Gastritis and gastric ulcers are common gastric diseases that are caused by infection, drugs, alcohol consumption, or stress. These conditions lead to increased inflammatory cytokines and recruitment of leukocytes, which damage the stomach mucosa and exacerbate disease severity. Sicyos angulatus (SA), an annual vine in the Cucurbitaceae family, is known to have an anti-inflammatory effect, but its efficacy for preventing gastritis and gastric ulcers has not yet been evaluated. In the present study, we investigated the gastroprotective effect of SA using a hydrochloric acid/ethanol-induced gastric mucosal injury mouse model and lipopolysaccharide (LPS)-stimulated KATO III cells. Macroscopic analysis revealed a reduction in gastric ulcer area. Similarly, histopathological analysis showed a dose-dependent decrease in gastric mucosal injury, with significant improvement at 750 mg/kg of SA treatment. Gene expressions of inflammatory cytokines, chemokines, and adhesion molecule were reduced in the SA-administered group. Immunohistochemical staining indicated that SA significantly decreased neutrophil infiltration in the lamina propria and epithelium of the stomach. Kaempferol, a major bioactive flavonoid of SA, also improved gastric injury by reducing macroscopic and microscopic lesions, inflammatory mediator gene expression, and neutrophil infiltration. Furthermore, both SA and kaempferol downregulated LPS-mediated increases in inflammatory cytokines and chemokines following inhibition of p38 and c-Jun N-terminal kinase (JNK) phosphorylation in KATO III cells. These results suggest that SA can ameliorate gastric mucosal injury by inhibiting the recruitment of inflammatory cells, particularly neutrophils, and by suppressing p38 and JNK phosphorylation.
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References
1.
SáenzJB, MillsJC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol, 2018; 15(5):257–273; doi:10.1038/nrgastro.2018.5
2.
AllenA, PearsonJP, BlackburnA, et al.Pepsins and the mucus barrier in peptic ulcer disease. Scand J Gastroenterol, 1988; 146:50–57; doi:10.3109/00365528809099130
3.
FuS, ChenJ, ZhangC, et al.Gastroprotective effects of Periplaneta americana L. Extract against ethanol-induced gastric ulcer in mice by suppressing apoptosis-related pathways. Front Pharmacol, 2021; 12:798421; doi:10.3389/fphar.2021.798421
4.
YibirinM, De OliveiraD, ValeraR, et al.Adverse effects associated with proton pump inhibitor use. Cureus, 2021; 13(1):e12759; doi:10.7759/cureus.12759
5.
HerzogP, HoltermüllerK. Antacid therapy–changes in mineral metabolism. Scand J Gastroenterol, 1982; 75:56–62.
6.
KwonSC, KimJH. Gastroprotective effects of irsogladine maleate on ethanol/hydrochloric acid induced gastric ulcers in mice. Korean J Intern Med, 2021; 36(1):67–75; doi:10.3904/kjim.2018.290
7.
YangHJ, KimMJ, KwonDY, et al.Gastroprotective actions of Taraxacum coreanum Nakai water extracts in ethanol-induced rat models of acute and chronic gastritis. J Ethnopharmacol, 2017; 208:84–93; doi:10.1016/j.jep.2017.06.045
8.
BodeC, BodeJC. Alcohol’s role in gastrointestinal tract disorders. Alcohol Health Res World, 1997; 21(1):76–83.
9.
LiuJ, LinH, YuanL, et al.Protective effects of Anwulignan against HCl/ethanol-induced acute gastric ulcer in mice. Evid Based Complement Alternat Med, 2021; 2021:9998982; doi:10.1155/2021/9998982
10.
KimYS, LeeJH, SongJ, et al.Gastroprotective effects of Inulae Flos on HCl/Ethanol-Induced gastric ulcers in rats. Molecules, 2020; 25(23):5623; doi:10.3390/molecules25235623
11.
ZhangSL, LollieTK, ChenZ, et al.Histopathologic diagnosis of gastritis and gastropathy: A narrative review. Dig Med Res, 2023; 6:9–9; doi:10.2103/7/dmr-22-42
12.
ToyoshimaO, NishizawaT, YoshidaS, et al.Endoscopy-based Kyoto classification score of gastritis related to pathological topography of neutrophil activity. World J Gastroenterol, 2020; 26(34):5146–5155; doi:10.3748/wjg.v26.i34.5146
13.
YoshikawaT, NaitoY. The role of neutrophils and inflammation in gastric mucosal injury. Free Radic Res, 2000; 33(6):785–794; doi:10.1080/10715760000301301
14.
GugliandoloE, CordaroM, FuscoR, et al.Protective effect of snail secretion filtrate against ethanol-induced gastric ulcer in mice. Sci Rep, 2021; 11(1):3638; doi:10.1038/s41598-021-83170-8
15.
LiWS, LinSC, ChuCH, et al.The gastroprotective effect of naringenin against ethanol-induced gastric ulcers in mice through inhibiting oxidative and inflammatory responses. Int J Mol Sci, 2021; 22(21):11985; doi:10.3390/ijms222111985
16.
PrinceLR, AllenL, JonesEC, et al.The role of interleukin-1β in direct and Toll-like receptor 4-mediated neutrophil activation and survival. Am J Pathol, 2004; 165(5):1819–1826; doi:10.1016/s0002-9440(10)63437-2
17.
FieldingCA, McLoughlinRM, McLeodL, et al.IL-6 regulates neutrophil trafficking during acute inflammation via STAT31. J Immunol, 2008; 181(3):2189–2195; doi:10.4049/jimmunol.181.3.2189
18.
AtaieKachoieP, PourgholamiMH, MorrisDL. Inhibition of the IL-6 signaling pathway: A strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev, 2013; 24(2):163–173; doi:10.1016/j.cytogfr.2012.09.001
19.
Van DammeJ, Van BeeumenJ, OpdenakkerG, et al.A novel, NH2-terminal sequence-characterized human monokine possessing neutrophil chemotactic, skin-reactive, and granulocytosis-promoting activity. J Exp Med, 1988; 167(4):1364–1376; doi:10.1084/jem.167.4.1364
20.
ManzoorZ, KohY-S. Mitogen-activated protein kinases in inflammation. J BacteriolVirol, 2012; 42(3):189–195; doi:10.4167/jbv.2012.42.3.189
21.
IpYT, DavisRJ. Signal transduction by the c-Jun N-terminal kinase (JNK)—from inflammation to development. Curr Opin Cell Biol, 1998; 10(2):205–219; doi:10.1016/s0955-0674(98)80143-9
22.
HerlaarE, BrownZ. p38 MAPK signalling cascades in inflammatory disease. Mol Med Today, 1999; 5(10):439–447; doi:10.1016/s1357-4310(99)01544-0
23.
TakahashiS, KetoY, FujitaT, et al.FR167653, a p38 mitogen-activated protein kinase inhibitor, prevents Helicobacter pylori-induced gastritis in Mongolian gerbils. J Pharmacol Exp Ther, 2001; 296(1):48–56.
24.
KobayashiH, KurokawaS, IkedaK. Dairyland populations of bur cucumber (Sicyos angulatus) as a possible seed source for riverbank populations along the Abukuma River, Japan. Weed Biol Manag, 2012; 12(4):147–155; doi:10.1111/j.1445-6664.2012.00447.x
25.
ChoiJH, NohJR, KimYH, et al.Sicyos angulatus prevents high-fat diet-induced obesity and insulin resistance in mice. Int J Med Sci, 2020; 17(6):787–798; doi:10.7150/ijms.42247
26.
KimYH, NohJR, HwangJH, et al.Sicyos angulatus ameliorates atherosclerosis through downregulation of aortic inflammatory responses in apolipoprotein E-deficient mice. Exp Ther Med, 2017; 14(6):5863–5870; doi:10.3892/etm.2017.5271
27.
AnJP, DangLH, HaTKQ, et al.Flavone glycosides from Sicyos angulatus and their inhibitory effects on hepatic lipid accumulation. Phytochemistry, 2019; 157:53–63; doi:10.1016/j.phytochem.2018.10.013
28.
AnJP, ChoiJH, HuhJ, et al.Anti-hepatic steatosis activity of Sicyos angulatus extract in high-fat diet-fed mice and chemical profiling study using UHPLC-qTOF-MS/MS spectrometry. Phytomedicine, 2019; 63:152999; doi:10.1016/j.phymed.2019.152999
29.
LiQ, HuX, XuanY, et al.Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO. Acta BiochimBiophys Sin (Shanghai), 2018; 50(3):246–253; doi:10.1093/abbs/gmy002
30.
KimSH, ParkJG, SungGH, et al.Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain. Mol Nutr Food Res, 2015; 59(7):1400–1405; doi:10.1002/mnfr.201400820
31.
BeberAP, de SouzaP, BoeingT, et al.Constituents of leaves from Bauhinia curvula Benth. exert gastroprotective activity in rodents: Role of quercitrin and kaempferol. Inflammopharmacology, 2018; 26(2):539–550; doi:10.1007/s10787-017-0313-8
32.
LiuJ, WangF, LuoH, et al.Protective effect of butyrate against ethanol-induced gastric ulcers in mice by promoting the anti-inflammatory, anti-oxidant and mucosal defense mechanisms. Int Immunopharmacol, 2016; 30:179–187; doi:10.1016/j.intimp.2015.11.018
33.
LaineL, WeinsteinWM. Histology of alcoholic hemorrhagic “gastritis”: A prospective evaluation. Gastroenterology, 1988; 94(6):1254–1262; doi:10.1016/0016-5085(88)90661-0
34.
CapucettiA, AlbanoF, BonecchiR. Multiple roles for chemokines in neutrophil biology. Front Immunol, 2020; 11:1259; doi:10.3389/fimmu.2020.01259
35.
TangX, LiuJ, DongW, et al.Protective effect of kaempferol on LPS plus ATP-induced inflammatory response in cardiac fibroblasts. Inflammation, 2015; 38(1):94–101; doi:10.1007/s10753-014-0011-2
36.
ZhangR, AiX, DuanY, et al.Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways. Biomed Pharmacother, 2017; 89:660–672; doi:10.1016/j.biopha.2017.02.081
37.
WenZ, LiX, LuQ, et al.Health related quality of life in patients with chronic gastritis and peptic ulcer and factors with impact: A longitudinal study. BMC Gastroenterol, 2014; 14:149; doi:10.1186/1471-230X-14-149
den HollanderWJ, KuipersEJ. Current pharmacotherapy options for gastritis. Expert OpinPharmacother, 2012; 13(18):2625–2636; doi:10.1517/14656566.2012.747510
WangchukP. Therapeutic applications of natural products in herbal medicines, biodiscovery programs, and biomedicine. J Biol Act Prod Nat, 2018; 8(1):1–20; doi:10.1080/22311866.2018.1426495
42.
NasimN, SandeepIS, MohantyS. Plant-derived natural products for drug discovery: Current approaches and prospects. Nucleus (Calcutta), 2022; 65(3):399–411; doi:10.1007/s13237-022-00405-3
43.
WangYL, YangMJ, LiR, et al.Simultaneous determination of eight analytes of Fuzheng Huayu recipe in beagle dog plasma by UHPLC–Q/exactive Orbitrap HRMS and its application to toxicokinetics. Biomed Chromatogr, 2022; 36(4):e5329; doi:10.1002/bmc.5329
44.
MarshallB, WarrenJR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1984; 1(8390):1311–1315; doi:10.1016/j.canlet.2013.08.016
WangYC. Medicinal plant activity on Helicobacter pylori related diseases. World J Gastroenterol, 2014; 20(30):10368–10382; doi:10.3748/wjg.v20.i30.10368
47.
D’EliosMM, AmedeiA, CapponA, et al.The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immune modulating agent. FEMS Immunol Med Microbiol, 2007; 50(2):157–164; doi:10.1111/j.1574-695X.2007.00258.x
48.
AkandaMR, KimI-S, AhnD, et al.Anti-inflammatory and gastroprotective roles of rabdosiainflexa through downregulation of pro-inflammatory cytokines and MAPK/NF-κB signaling pathways. Int J Mol Sci, 2018; 19(2):584; doi:10.3390/ijms19020584
49.
KimJK, ChoiE, HongYH, et al.Syk/NF-κB-targeted anti-inflammatory activity of Melicope accedens (Blume) TG Hartley methanol extract. J Ethnopharmacol, 2021; 271:113887; doi:10.1016/j.jep.2021.113887
50.
Al QuraishyS, OthmanMS, DkhilMA, et al.Olive (Olea europaea) leaf methanolic extract prevents HCl/ethanol-induced gastritis in rats by attenuating inflammation and augmenting antioxidant enzyme activities. Biomed Pharmacother, 2017; 91:338–349; doi:10.1016/j.biopha.2017.04.069
51.
KimSA, OhJ, ChoiSR, et al.Anti-gastritis and anti-lung injury effects of pine tree ethanol extract targeting both NF-κB and AP-1 pathways. Molecules, 2021; 26(20):6275; doi:10.3390/molecules26206275
52.
TsioumpekouM, KrijgsmanD, LeusenJH, et al.The role of cytokines in neutrophil development, tissue homing, function and plasticity in health and disease. Cells, 2023; 12(15):1981; doi:10.3390/cells12151981
53.
WangJ. Neutrophils in tissue injury and repair. Cell Tissue Res, 2018; 371(3):531–539; doi:10.1007/s00441-017-2785-7
54.
FilepJG. Targeting neutrophils for promoting the resolution of inflammation. Front Immunol, 2022; 13:866747; doi:10.3389/fimmu.2022.866747
55.
FilippiMD. Neutrophil transendothelial migration: Updates and new perspectives. Blood, 2019; 133(20):2149–2158; doi:10.1182/blood-2018-12-844605
56.
KvietysPR, TwohigB, DanzellJ, et al.Ethanol-induced injury to the rat gastric mucosa: Role of neutrophils and xanthine oxidase-derived radicals. Gastroenterology, 1990; 98(4):909–920; doi:10.1016/0016-5085(90)90015-s
57.
García MediavillaV, CrespoI, ColladoPS, et al.The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol, 2007; 557(2–3):221–229; doi:10.1016/j.ejphar.2006.11.014
58.
ZhangW, LiuHT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res, 2002; 12(1):9–18; doi:10.1038/sj.cr.7290105
59.
DingSZ, SmithMF, Jr.,GoldbergJB. Helicobacter pylori and mitogen‐activated protein kinases regulate the cell cycle, proliferation and apoptosis in gastric epithelial cells. J Gastroenterol Hepatol, 2008; 23(7 Pt 2):e67–e78.
60.
AllisonCC, KuferTA, KremmerE, et al.Helicobacter pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol, 2009; 183(12):8099–8109.
61.
HuangY, ChenS, YaoY, et al.Ovotransferrin alleviated acute gastric mucosal injury in BALB/c mice caused by ethanol. Food Funct, 2023; 14(1):305–318; doi:10.1039/d2fo02364d
62.
YangJY, KimJ-B, LeeP, et al.Evodiamine inhibits Helicobacter pylori growth and Helicobacter pylori-induced inflammation. Int J Mol Sci, 2021; 22(7):3385; doi:10.3390/ijms22073385
63.
MaX, YouP, XuY, et al.Anti-Helicobacter pylori-associated gastritis effect of the ethyl acetate extract of Alpinia officinarum Hance through MAPK signaling pathway. J Ethnopharmacol, 2020; 260:113100; doi:10.1016/j.jep.2020.113100
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