An anti-inflammatory agent, 2-Hydroxyisocaproic Acid, prevents Del-1 fragmentation in vitro
Main Article Content
Abstract
Inflammation, a critical aspect of the immune system's defense and recovery processes, manifests in two primary forms: acute and chronic. Understanding and controlling these responses are vital for managing various inflammatory conditions. 2-Hydroxyisocaproic acid is a physiological substance and the 2-hydroxy-analogue of the essential amino acid leucine. This research focuses on the interaction of 2-Hydroxyisocaproic acid with key inflammatory mediators, matrix metalloproteinase 8, and Developmental Endothelial Locus 1. Matrix metalloproteinase 8 plays a significant role in the inflammatory process. Developmental Endothelial Locus 1 acts as a crucial immunomodulator, maintaining tissue homeostasis. Our findings reveal that 2-Hydroxyisocaproic acid inhibits the fragmentation of Developmental Endothelial Locus 1 by dose-dependently modulating and reducing the matrix metalloproteinase 8 activity. Notably, 2-Hydroxyisocaproic acid’s reversible inhibition of matrix metalloproteinase 8 does not eventually involve covalent bonding, positioning it as an enzyme modulator or down regulator rather than a direct inhibitor. This property of active matrix metalloproteinase 8 reduction by 2-Hydroxyisocaproic acid opens new avenues for therapeutic intervention, particularly in managing excessive inflammatory responses, such as the "cytokine storm" observed in lung tissue inflammation or arthritic joints like in osteoarthritis.
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KARILA, Tuomo et al.
An anti-inflammatory agent, 2-Hydroxyisocaproic Acid, prevents Del-1 fragmentation in vitro.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5466>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5466.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Hajishengallis G, Chavakis T. DEL-1-Regulated Immune Plasticity and Inflammatory Disorders. Trends Mol Med. May 2019;25(5):444-459. Doi:10.1016/j.molmed.2019.02.010
4. Yang N, Baban B, Isales CM, Shi X-M. Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. The FASEB Journal. Sep 2015;29(9):3954-3963. Doi:10.1096/fj.15-273664
5. Maekawa T, Hosur K, Abe T, et al. Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3beta-C/EBPbeta pathway. Nat Commun. Sep 16 2015;6:8272. Doi:10.1038/ncomms9272
6. Hajishengallis G, Chavakis T. DEL-1: a potential therapeutic target in inflammatory and autoimmune disease? Expert Rev Clin Immunol. Jun 2021;17(6):549-552. Doi:10.1080/1744666X.2021.1915771
7. Choi EY, Chavakis E, Czabanka MA, et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science. Nov 14 2008;322(5904):1101-4. Doi:10.1126/science.1165218
8. Mitroulis I, Kang YY, Gahmberg CG, et al. Developmental endothelial locus-1 attenuates complement-dependent phagocytosis through inhibition of Mac-1-integrin. Thromb Haemost. May 5 2014;111(5):1004-6. Doi:10.1160/TH13-09-0794
9. Karila T, Tervahartiala T, Cohen B, Sorsa T. The collagenases: are they tractable targets for preventing cartilage destruction in osteoarthritis? Expert Opin Ther Targets. Feb 2 2022:1-13. Doi:10.1080/14728222.2022.2035362
10. Shlopov BV, Lie WR, Mainardi CL, Cole AA, Chubinskaya S, Hasty KA. Osteoarthritic lesions. Involvement of three different collagenases. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. Nov 1997;40(11):2065-2074. Doi:10.1002/art.1780401120
11. Hanemaaijer R, Sorsa T, Konttinen YT, et al. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells regulation by tumor necrosis factor-α and doxycycline. Journal of Biological Chemistry. Dec 12 1997;272(50):31504-31509. Doi:10.1074/jbc.272.50.31504
12. Takayama Y. Studies on Amino-Acids and Related Compounds. Part iv. Electrolytic Reactions of Leucic Acid. Bulletin of the Chemical Society of Japan. 1933;8(6):173-178.
13. Hoffer LJ, Taveroff A, Robitaille L, Mamer OA, Reimer ML. Alpha-keto and alpha-hydroxy branched-chain acid interrelationships in normal humans. J Nutr. Sep 1993;123(9):1513-21. Doi:10.1093/jn/123.9.1513
14. Holecek M. Relation between glutamine, branched-chain amino acids, and protein metabolism. Nutrition. Feb 2002;18(2):130-3. Doi:10.1016/s0899-9007(01)00767-5
15. Mero AA, Ojala T, Hulmi JJ, Puurtinen R, Karila TA, Seppala T. Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes. J Int Soc Sports Nutr. 2010;7:1. Doi:1550-2783-7-1 [pii] 10.1186/1550-2783-7-1
16. Ojala T, Wilson JM, Hulmi JJ, Karila T, Seppälä TA, Mero AA. α-Hydroxy-Isocaproic Acid (HICA)—Effects on Body Composition, Muscle Soreness and Athletic Performance. Nutrition and Enhanced Sports Performance. Elsevier; 2013:213-216.
17. Hietala P, Karila TAM, Seppälä TA, Tähtivuori K, inventors; Nutrient supplement and use of the same. Finland patent application PCT/FI2005/050365. 2005.
18. Kurling S, Kankaanpaa A, Ellermaa S, Karila T, Seppala T. The effect of sub-chronic nandrolone decanoate treatment on dopaminergic and serotonergic neuronal systems in the brains of rats. Brain Res. May 17 2005;1044(1):67-75. Doi:10.1016/j.brainres.2005.02.071
19. Smoczer C, Park YK, Herrington JB, et al. A Potential Intracanal Medicament, 2-Hydroxyisocaproic Acid (HICA): Cytotoxicity, Genotoxicity, and Its Effect on SCAP Differentiation. Dentistry Journal. 2023;11(12):270. Doi:10.3390/dj11120270
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