alleviate inflammatory syndrome in patients
[172] and prevent lipid peroxidation in the mucosa [173].
However, when administered alone, it is ineffective in
eradicating Helicobacter. A randomized, placebo-con-
trolled study indicated that administration of broccoli
sprouts, which contain sulforaphane, an isothiocyanate
with potent anti-inflammatory and antioxidant prop-
erties, has been shown to reduce levels of urease, Heli-
cobacter stool antigen, and serum pepsinogens I and II
[174]. Besides, Glycyrrhiza glabra (licorice) has also
entered clinical trials in HAG, and randomized con-
trolled clinical trials demonstrated licorice alleviated
Helicobacter infection, chronic inflammation, and gas-
trointestinal symptoms in humans [175, 176]. A rand-
omized double-blind, placebo-controlled studyrevealed
that β-caryophyllene relieved Helicobacter-infected
patients’ nausea and epigastric pain and decreased the
serum IL-1β levels [177]. Additionally, berberine [178],
mastic gum [179], Japanese apricot (Prunus mume Sie-
bold et Zucc.) [180], Korean red ginseng [181], and
Brazilian green propolis [182] have demonstrated posi-
tive effects on Helicobacter eradication in clinical ran-
domized controlled trials. Further investigation into
optimal dosages and co-administration strategies in
human clinical trials is warranted. Moreover, a South
Korean clinical study observed that the intake of total
dietary carotenoids or specific carotenoid subclasses was
inversely correlated with the risk of GC. is association
was also evident in patients infected with Helicobacter
[183]. Furthermore, a population-based study in China
suggested that garlic consumption was inversely associ-
ated with Helicobacter infection and may have a preven-
tive effect on GC [184]. However, two large prospective
cohort studies in the United States found no significant
association between garlic intake and the risk of Helico-
bacter infection or gastric cancer [185].
Moreover, after conducting an exhaustive search of the
official websites of WHO’s Tier 1 Clinical Trial Registries
(including those of China, the United States, the Euro-
pean Union, Japan, and Iran), we found that berberine,
when combined with antibiotics and acid inhibitors, con-
stitutes a significant proportion of therapeutic regimens
in ongoing or completed clinical trials for HAG. ese
protocols are anticipated to provide additional clinical
observational evidence in the future. eir registration
numbers are as follows: ChiCTR2300077074, ChiCTR-
IOR-17013319 (for more information, visit http://
www. chictr. org. cn), NCT06603688, NCT06514274,
NCT05014334, NCT04697186, NCT03609892,
NCT02633930, and NCT02296021 (for more informa-
tion, visit http:// clini calTr ials. gov/). In addition, the
registration protocols for the clinical trials of Banxia
Xiexin Decoction (ChiCTR2000034509, for more infor-
mation, visit http:// www. chictr. org. cn. NCT06340724,
for more information, visit http:// clini calTr ials. gov/) in
Page 38 of 44
Chenetal. Chinese Medicine (2025) 20:53
the treatment of HAG merit particular attention. is is
because Banxia Xiexin Decoction is extensively utilized
in clinical practice for HAG treatment in China [186],
and berberine, an important component derived from
Huanglian (Coptis chinensis Franch.), plays a crucial role
in this formula. erefore, we conclude that the afore-
mentioned plant extracts and compounds hold signifi-
cant potential for clinical development.
Conclusion andfuture prospect
is systematic review demonstrates that plant-derived
extracts and compounds have favorable anti-Helicobacter
and anti-inflammatory properties through modulating
different mechanisms and signaling pathways including
NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT,
NLRP3/Caspase-1 and NRF2/HO-1. Further exploration
of the application of plant extracts and compounds to
humans is needed.
For HAG, bacterial infection and inflammation are
the earliest lesions. is systematic review concen-
trates on the field of phytopharmaceuticals through a
comprehensive search of databases, focusing on anti-
Helicobacter and anti-inflammatory effects as essential
indications to identify therapies that can curb HAG at
an early stage. Both traditional alternative therapies
and modern medicine agree on the importance of early
treatment in reversing disease outcomes and improving
patient prognosis [187]. According to the Correa cas-
cade [3], infection and gastritis are the starting points
for later atrophy, hyperplasia and cancer, so the active
search for antimicrobial and anti-inflammatory [2] phy-
tomedicines is highly valuable for the prevention of
precancerous lesions and cancer. As presented in Fig.9.
(Phytomedicines act on Correa cascade), we identify
plants or compounds based on their advantages at dif-
ferent stages, which will facilitate researchers in select-
ing a specific plant or compound corresponding with
their study purpose.
Additionally, the ever-increasing antibiotic resistance
has led to low efficiency in eradicating Helicobacter.
Urgent requirements for novel drugs or new personal-
ized combined therapies are challenging assignments
for researchers. Aside from the inefficient bacteria elimi-
nation dilemma, the overuse of antibiotics elicits gut
microbiota alterations, which could induce multiple gas-
trointestinal invalidities such as low digestive and absorp-
tive function and inflammatory bowel disease [188]. is
systematic review, which excavates therapeutic medicinal
plants and bioactive phytochemicals, may alleviate the
pressing need for antibiotic replacement and gastrointes-
tinal microbiota-regulating drugs.
According to our comprehensive findings, sixteen
families, especially Asteraceae, Fabaceae and Rosaceae
, and compounds from Terpenoids, Alkaloids, Phenols,
and Flavonoids that are potential candidates for new
drugs treating HAG show promise for clinical trials. Ter-
penes, which could transform into Terpenoids and act
as anti-oxidative active substances in bodies, are worth
studying. Owing to the close relationship between Flavo-
noids’ structure and activity, these natural agents possess
an outstanding anti-Helicobacter effect [189]. Prunus
mume Sieb. et Zucc. (Wumei) and Chaenomeles speciosa
(Sweet) Nakai (Mugua) from Rosaceae; Curcuma longa L.
(Jianghuang) and Alpinia officinarum Hance (Gaoliangji-
ang) from Zingiberaceae; Artemisia annua L. (Qinghao),
Arctium lappa L. (Niubangzi), and Artemisia capillaris
unb. (Yinchen) from Asteraceae are promising sources
for new drugs. We propose researchers prioritize plants
or compounds belonging to these families or com-
poundclasses, as they may offer promising prospects for
enhanced clinical outcomes and novel drug development
within this domain. (Figs.11 and 12).
Furthermore, we have summarized plant extracts and
plant-derived compounds that hold significant potential
for clinical development, thereby providing readers with
valuable insights. Broccoli, licorice, Prunus mume Sie-
bold et Zucc., mastic gum, Korean red ginseng, Brazilian
green propolis, garlic, β-caryophyllene, berberine, and
carotenoids have been evaluated in clinical trials, dem-
onstrating their potential value in the treatment of HAG.
Notably, berberine shows promise as a potential combi-
nation drug for triple or quadruple therapies, supported
by a series of high-quality completed or ongoing clinical
trials. e mechanisms of multiple components in Banxia
Xiexin Decoction warrant further investigation, given its
prominence as a traditional medicine for gastritis and the
fact that berberine is derived from this decoction.
Nevertheless, quality of included studies in this system-
atic review was medium. For instance, some studies had
incomplete randomization method and blinding informa-
tion regarding the experimental procedure, which made
it difficult to ensure the accuracy of evaluation using the
SYRCLE tool [9]. Additionally, all studies were conducted
on animal models due to their physiological similarities
with humans; thus, it remains uncertain whether these
plant-derived components can be effective in humans.
Furthermore, diverse methods employed in animal
models and drug administrations pose challenges when
comparing therapies efficacy. Intervention of extracts or
compounds is various; indicators and parameter units
of anti-Helicobacter or anti-inflammatory activities are
multiple, which lead to difficulty in data incorporation
and cause a comprehensive meta-analysis or one specific
intervention meta-analysis hard to achieve.
Abbreviations
HAG Helicobacter-associated gastritis
Page 39 of 44
Chenetal. Chinese Medicine (2025) 20:53
Hp Helicobacter
CagA Cytotoxin-associated gene A protein
VacA Vacuolating cytotoxin A
IL-1β Interleukin-1β
TNF-α Tumor necrosis factor α
IFN-γ Interferon γ
iNOS Inducible nitric oxide synthase
NO Nitric oxide
COX-2 Cyclooxygenase-2
PGE2 Prostaglandin E2
ROS Reactive oxygen species
LPS Lipopolysaccharides
IKK IκB kinase
IκBα Inhibitor of kappa B
JAK Janus kinase
STAT3 Signal transducer and activator of transcription 3
MEK Mitogen-activated extracellular signal-regulated kinase
ERK1/2 Extracellular signal-regulated kinase 1/2
JNK Jun N-terminal kinase
PI3K Phosphoinositide 3-kinase
AKT Protein kinase B
TLR4 Toll-like receptor 4
MyD88 Myeloid differentiation primary response gene 88
NLRP3 NOD-like receptor thermal protein domain associated protein 3
AP-1 Activator protein 1
Keap1 Kelch-like ECH-associated protein1
NRF2 Nuclear factor erythroid-2-related factor 2
HO-1 Heme oxygenase-1
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s13020- 025- 01093-2.
Supplementary Material 1
Acknowledgements
Not applicable.
Author’s contribution
ZHL, ZY, and HXZ designed the study; WLW, XYC, DNC, NL collected and
analyzed the data; NL, JWL, WD, HRZ assessed the methodological quality and
drew the figures; DNC wrote the manuscript. All authors read and approved
the final manuscript.
Funding
This research was funded by the Scientific and Technological Innovation
Project, China Academy of Chinese Medical Sciences (CI2021A00606); Young
Elite Scientists Sponsorship Program by China Association of Chinese Medi-
cine (CACM-(2022-QNRC2-B06)); Funding for Clinical Research at High-Level
Traditional Chinese Medicine Hospitals in China Central (DZMG-QNGG0005);
the Fundamental Research Funds for the Central Public Welfare Research Insti-
tutes (YZX-202237 and YZX-202241); and Beijing Traditional Chinese Medicine
Inheritance “3 + 3 Project” (2015-JC-31).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Hai-
yuncang, Dongcheng District, Beijing 100700, China. 2 College of Traditional
Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San
Huan Dong Lu, Chaoyang District, Beijing 100029, China. 3 Institute for Brain
Disorders, Beijing University of Chinese Medicine, Beijing 100700, China.
4 Institute of Basic Theory for Chinese Medicine, China Academy of Chinese
Medical Sciences, No. 16 Nanxiaojie, Dongzhimen Nei, Dongcheng District,
Beijing 100700, China. 5 Institute of Basic Research in Clinical Medicine, China
Academy of Chinese Medical Sciences, Beijing 100700, China.
Received: 21 June 2024 Accepted: 10 March 2025
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