Long-term GABA Supplementation Regulates Diabetic Gastroenteropathy through GABA Receptor/trypsin-1/PARs/Akt/COX-2 Axis.
COX-2
GABA
NOS1
Protease-activated receptors
trypsin-1
type 2 diabetes
Journal
Doklady. Biochemistry and biophysics
ISSN: 1608-3091
Titre abrégé: Dokl Biochem Biophys
Pays: United States
ID NLM: 101126895
Informations de publication
Date de publication:
28 Aug 2024
28 Aug 2024
Historique:
received:
15
06
2024
accepted:
05
07
2024
revised:
02
07
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
28
8
2024
Statut:
aheadofprint
Résumé
Molecular alterations of diabetic gastroenteropathy are poorly identified. This study investigates the effects of prolonged GABA supplementation on key protein expression levels of trypsin-1, PAR-1, PAR-2, PAR-3, PI3K, Akt, COX-2, GABAA, and GABAB receptors in the gastric tissue of type 2 diabetic rats (T2DM). -To induce T2DM, a 3-month high-fat diet and 35 mg/kg of streptozotocin was used. Twenty-four male Wistar rats were divided into 4 groups: (1) control, (2) T2DM, (3) insulin-treated (2.5 U/kg), and (4) GABA-treated (1.5 g/kg GABA). Blood glucose was measured weekly. The protein expressions were assessed using western blotting. Histopathological changes were examined by H&E and Masson's staining. -Diabetic rats show reduced NOS1 and elevated COX-2 and trypsin-1 protein expression levels in gastric tissue. Insulin and GABA therapy restored the NOS1 and COX-2 levels to control values. Insulin treatment increased PI3K, Akt, and p-Akt and, decreased trypsin-1, PAR-1, PAR-2, and PAR-3 levels in the diabetic rats. Levels of GABAA and GABAB receptors normalized following insulin and GABA therapy. H&E staining indicated an increase in mucin secretion following GABA treatment. -These results suggest that GABA by acting on GABA receptors may regulate the trypsin-1/PARs/Akt/COX-2 pathway and thereby improve complications of diabetic gastroenteropathy.
Identifiants
pubmed: 39196532
doi: 10.1134/S1607672924600386
pii: 10.1134/S1607672924600386
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. Pleiades Publishing, Ltd.
Références
Cichosz, S.L. and Hejlesen, O., Classification of gastroparesis from glycemic variability in type 1 diabetes: a proof-of-concept study, J. Diabetes Sci. Technol., 2022, vol. 16, no. 5, pp. 1190–1195.
doi: 10.1177/19322968211015206
pubmed: 33993744
Dickman, R., Kislov, J., Boaz, M., Y, R., Beniashvili, Z., Raz, I., et al., Prevalence of symptoms suggestive of gastroparesis in a cohort of patients with diabetes mellitus, J. Diabetes Its Complications, 2013, vol. 27, no. 4, pp. 376–379.
Locke III, R.G., Schleck, C.D., Zinsmeister, A.R., Melton III, J.L., and Talley, N.J., Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population, Off. J. Am. Coll. Gastroenterol. (ACG), 2012, vol. 107, no. 1, pp. 82–88.
doi: 10.1038/ajg.2011.310
Zawada, A.E., Moszak, M., Skrzypczak, D., and Grzymisławski, M., Gastrointestinal complications in patients with diabetes mellitus, Adv. Clin. Exp. Med., 2018, vol. 27, no. 4, pp. 567–572.
doi: 10.17219/acem/67961
pubmed: 29533548
Min, Y.W., Ko, E.-J., Lee, J.-Y., and Rhee, P.-L., Impaired neural pathway in gastric muscles of patients with diabetes, Sci. Rep., 2018, vol. 8, no. 1, p. 7101.
doi: 10.1038/s41598-018-24147-y
pubmed: 29739973
pmcid: 5940896
Jin, Q.-H., Shen, H.-X., Wang, H., Shou, Q.-Y., and Liu, Q., Curcumin improves expression of SCF/c-kit through attenuating oxidative stress and NF-κB activation in gastric tissues of diabetic gastroparesis rats, Diabetol. Metab. Syndr., 2013, vol. 5, pp. 1–12.
doi: 10.1186/1758-5996-5-12
Olsen, R.W. and Delorey, T.M., GABA receptor physiology and pharmacology, Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Philadelphia: Lippincott-Raven, 1999, vol. 6.
Mcmenamin, C.A., Travagli, R.A., and Browning, K.N., Inhibitory neurotransmission regulates vagal efferent activity and gastric motility, Exp. Biol. Med., 2016, vol. 241, no. 12, pp. 1343–1350.
doi: 10.1177/1535370216654228
Collares, E.F. and Vinagre, A.M., Effect of baclofen on liquid and solid gastric emptying in rats, Arq. Gastroenterol., 2010, vol. 47, pp. 290–296.
doi: 10.1590/S0004-28032010000300015
pubmed: 21140092
Krantis, A. and Harding, R.K., GABA-related actions in isolated in vitro preparations of the rat small intestine, Eur. J. Pharmacol., 1987, vol. 141, no. 2, pp. 291–298.
doi: 10.1016/0014-2999(87)90274-3
pubmed: 2824220
Soltani, N., Qiu, H., Aleksic, M., Glinka, Y., Zhao, F., Liu, R., et al., GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes, Proc. Natl. Acad. Sci. U. S. A., 2011, vol. 108, no. 28, pp. 11692–11697.
doi: 10.1073/pnas.1102715108
pubmed: 21709230
pmcid: 3136292
Liu, W., Lau, H.K., Son, D.O., Yang, J.T., Zhang, Y., and Z, Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis, J. Endocrinol., 2021, vol. 248, no. 2, pp. 133–143.
doi: 10.1530/JOE-20-0315
pubmed: 33258801
Son, D.O., Liu, W., Li, X., Prud’homme, G.J., and Wang, Q., Combined effect of GABA and glucagon-like peptide-1 receptor agonist on cytokine-induced apoptosis in pancreatic β-cell line and isolated human islets, J. Diabetes, 2019, vol. 11, no. 7, pp. 563–572.
doi: 10.1111/1753-0407.12881
pubmed: 30520247
Chen, B.C., Hung, M.Y., Wang, H.F., Yeh, L.J., Pandey, S., and Chen, R.J., GABA tea attenuates cardiac apoptosis in spontaneously hypertensive rats (SHR) by enhancing PI3K/Akt-mediated survival pathway and suppressing Bax/Bak dependent apoptotic pathway, Environ. Toxicol., 2018, vol. 33, no. 7, pp. 789–797.
doi: 10.1002/tox.22565
pubmed: 29708300
Sun, Z., Sun, L., and Tu, L., GABA B receptor-mediated PI3K/Akt signaling pathway alleviates oxidative stress and neuronal cell injury in a rat model of Alzheimer’s disease, J. Alzheimer’s Dis., 2020, vol. 76, no. 4, pp. 1513–1526.
doi: 10.3233/JAD-191032
Huang, X., Liu, G., Guo, J., and Su, Z., The PI3K/AKT pathway in obesity and type 2 diabetes, Int. J. Biol. Sci., 2018, vol. 14, no. 11, p. 1483.
doi: 10.7150/ijbs.27173
pubmed: 30263000
pmcid: 6158718
Du, C., Zhang, T., Xiao, X., Shi, Y., Duan, H., and Ren, Y., Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway, Biochem. J., 2017, vol. 474, no. 16, pp. 2733–2747.
doi: 10.1042/BCJ20170272
pubmed: 28694352
Baynes, J.W., Role of oxidative stress in development of complications in diabetes, Diabetes, 1991, vol. 40, no. 4, pp. 405–412.
doi: 10.2337/diab.40.4.405
pubmed: 2010041
Greenhough, A., Smartt, H.J., Moore, A.E., Ro-berts, H.R., Williams, A.C., and Paraskeva, C., The COX-2/PGE 2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment, Carcinogenesis, 2009, vol. 30, no. 3, pp. 377–386.
doi: 10.1093/carcin/bgp014
pubmed: 19136477
Yang, J., Wang, X., Gao, Y., Fang, C., Ye, F., Huang, B., et al., Inhibition of PI3K-AKT signaling blocks PGE2-induced COX-2 expression in lung adenocarcinoma, OncoTargets Ther., 2020, pp. 8197–8208.
Xia, S., Zhao, Y., Yu, S., and Zhang, M., Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells, Cancer Biother. Radiopharm., 2010, vol. 25, no. 3, pp. 317–323.
pubmed: 20578837
Grover, M., Dasari, S., Bernard, C.E., Chikkamenahalli, L.L., Yates, K.P., and Pasricha, P.J., Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis, Am. J. Physiol.: Gastrointest. Liver Physiol., 2019, vol. 317, no. 5, pp. g716–g726.
pubmed: 31482734
Pop-Busui, R., Kellogg, A.P., and Cheng, H.T., Cyclooxygenase-2 pathway as a potential therapeutic target in diabetic peripheral neuropathy, Curr. Drug Targets, 2008, vol. 9, no. 1, pp. 68–76.
doi: 10.2174/138945008783431691
pubmed: 18220714
Cosentino, F., Eto, M., De Paolis, P., van der Loo, B., Bachschmid, M., and Ullrich, V., High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species, Circulation, 2003, vol. 107, no. 7, pp. 1017–1023.
doi: 10.1161/01.CIR.0000051367.92927.07
pubmed: 12600916
Xu, J. and Chen, J., Effects of cyclooxygenase-2 inhibitor on glucagon-induced delayed gastric emptying and gastric dysrhythmia in dogs, Neurogastroenterol. Motil., 2007, vol. 19, no. 2, pp. 144–151.
doi: 10.1111/j.1365-2982.2006.00887.x
pubmed: 17244169
Li, Y., Yang, W., Quinones-Hinojosa, A., Wang, B., Xu, S., and Zhu, W., Interference with protease-activated receptor 1 alleviates neuronal cell death induced by lipopolysaccharide-stimulated microglial cells through the PI3K/Akt pathway, Sci. Rep., 2016, vol. 6, no. 1, p. 38247.
doi: 10.1038/srep38247
pubmed: 27910893
pmcid: 5133627
Sung, T.S., Kim, H.U., Kim, J.H., Lu, H., Sanders, K.M., and Koh, S.D., Protease-activated receptors modulate excitability of murine colonic smooth muscles by differential effects on interstitial cells, J. Physiol., 2015, vol. 593, no. 5, pp. 1169–1181.
doi: 10.1113/jphysiol.2014.285148
pubmed: 25641660
pmcid: 4358678
Sohrabipour, S., Sharifi, M.R., Talebi, A., Sharifi, M., and Soltani, N., GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet, Eur. J. Pharmacol., 2018, vol. 826, pp. 75–84.
doi: 10.1016/j.ejphar.2018.01.047
pubmed: 29391158
Steinsvik, E.K., Sangnes, D.A., Søfteland, E., Biermann, M., Assmus, J., and Dimcevski, G., Gastric function in diabetic gastroparesis assessed by ultrasound and scintigraphy, Neurogastroenterol. Motil., 2022, vol. 34, no. 4, p. e14235.
doi: 10.1111/nmo.14235
pubmed: 34378839
Aswath, G.S., Foris, L.A., Ashwath, A.K., and Patel, K., Diabetic Gastroparesis, Treasure Island (FL): StatPearls Publishing, 2017.
Castelli, M.P., Ingianni, A., Stefanini, E., and Gessa, G.L., Distribution of GABAB receptor mRNAs in the rat brain and peripheral organs, Life Sci., 1999, vol. 64, no. 15, pp. 1321–1328.
doi: 10.1016/S0024-3205(99)00067-3
pubmed: 10227588
Matuszek, M., Jesipowicz, M., and Kleinrok, Z., GABA content and GAD activity in gastric cancer, Med. Sci. Monitor., 2001, vol. 7, no. 3, pp. 377–381.
Zhu, Y., Devi, S., Kumar, M., and Dahiya, R.S., Evaluation of gamma amino butyric acid (GABA) and glibenclamide combination therapy in streptozotocin induced diabetes, Endocr., Metab. Immune Disord.: Drug Targets, 2021, vol. 21, no. 11, pp. 2005–2016.
doi: 10.2174/1871530320666201208110945
pubmed: 33292127
Gangula, P., Sekhar, K., and Mukhopadhyay, S., Gender bias in gastroparesis: is nitric oxide the answer?, Digestive Dis. Sci., 2011, vol. 56, pp. 2520–2527.
doi: 10.1007/s10620-011-1735-6
Liu, L., Wu, X.-F., Zheng, X.-N., Guo, X., Yue, Z.-H., Liu, M., et al., Effect of point-moxibustion and electroacupuncture on the expression of endothelial nitric oxide synthase mRNA and angiotensin 2 mRNA in gastric antrum in diabetic gastroparesis rats, Zhen Ci Yan Jiu = Acupuncture Res., 2017, vol. 42, no. 3, pp. 240–245.
Rotondo, A., Serio, R., and Mulè, F., Functional evidence for different roles of GABA
doi: 10.1016/j.neuropharm.2010.01.004
pubmed: 20080114
Untereiner, A., Xu, J., Bhattacharjee, A., Cabrera, O., Hu, C., Dai, F.F., et al., γ-aminobutyric acid stimulates β-cell proliferation through the mTORC1/p70S6K pathway, an effect amplified by Ly49, a novel γ-aminobutyric acid type A receptor positive allosteric modulator, Diabetes, Obes. Metab., 2020, vol. 22, no. 11, pp. 2021–2031.
doi: 10.1111/dom.14118
pubmed: 32558194
Rezazadeh, H., Sharifi, M.R., Sharifi, M., and Soltani, N., Gamma-aminobutyric acid attenuates insulin resistance in type 2 diabetic patients and reduces the risk of insulin resistance in their offspring, Biomed. Pharmacother., 2021, vol. 138, p. 111440.
doi: 10.1016/j.biopha.2021.111440
pubmed: 33667789
Santos, C., Medeiros, B., Palheta-Junior, R., Macedo, G., Nobre-E-Souza, M., Troncon, L., et al., Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats 1, Neurogastroenterol. Motil., 2007, vol. 19, no. 3, pp. 225–232.
doi: 10.1111/j.1365-2982.2007.00913.x
pubmed: 17300293
Heuberger, D.M. and Schuepbach, R.A., Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases, Thromb. J., 2019, vol. 17, no. 1, p. 4.
doi: 10.1186/s12959-019-0194-8
pubmed: 30976204
pmcid: 6440139
Seo, J.H., Seo, J.Y., Chung, H.-Y., and Kim, H., Effect of pertussis toxin and herbimycin A on proteinase-activated receptor 2-mediated cyclooxygenase 2 expression in Helicobacter pylori-infected gastric epithelial AGS cells, Yonsei Med. J., 2011, vol. 52, no. 3, pp. 522–526.
doi: 10.3349/ymj.2011.52.3.522
pubmed: 21488197
pmcid: 3101059
Zhang, C., Gao, G.-R., Lv, C.-G., Zhang, B.-L., Zhang, Z.-L., and Zhang, X.-F., Protease-activated receptor-2 induces expression of vascular endothelial growth factor and cyclooxygenase-2 via the mitogen-activated protein kinase pathway in gastric cancer cells, Oncol. Rep., 2012, vol. 28, no. 5, pp. 1917–1923.
doi: 10.3892/or.2012.1998
pubmed: 22941376