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Cardiovascular & Hematological Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Research Article

Therapeutic Potential of Syzygium aromaticum in Gut Dysbiosis via TMAO Associated Diabetic Cardiomyopathy

Author(s): Shivani Singhal and Vibha Rani*

Volume 22, Issue 4, 2024

Published on: 04 September, 2023

Page: [441 - 455] Pages: 15

DOI: 10.2174/1871525721666230822100142

Price: $65

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Abstract

Background: Dysbiosis of the gastrointestinal microbiota is not only related to the pathogenesis of intestinal disorders but also associated with extra-intestinal diseases. Various studies have revealed the role of an imbalance of intestinal microbiota and their metabolites including bile acids, indole derivatives, polyamines, and trimethylamine in the progression of various diseases. The elevated plasma level of the oxidized form of trimethylamine is associated with the increased risk of cardiovascular diseases. Literature supports that herbal medicines can modulate human health by altering the diversity of gut microbiota and their metabolites and proposes the use of prebiotics to improve dysbiotic conditions as a new way of therapeutic strategy.

Methods: In silico studies including drug likeliness, toxicity prediction, and molecular interaction of phytochemicals against trimethylamine lyase enzyme have been done. Antimicrobial activity of extracts of selected plant i.e. Syzygium aromaticum was done by disc diffusion and the protective effects of plant compounds were examined on trimethylamine-n-oxide a bacterial metabolic product and high glucose induced toxicity.

Results: The current study has found that the phytochemicals of S. aromaticum identified as nontoxic and followed the standard rules of drug likeliness and showed a significant binding affinity against trimethylamine-n-oxide producing enzymes. Furthermore, S. aromaticum extract was found to have antimicrobial potential and cardioprotective effects by reducing the production of intracellular reactive oxygen species and correcting the distorted nuclear morphology in the presence of high trimethylamine-n-oxide.

Conclusion: Conclusively, our study explored the herbal intervention in intestinal dysbiosis and suggested a natural therapy against dysbiosis associated with cardiac disease, and S, aromaticum was found to have exceptional cardioprotective potential against TMAO induced gut dysbiosis, which provides a novel future therapeutic intervention for treating cardiovascular complications.

Keywords: Gut microbiota, metabolites, dysbiosis, cardiovascular diseases, trimethylamine lyase, Syzygium aromaticum.

Graphical Abstract
[1]
Wu, Y.; Ding, Y.; Tanaka, Y.; Zhang, W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int. J. Med. Sci., 2014, 11(11), 1185-1200.
[http://dx.doi.org/10.7150/ijms.10001] [PMID: 25249787]
[2]
Laakso, M. Biomarkers for type 2 diabetes. Mol. Metab., 2019, 27S(Suppl.), S139-S146.
[http://dx.doi.org/10.1016/j.molmet.2019.06.016] [PMID: 31500825]
[3]
Rani, V.; Sharma, K. Therapeutic potential of stable organosulfur compounds of aged garlic. Cardiovasc. Hematol. Agents Med. Chem., 2023, 21(2), 84-95.
[http://dx.doi.org/10.2174/1871525721666221020123056] [PMID: 36278448]
[4]
King, C.H.; Desai, H.; Sylvetsky, A.C.; LoTempio, J.; Ayanyan, S.; Carrie, J.; Crandall, K.A.; Fochtman, B.C.; Gasparyan, L.; Gulzar, N.; Howell, P.; Issa, N.; Krampis, K.; Mishra, L.; Morizono, H.; Pisegna, J.R.; Rao, S.; Ren, Y.; Simonyan, V.; Smith, K. VedBrat, S.; Yao, M.D.; Mazumder, R. Baseline human gut microbiota profile in healthy people and standard reporting template. PLoS One, 2019, 14(9), e0206484.
[http://dx.doi.org/10.1371/journal.pone.0206484] [PMID: 31509535]
[5]
Yang, G.; Wei, J.; Liu, P.; Zhang, Q.; Tian, Y.; Hou, G.; Meng, L.; Xin, Y.; Jiang, X. Role of the gut microbiota in type 2 diabetes and related diseases. Metabolism, 2021, 117, 154712.
[http://dx.doi.org/10.1016/j.metabol.2021.154712] [PMID: 33497712]
[6]
DeGruttola, A.K.; Low, D.; Mizoguchi, A.; Mizoguchi, E. Current understanding of dysbiosis in disease in human and animal models. Inflamm. Bowel Dis., 2016, 22(5), 1137-1150.
[http://dx.doi.org/10.1097/MIB.0000000000000750] [PMID: 27070911]
[7]
Lin, L.; Zhang, J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol., 2017, 18(1), 2.
[http://dx.doi.org/10.1186/s12865-016-0187-3] [PMID: 28061847]
[8]
Zhu, W.; Romano, K.A.; Li, L.; Buffa, J.A.; Sangwan, N.; Prakash, P.; Tittle, A.N.; Li, X.S.; Fu, X.; Androjna, C.; DiDonato, A.J.; Brinson, K.; Trapp, B.D.; Fischbach, M.A.; Rey, F.E.; Hajjar, A.M.; DiDonato, J.A.; Hazen, S.L. Gut microbes impact stroke severity via the trimethylamine N-oxide pathway. Cell Host Microbe, 2021, 29(7), 1199-1208.e5.
[http://dx.doi.org/10.1016/j.chom.2021.05.002] [PMID: 34139173]
[9]
Rexidamu, M.; Li, H.; Jin, H.; Huang, J. Serum levels of trimethylamine-N-oxide in patients with ischemic stroke. Biosci. Rep., 2019, 39(6), BSR20190515.
[http://dx.doi.org/10.1042/BSR20190515] [PMID: 31142624]
[10]
Rath, S.; Heidrich, B.; Pieper, D.H.; Vital, M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome, 2017, 5(1), 54.
[http://dx.doi.org/10.1186/s40168-017-0271-9] [PMID: 28506279]
[11]
Sudheer, S.; Gangwar, P.; Usmani, Z.; Sharma, M.; Sharma, V.K.; Sana, S.S.; Almeida, F.; Dubey, N.K.; Singh, D.P.; Dilbaghi, N.; Khayat Kashani, H.R.; Gupta, V.K.; Singh, B.N.; Khayatkashani, M.; Nabavi, S.M. Shaping the gut microbiota by bioactive phytochemicals: An emerging approach for the prevention and treatment of human diseases. Biochimie, 2022, 193, 38-63.
[http://dx.doi.org/10.1016/j.biochi.2021.10.010] [PMID: 34688789]
[12]
Tresserra-Rimbau, A.; Medina-Remón, A.; Pérez-Jiménez, J.; Martínez-González, M.A.; Covas, M.I.; Corella, D.; Salas-Salvadó, J.; Gómez-Gracia, E.; Lapetra, J.; Arós, F.; Fiol, M.; Ros, E.; Serra-Majem, L.; Pintó, X.; Muñoz, M.A.; Saez, G.T.; Ruiz-Gutiérrez, V.; Warnberg, J.; Estruch, R.; Lamuela-Raventós, R.M. Dietary intake and major food sources of polyphenols in a Spanish population at high cardiovascular risk: The PREDIMED study. Nutr. Metab. Cardiovasc. Dis., 2013, 23(10), 953-959.
[http://dx.doi.org/10.1016/j.numecd.2012.10.008] [PMID: 23332727]
[13]
Vicidomini, C.; Roviello, V.; Roviello, G.N. Molecular basis of the therapeutical potential of clove (Syzygium aromaticum L.) and clues to its anti-COVID-19 utility. Molecules, 2021, 26(7), 1880.
[http://dx.doi.org/10.3390/molecules26071880] [PMID: 33810416]
[14]
Keegan, K.P.; Glass, E.M.; Meyer, F. MG-RAST, a metagenomics service for analysis of microbial community structure and function. Methods Mol. Biol., 2016, 1399, 207-233.
[http://dx.doi.org/10.1007/978-1-4939-3369-3_13] [PMID: 26791506]
[15]
Yen, S.; Johnson, J.S. Metagenomics: A path to understanding the gut microbiome. Mamm. Genome, 2021, 32(4), 282-296.
[http://dx.doi.org/10.1007/s00335-021-09889-x] [PMID: 34259891]
[16]
Ondov, B.D.; Bergman, N.H.; Phillippy, A.M. Interactive metagenomic visualization in a Web browser. BMC Bioinformatics, 2011, 12(1), 385.
[http://dx.doi.org/10.1186/1471-2105-12-385] [PMID: 21961884]
[17]
Abubakar, A.; Haque, M. Preparation of medicinal plants: Basic extraction and fractionation procedures for experimental purposes. J. Pharm. Bioallied Sci., 2020, 12(1), 1-10.
[http://dx.doi.org/10.4103/jpbs.JPBS_175_19] [PMID: 32801594]
[18]
Nzeako, B.C.; Al-Kharousi, Z.S.; Al-Mahrooqui, Z. Antimicrobial activities of clove and thyme extracts. Sultan Qaboos Univ. Med. J., 2006, 6(1), 33-39.
[PMID: 21748125]
[19]
Tekwu, E.M.; Pieme, A.C.; Beng, V.P. Investigations of antimicrobial activity of some Cameroonian medicinal plant extracts against bacteria and yeast with gastrointestinal relevance. J. Ethnopharmacol., 2012, 142(1), 265-273.
[http://dx.doi.org/10.1016/j.jep.2012.05.005] [PMID: 22583961]
[20]
Li, M.; Liu, Q.; Teng, Y.; Ou, L.; Xi, Y.; Chen, S.; Duan, G. The resistance mechanism of Escherichia coli induced by ampicillin in laboratory. Infect. Drug Resist., 2019, 12, 2853-2863.
[http://dx.doi.org/10.2147/IDR.S221212] [PMID: 31571941]
[21]
Zhou, P.; Zhao, X.N.; Ma, Y.Y.; Tang, T.J.; Wang, S.S.; Wang, L.; Huang, J.L. Virtual screening analysis of natural flavonoids as trimethylamine (TMA)‐lyase inhibitors for coronary heart disease. J. Food Biochem., 2022, 46(12), e14376.
[http://dx.doi.org/10.1111/jfbc.14376] [PMID: 35945702]
[22]
Ramireddy, L.; Tsen, H.Y.; Chiang, Y.C.; Hung, C.Y.; Chen, F.C.; Yen, H.T. The gene expression and bioinformatic analysis of choline trimethylamine-lyase (CutC) and its activating enzyme (CutD) for gut microbes and comparison with their TMA production levels. Curr. Res. Microb, 2021, 2, 100043.
[http://dx.doi.org/10.1016/j.crmicr.2021.100043] [PMID: 34841334]
[23]
El-Saber Batiha, G.; Alkazmi, L.M.; Wasef, L.G.; Beshbishy, A.M.; Nadwa, E.H.; Rashwan, E.K. Syzygium aromaticum L. (Myrtaceae): Traditional uses, bioactive chemical constituents, pharmacological and toxicological activities. Biomolecules, 2020, 10(2), 202.
[http://dx.doi.org/10.3390/biom10020202] [PMID: 32019140]
[24]
Liu, J.; Lai, L.; Lin, J.; Zheng, J.; Nie, X.; Zhu, X.; Xue, J.; Liu, T. Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota. Int. J. Biol. Sci., 2020, 16(5), 790-802.
[http://dx.doi.org/10.7150/ijbs.40934] [PMID: 32071549]
[25]
Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Computeraided Drug Des., 2011, 7(2), 146-157.
[http://dx.doi.org/10.2174/157340911795677602] [PMID: 21534921]
[26]
Branco, A.F.; Pereira, S.P.; Gonzalez, S.; Gusev, O.; Rizvanov, A.A.; Oliveira, P.J. Gene expression profiling of H9c2 myoblast differentiation towards a cardiac-like phenotype. PLoS One, 2015, 10(6), e0129303.
[http://dx.doi.org/10.1371/journal.pone.0129303] [PMID: 26121149]
[27]
Boccalini, G.; Sassoli, C.; Formigli, L.; Bani, D.; Nistri, S. Relaxin protects cardiac muscle cells from hypoxia/reoxygenation injury: Involvement of the Notch‐1 pathway. FASEB J., 2015, 29(1), 239-249.
[http://dx.doi.org/10.1096/fj.14-254854] [PMID: 25342127]
[28]
Witek, P.; Korga, A.; Burdan, F.; Ostrowska, M.; Nosowska, B.; Iwan, M.; Dudka, J. The effect of a number of H9C2 rat cardiomyocytes passage on repeatability of cytotoxicity study results. Cytotechnology, 2016, 68(6), 2407-2415.
[http://dx.doi.org/10.1007/s10616-016-9957-2] [PMID: 26946144]
[29]
Atale, N.; Chakraborty, M.; Mohanty, S.; Bhattacharya, S.; Nigam, D.; Sharma, M.; Rani, V. Cardioprotective role of Syzygium cumini against glucose-induced oxidative stress in H9C2 cardiac myocytes. Cardiovasc. Toxicol., 2013, 13(3), 278-289.
[http://dx.doi.org/10.1007/s12012-013-9207-1] [PMID: 23512199]
[30]
Atale, N.; Mishra, C.B.; Kohli, S.; Mongre, R.K.; Prakash, A.; Kumari, S.; Yadav, U.C.S.; Jeon, R.; Rani, V. Anti-inflammatory effects of S. cumini seed extract on gelatinase-b (MMP-9) regulation against hyperglycemic cardiomyocyte stress. Oxid. Med. Cell. Longev., 2021, 2021, 1-14.
[http://dx.doi.org/10.1155/2021/8839479] [PMID: 33747350]
[31]
Jain, A.; Rani, V. Curcumin-mediated effects on anti-diabetic drug-induced cardiotoxicity. 3 Biotech, 2018, 8(9), 399.
[32]
Rani, V.; Sharma, K. Organosulfur compounds in aged garlic extract ameliorate glucose induced diabetic cardiomyopathy by attenuating oxidative stress, cardiac fibrosis, and cardiac apoptosis. Cardiovasc. Hematol. Agents Med. Chem., 2023, 21.
[http://dx.doi.org/10.2174/1871525721666230223145218] [PMID: 36825728]
[33]
Chacko, S.M.; Nevin, K.G.; Dhanyakrishnan, R.; Kumar, B.P. Protective effect of p -coumaric acid against doxorubicin induced toxicity in H9c2 cardiomyoblast cell lines. Toxicol. Rep., 2015, 2, 1213-1221.
[http://dx.doi.org/10.1016/j.toxrep.2015.08.002] [PMID: 28962464]
[34]
Khan, A.; Gillis, K.; Clor, J.; Tyagarajan, K. Simplified evaluation of apoptosis using the Muse cell analyzer. Postepy Biochem., 2012, 58(4), 492-496.
[PMID: 23662443]
[35]
Dziedzic, A.; Kubina, R.; Kabała-Dzik, A.; Tanasiewicz, M. Induction of cell cycle arrest and apoptotic response of head and neck squamous carcinoma cells (detroit 562) by caffeic acid and caffeic acid phenethyl ester derivative. Evid. Based Complement. Alternat. Med., 2017, 2017, 1-10.
[http://dx.doi.org/10.1155/2017/6793456] [PMID: 28167973]
[36]
Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res., 2019, 47(W1), W357-W364.
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]
[37]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[38]
Martínez-del Campo, A.; Bodea, S.; Hamer, H.A.; Marks, J.A.; Haiser, H.J.; Turnbaugh, P.J.; Balskus, E.P. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio, 2015, 6(2), e00042-e15.
[http://dx.doi.org/10.1128/mBio.00042-15] [PMID: 25873372]
[39]
Dalla Via, A.; Gargari, G.; Taverniti, V.; Rondini, G.; Velardi, I.; Gambaro, V.; Visconti, G.L.; De Vitis, V.; Gardana, C.; Ragg, E.; Pinto, A.; Riso, P.; Guglielmetti, S. Urinary TMAO levels are associated with the taxonomic composition of the gut microbiota and with the choline TMA-lyase gene (cutC) harbored by enterobacteriaceae. Nutrients, 2019, 12(1), 62.
[http://dx.doi.org/10.3390/nu12010062] [PMID: 31881690]
[40]
Wagner, J.A.; Colombo, J.M. Medicine and media: The ranitidine debate. Clin. Transl. Sci., 2020, 13(4), 649-651.
[http://dx.doi.org/10.1111/cts.12753] [PMID: 32107850]
[41]
Polatli, M. Methimazole-induced asthma? Chest, 2002, 121(1), 305-306.
[http://dx.doi.org/10.1378/chest.121.1.305] [PMID: 11796476]
[42]
Craciun, S.; Balskus, E.P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl. Acad. Sci. USA, 2012, 109(52), 21307-21312.
[http://dx.doi.org/10.1073/pnas.1215689109] [PMID: 23151509]

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