Uncaria gambir Roxb., a plant known for its health-promoting properties and rich in bioactive compounds, offers an alternative treatment for acute gastritis. This research involved the approach of network pharmacology, pathway analysis, and molecular docking to predict signaling pathways of Bajakah kalalawit (Uncaria gambir Roxb.) extract in treating acute gastritis. The results were validated through an in vivo experiment using 25 rats, divided into normal healthy group, negative control, positive control, and treatment groups, and administered with the extract at a dose of 100 and 200 mg/kg BW. The rats were induced with acute gastritis using HCl/ethanol. In vivo parameters include the severity of gastric lesions, histopathological examination, ELISA assay, and immunohistochemistry to measure the levels of pro-inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Network pharmacology proved that there was a significant connection between the active secondary metabolite of the extract and acute gastritis-related genes. Although molecular docking proved that these compounds have limited potential in directly inhibiting TNF-α and IL-6, the in vivo findings nonetheless proved the gastroprotective effect, where the administered groups showed reduced gastric lesions and retained mucosal integrity through histopathological staining. The results of immunohistochemistry and ELISA proved that the extract modulated the levels of TNF-α and IL-6.
Mustika AA, Sutardi LN, Andriyanto A, Aurellia S, Rahma A, Wiranti RW, Prawira AY, Jati DT, Handharyani E, Wahyudi ST. Therapeutic effects of Bajakah kalalawit extract (Uncaria gambir Roxb.) in HCl/ethanol-induced rats as an animal model in acute gastritis: UHPLC MS/MS profiling and in vivo approach with in silico validation. J Appl Pharm Sci. 2025. Article in Press. http://doi.org/10.7324/JAPS3.2025.231503
1. Smith S, Muinah F, Rinaldo P. Infections with Helicobacter pylori and challenges encountered in Africa. World J Gastroenterol. 2019;25(25):3183-95. https://doi.org/10.3748/wjg.v25.i25.3183
2. Miranda A, Caldato C, Said N, Levy S, Teixeira C, Quaresma S. Gender, age, endoscopic findings, urease and Helicobacter pylori: all uncorrelated within a sample of a high gastric cancer prevalence population in Amazon. Arq Gastroenterol. 2019;(6):264-69. https://doi.org/10.1590/s0004-2803.201900000-50
3. Yuan S, Chen J, Ruan X, Sun Y, Zhang K, Wang X, et al. Smoking, alcohol consumption, and 24 gastrointestinal diseases: mendelian randomization analysis. Elife. 2023;12:e840519. https://doi.org/10.7554/eLife.84051
4. Elseweidy MM. Brief review on the causes, diagnosis, and therapeutic treatment of gastritis disease. Altern Integr Med. 2017;6(1):231. https://doi.org/10.4172/2327-5162.1000231
5. Chang W, Bai J, Tian S, Ma M, Li W, Yin Y, et al. Autophagy protects gastric mucosal epithelial cells from ethanol-induced oxidative damage via mTOR signaling pathway. Exp Biol Med. 2017;24:1025-33. https://doi.org/10.1177/1535370216686221
6. Nam HH, Choo BK. Geranium koreanum, a medicinal plant Geranii Herba, ameliorate the gastric mucosal injury in gastritis-induced mice. J Ethnopharmacol. 2021;265:113041. https://doi.org/10.1016/j.jep.2020.113041
7. Santos MP, Pereira JN, Delabio RW, Smith MAC, Payão SLM, Carneiro LC, et al. Increased expression of interleukin-6 gene in gastritis and gastric cancer. Braz J Med Biol Res. 2021;54(7):e10687. https://doi.org/10.1590/1414-431x2020e10687
8. Kim JM, Kim SH, Ko SH, Jung J, Chun J, Kim N, et al. The guggulsterone derivative GG-52 inhibits NF-kB signaling in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice. Am J Physiol Gastrointest Liver Physiol. 2014;304(2):193-202. https://doi.org/10.1152/ajpgi.00103.2012
9. Garg V, Narang P, Taneja R. Antacids revisited: review on contemporary facts and relevance for self-management. Int J Med Res. 2022;50(3):3000605221086457. https://doi.org/10.1177/03000605221086457
10. Kawashima R, Tamaki S, Kawakami F, Maekawa T, Ichikawa T. Histamine H2-receptor antagonists improve non-steroidal anti-inflammatory drug-induced intestinal dysbiosis. Int J Mol Sci. 2020;21(21):8166. https://doi.org/10.3390/ijms21218166
11. Elmahdy MF, Almater JS. Omeprazole induced increase in liver markers-a case report. J Clin Diagn Res. 2019;13(10):1-2. https://doi.org/10.7860/JCDR/2019/41848.13218
12. Yibrin M, Oliveira D, Valera R, Pitt AE, Lutgen S. Adverse effects associated with proton pump inhibitor use. Cureus. 2021;13(1):e12759. https://doi.org/10.7759/cureus.12759
13. Munggari IP, Kurnia D, Deawati Y, Julaeha E. Current research of phytochemical, medicinal, and non-medicinal uses of Uncaria gambir Roxb.: a review. Molecules. 2022;27(19):6551. https://doi.org/10.3390/molecules27196551
14. Andre N, Wang X, He Y, Pan G, Kojo A, Liu Y. A review of the occurrence of non-alkaloid constituents in Uncaria species and their structure-activity relationships. Am J Biomed Life Sci. 2013;1:79-98. https://doi.org/10.11648/j.ajbls.20130104.13
15. Ismail AS, Rizal Y, Armenia A, Kasim A. Identification of bioactive compounds in gambier (Uncaria gambir) liquid by-product in West Sumatra, Indonesia. Biodivers J. 2021;22(3):1474-80. https://doi.org/10.13057/biodiv/d220351
16. Windarsih A, Warmiko HD, Indrianingsih AW, Rohman A, Ulumuddin YI. Untargeted metabolomics and proteomics approach using liquid chromatography-orbitrap high resolution mass spectrometry to detect pork adulteration in Pangasius hypopthalmus meat. Food Chem. 2022;386:132856. https://doi.org/10.1016/j.foodchem.2022.132856
17. Tran QH, Nguyen QT, Vo NQH, Mai TT, Tran TTN, Tran TD, et al. Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: an in silico screening, molecular dynamics simulations and binding free energy calculations. PLoS One. 2022;17(4):1-21. https://doi.org/10.1371/journal.pone.0266632
18. Salman HA, Yaakop AS, Aladaileh S, Mustafa M, Gharaibeh M, Kahar UM. Inhibitory effects of Ephedra alte on IL-6, hybrid TLR4, TNF-α, IL-1β, and extracted TLR4 receptors: in silico molecular docking. Heliyon. 2023;9(1):e12730. https://doi.org/10.1016/j.heliyon.2022.e12730
19. Babalola S, Igie N, Odeyemi I. Molecular docking, drug-likeness analysis, in silico pharmacokinetics, and toxicity studies of p-nitrophenyl hydrazones as anti-inflammatory compounds against COX-2, 5-LOX, and H+/K+ ATPase. Pharm Front. 2022;4(4):250-66. https://doi.org/10.1055/s-0042-1759688
20. Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015;1263:243-50. https://doi.org/10.1007/978-1-4939-2269-7_19
21. Dyas RAA, Wijianto BH. Docking studies for screening antibacterial compounds of Red Jeringau (Acorus calamus L.) using Shigella flexneri protein as a model system. Acta Chim Asiana. 2023;6(2):343- 50. https://doi.org/10.29303/aca.v6i2.161
22. Arifin WN, Zahiruddin WM. Sample size calculation in animal studies using resource equation approach. Malays J Med Sci. 2017;24(5):101-5. https://doi.org/10.21315/mjms2017.24.5.11
23. Al-Quraishy S, Othman MS, Dkhil MA, Moneim AEA. Olive (Olea europaea) leaf methanolic extract prevents HCl/ethanol induced gastritis in rats by attenuating inflammation and augmenting antioxidant enzyme activities. Biomed Pharmacother. 2017;91:338-49. https://doi.org/10.1016/j.biopha.2017.04.069
24. Wafaey AA, El-Hawary SS, Mohamed OG, Abdelrahman SS, Ali AM, El-Rashedy AA, et al. UHPLC-QTOF-MS/MS profiling, molecular networking, and molecular docking analysis of Gliricidia sepium (Jacq.) Kunth. ex. Walp. stem ethanolic extract and its gastroprotective effect on gastritis in rats. Toxicol Rep. 2025;14:101944. https://doi.org/10.1016/j.toxrep.2025.101944
25. Cavallini ME, Andreollo NA, Metze K, Araújo MR. Omeprazole and misoprostol for preventing gastric mucosa effects caused by indomethacin and celecoxib in rats. Acta Cir Bras. 2006;21:168-76. https://doi.org/10.1590/S0102-86502006000300009
26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75. https://doi.org/10.1016/S0021-9258(19)52451-6
27. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4:682-90. https://doi.org/10.1038/nchembio.118
28. Yang CS, Chen G, Wu Q. Recent scientific studies of a traditional Chinese medicine, tea, on prevention of chronic diseases. J Tradit Med Complement. 2014;4:17-23. https://doi.org/10.4103/2225-4110.124326
29. Kim JM, Heo HJ. The roles of catechins in regulation of systemic inflammation. Food Sci Biotechnol. 2022;31(8):957-70. https://doi.org/10.1007/s10068-022-01069-0
30. Shenhar-Tsarfaty S, Berliner S, Bornstein NM, Soreq H. Cholinesterases as biomarkers for parasympathetic dysfunction andinflammation-related disease. J Mol Neurosci. 2014;53:298-305. https://doi.org/10.1007/s12031-013-0176-4
31. Zeng J, Weng Y, Lai T, Chen L, Li Y, Huang Q, et al. Procyanidin alleviates ferroptosis and inflammation of LPS-induced RAW264. 7 cell via the Nrf2/HO-1 pathway. Naunyn-Schmiedeberg’s Arch Pharmacol. 2024;397(1):4055-67. https://doi.org/10.1007/s00210-023-02854-2
32. Sakthivel KM, Vishnupriya S, Priya DLC, Rasmi RR, Ramesh B. Modulation of multiple cellular signalling pathways as targets for anti-inflammatory and anti-tumorigenesis action of Scopoletin. J Pharm Pharmacol. 2022;74(2):147-61. https://doi.org/10.1093/jpp/rgab047
33. Khan AA, Iadarola M, Yang HT, Dionne RA. Expression of COX- 1 and COX-2 in a clinical model of acute inflammation. J Pain. 2007;8(4):349-54. https://doi.org/10.1016/j.jpain.2006.10.004
34. Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. Int Rev Psychiatry. 2018;30(4):363-75. https://doi.org/10.1080/09540261.2018.1481827
35. Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD. Structure-activity relationship analysis of psychedelics in a rat model of asthma reveals the anti-inflammatory pharmacophore. ACS Pharmacol Transl Sci. 2020;4(2):488-502. https://doi.org/10.1021/acsptsci.0c00063
36. Yajima A, Yabuta G. Synthesis and absolute configuration of MQ-A3 [1-(14’-methylhexadecanoyl) pyrrolidine], a novel aliphatic pyrrolidine amide from the tropical convolvulaceous species. Biosci Biotechnol Biochem. 2001;65(2):463-5. https://doi.org/10.1271/bbb.65.463
37. Muhammad DBA, Zainul FM, Bintari YR. Studi in silico: potensi antibakteri senyawa aktif alga merah Gracillaria verrucosa untuk menghambat Penicillin Binding Protein (PBP) bakteri Escherichia coli. J Kedokt Komunitas. 2023;11(2):1-14.
38. Ferdian PR, Elfirta RR, Ikhwani AZN, Kasirah K, Haerul H, Sutardi D, et al. Studi in silico senyawa fenolik madu sebagai kandidat inhibitor Mpro SARS-CoV-2. Media Penelit Pengemb Kesehat. 2021;31(3):213-32. https://doi.org/10.22435/mpk.v31i3.4920
39. Fakhruri M, Rahmayanti Y, Isfanda. Potensi fitokimia Citrus aurantum (Hesperetin, naringenin) dalam menghambat xantin oxidase pada hiperurisemia secara in silico. J Heal Sains. 2021;2(1):79-89. https://doi.org/10.46799/jhs.v2i1.80
40. Ha NX, Anh HTN, Khanh PN, Ha VT, Ha NV, Huong TT, et al. In silico and ADMET study of Morinda longissima phytochemicals against TNF-α for treatment of inflammation-mediated diseases. Vietnam J Chem. 2023;61(S1):57-63. https://doi.org/10.1002/vjch.202200214
41. Liu J, Wang J, Shi Y, Su W, Chen J, Zhang Z. Short chain fatty acid acetate protects against ethanol-induced acute gastric mucosal lesion in mice. Biol Pharm Bull. 2017;40:1439-46. https://doi.org/10.1248/bpb.b17-00240
42. Whary MT, Baumgarth N, Fox JG, Barthold SW. Biology and diseases of mice. In: Laboratory animal medicine. 3rd ed. Amsterdam, The Netherlands: Elsevier Science; 2015. pp. 43-149. https://doi.org/10.1016/B978-0-12-409527-4.00003-1
43. Narayanan M, Reddy KM, Marsicano E. Peptic ulcer disease and Helicobacter pylori infection. Mo Med. 2018;115:219-24.
44. Gustia E, Yufri A, Hefni D, Kamal S, Dachriyanus, Wahyuni FS. The immunostimulant activities of the Gambir (Uncaria gambir Roxb) on Raw 264.7 cell. Proceedings of the 2nd International Conference on Contemporary Science and Clinical Pharmacy 2021 (ICCSCP 2021); 2021 Oct 30-31; Padang, Indonesia. Paris: Atlantis press; 2021. Vol. 40, pp 282-8. https://doi.org/10.2991/ahsr.k.211105.041
45. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2016;6(10): a016295. https://doi.org/10.1101/cshperspect.a016295
46. Sánchez-Zauco N, Torres J, Gómez A, Camorlinga-Ponce M, Muãoz-Pérez L, Herrera-Goepfert R. Circulating blood levels of IL-6, IFN-γ, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study. BMC Cancer. 2017;17:1-10. https://doi.org/10.1186/s12885-017-3657-y
47. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448-57. https://doi.org/10.1038/ni.3153
48. Asensi V, Valle E, Meana A. In vivo interleukin-6 protects neutrophils from apoptosis in osteomyelitis. Infect Immun. 2004;72(7): 3823-8. https://doi.org/10.1128/IAI.72.7.3823-3828.2004
49. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev. 2013;13:159-75. https://doi.org/10.1038/nri3399
50. Bradley JR. TNF-Mediated inflammatory disease. J Pathol. 2008;214:149-60.
51. Sitepu RR, Darmadi D, Siregar GA. Correlation between TNF-α and degree of gastritis. J Gastroenterol Hepatol Dig Endosc. 2018;19(1):16-9. https://doi.org/10.24871/191201816-19
52. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38:414-23. https://doi.org/10.1016/j.immuni.2013.03.002
53. Jang D, Lee A, Shin HY, Song H, Park J, Kang T, et al. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci. 2021;22(5):2719. https://doi.org/10.3390/ijms22052719
54. Van Loo G, Bertrand MJM. Death by TNF: a road to inflammation. Nat Rev Immunol. 2023;23:289-303. https://doi.org/10.1038/s41577-022-00792-3
55. Muth KN, Rech J, Losch FO, Hoerning A. Reversing the inflammatory process - 25 years of tumor necrosis factor-α inhibitors. J Clin Med. 2023;12(15):5039. https://doi.org/10.3390/jcm12155039
56. Jumina J, Siswanta D, Zulkarnain AK, Triono S, Priatmoko P, Yuanita E, et al. Development of C-Arylcalix[4]resorcinarenes and C-Arylcalix[4]pyrogallolarenes as antioxidant and UV-B protector. Indones J Chem. 2019;19(2):273. https://doi.org/10.22146/ijc.26868
57. Kozlov AV, Javadov S, Sommer N. Cellular ROS and antioxidants: physiological and pathological role. Antioxidants. 2024;13(5):602. https://doi.org/10.3390/antiox13050602
58. Ma Q. Transcriptional responses to oxidative stress: pathological and toxicological implications. Pharmacol Ther. 2010;125:376-93. https://doi.org/10.1016/j.pharmthera.2009.11.004
59. Hong Y, Boiti A, Vallone D, Foulkes NS. Reactive oxygen species signaling and oxidative stress: transcriptional regulation and evolution. Antioxidants. 2004;13(3):312. https://doi.org/10.3390/antiox13030312
60. Kwiecien S, Jasnos K, Magierowski M, Sliwowski Z, Pajdo R, Brzozowski B, et al. Lipid peroxidation, reactive oxygen species and antioxidative factors in the pathogenesis of gastric mucosal lesions and mechanism of protection against oxidative stress-induced gastric injury. J Physiol Pharmacol. 2014;65(5):613-22.
61. Keyhanmanesh R, Boskabady MH, Eslamizadeh MJ, Khamneh S, Ebrahimi MA. The effect of thymoquinone, the main constituent of Nigella sativa on tracheal responsiveness and white blood cell count in lung lavage of sensitized guinea pigs. Planta Med. 2010;76:218-22. https://doi.org/10.1055/s-0029-1186054
62. Kangwan N, Park JM, Kim EH, Hahm KB. Quality of healing of gastric ulcers: natural products beyond acid suppression. World J Gastrointest Pathophysiol. 2014;5(1):40-7. https://doi.org/10.4291/wjgp.v5.i1.40
63. Repetto MG, Llesuy SF. Antioxidant properties of natural compounds used in popular medicine for gastric ulcers. Braz J Med Biol Res. 2002;35(5):523-34. https://doi.org/10.1590/S0100-879X2002000500003
64. Bai SK, Lee SJ, Na HJ, Ha KS, Han JA, Lee H, et al. β-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages by suppressing redox-based NF-κB activation. Exp Mol Med. 2005;37(4):323-34. https://doi.org/10.1038/emm.2005.42
65. Sliwoski G, Kothiwale S, Meiler J, Lowe EW. Computational methods in drug discovery. Pharmacol Rev. 2014;66(1):334-95. https://doi.org/10.1124/pr.112.007336
66. Liu H, Wu J, Chen H, Tang Y, Xue F, Wang Y. Predictive evaluation of intestinal absorption of flavonoids based on molecular weight and oral bioavailability. Food Funct. 2019;10(8):4991-5002.
67. Lawrence T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. https://doi.org/10.1101/cshperspect.a001651
68. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2-3):97-110. https://doi.org/10.1016/j.phymed.2008.12.018
69. Kuribayashi T. Elimination half-lives of interleukin-6 and cytokine-induced neutrophil chemoattractant-1 synthesized in response to inflammatory stimulation in rats. Lab Anim Res. 2018;34:80-3. https://doi.org/10.5625/lar.2018.34.2.80
70. Van Griensven M. Zytokine als Marker bei Polytrauma. Der Unf. 2014;117:699-702. https://doi.org/10.1007/s00113-013-2543-6
71. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986;4753:977-80. https://doi.org/10.1126/science.3754653
72. Ksontini R, MacKay SL, Moldawer LL. Revisiting the role of tumor necrosis factor alpha and the response to surgical injury and inflammation. Arch Surg. 1998;5:558-67. https://doi.org/10.1001/archsurg.133.5.558
73. Cairns CB, Panacek EA, Harken AH, Banerjee A. Bench to bedside: tumor necrosis factor-alpha: from inflammation to resuscitation. Acad Emerg Med. 2000;8:930-41. https://doi.org/10.1111/j.1553-2712.2000.tb02077.x
Year
Month