Effect of diosmin and diosmetin on the level of pro-inflammatory factors in the endothelium artificially induced with inflammatory stimuli
Abstract
Introduction: Diosmin and its aglycone diosmetin are phlebotropic drugs used in the treatment of chronic venous insufficiency (CVI). Diosmin increases the elasticity and tension of blood vessel walls, exhibits an antiedematous effect, and acts as an anti-inflammatory agent. As it is commonly known that the endothelium layer plays a significant role in the physiology and pathophysiology of the cardiovascular system, this paper investigates the effect of diosmin and diosmetin on modulating the levels of pro-inflammatory factors in an endothelial cell culture (HUVEC) stimulated by lipopolysaccharide (LPS) or phorbol (PMA).
Material and methods: A normal human umbilical vein/vascular endothelium cell line HUV-EC-C (HUVEC) was stimulated with lipopolysaccharide (LPS) or phorbol 12-myristate-13-acetate (PMA). Cell viability was assessed using NR and MTT assays. The levels of human IL-1β, IL-6, IL-10, COX-2, and PGE2 were measured using ELISA kits.
Results: Depending on the agent used to initiate inflammation, different levels of factors associated with this state were obtained. Diosmetin significantly decreased the levels of pro-inflammatory IL-1β and IL-6 as well as COX-2 in PMA-treated cells. Meanwhile, diosmin did not affect the interleukins but it lowered COX-2 and increased PGE-2. Upon the LPS stimulation of HUVEC cells, diosmetin increased the levels of PGE2, IL-1β, COX-2, and nitric oxide (NO), while diosmin increased NO and IL-6.
Conclusion: Diosmin and diosmetin have different impacts on the levels of pro-inflammatory factors depending on the inflammation inducer. Diosmetin more effectively modulated inflammation than diosmin, suggesting that the attachment of the sugar moiety to the aglycone attenuates its activity.
Keywords: diosmindiosmetinlipopolysaccharidephorbol 12-myristate 13-acetateendothelial cells
References
- Bogucka-Kocka A, Woźniak M, Feldo M, et al. Diosmin-isolation techniques, determination in plant material and pharmaceutical formulations, and clinical use. Nat Prod Commun. 2013; 8(4): 545–550.
- Yu Ge, Wan R, Yin G, et al. Diosmetin ameliorates the severity of cerulein-induced acute pancreatitis in mice by inhibiting the activation of the nuclear factor-κB. Int J Clin Exp Pathol. 2014; 7(5): 2133–2142.
- Feldo M, Wójciak M, Ziemlewska A, et al. Modulatory Effect of Diosmin and Diosmetin on Metalloproteinase Activity and Inflammatory Mediators in Human Skin Fibroblasts Treated with Lipopolysaccharide. Molecules. 2022; 27(13).
- Steinbruch M, Nunes C, Gama R, et al. Is Nonmicronized Diosmin 600 mg as Effective as Micronized Diosmin 900 mg plus Hesperidin 100 mg on Chronic Venous Disease Symptoms? Results of a Noninferiority Study. Int J Vasc Med. 2020; 2020: 4237204.
- Feldo M, Wójciak-Kosior M, Sowa I, et al. Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules. 2019; 24(18).
- Feldo M, Woźniak M, Wójciak-Kosior M, et al. Influence of Diosmin Treatment on the Level of Oxidative Stress Markers in Patients with Chronic Venous Insufficiency. Oxid Med Cell Longev. 2018; 2018: 2561705.
- Wójciak M, Feldo M, Borowski G, et al. Antioxidant Potential of Diosmin and Diosmetin against Oxidative Stress in Endothelial Cells. Molecules. 2022; 27(23).
- Jantet G. Chronic Venous Insufficiency: Worldwide Results of the RELIEF Study. Angiology. 2016; 53(3): 245–256.
- Medina-Leyte DJ, Zepeda-García O, Domínguez-Pérez M, et al. Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. Int J Mol Sci. 2021; 22(8).
- Peyter AC, Armengaud JB, Guillot E, et al. Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches. Int J Mol Sci. 2021; 22(13).
- Yu J, Ming H, Li HY, et al. IMM-H007, a novel small molecule inhibitor for atherosclerosis, represses endothelium inflammation by regulating the activity of NF-κB and JNK/AP1 signaling. Toxicol Appl Pharmacol. 2019; 381: 114732.
- Gao F, Li JM, Xi C, et al. Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway. Acta Pharmacol Sin. 2019; 40(7): 867–878.
- Zhu X, Chen D, Liu Y, et al. Long Noncoding RNA HOXA-AS3 Integrates NF-κB Signaling To Regulate Endothelium Inflammation. Mol Cell Biol. 2019; 39(19).
- Wang YF, Hsu YJ, Wu HF, et al. Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation. Circ Res. 2016; 119(2): 222–236.
- Gerges SH, Wahdan SA, Elsherbiny DA, et al. Diosmin ameliorates inflammation, insulin resistance, and fibrosis in an experimental model of non-alcoholic steatohepatitis in rats. Toxicol Appl Pharmacol. 2020; 401: 115101.
- Alkhalaf M. Diosmin protects against acrylamide-induced toxicity in rats: Roles of oxidative stress and inflammation. Journal of King Saud University - Science. 2020; 32(2): 1510–1515.
- Ali TM, Abo-Salem OM, El Esawy BH, et al. The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats. Am J Med Sci. 2020; 359(1): 32–41.
- Carballo-Villalobos AI, González-Trujano ME, Pellicer F, et al. Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats. Biomed Pharmacother. 2018; 97: 310–320.
- Berkoz M. Diosmin suppresses the proinflammatory mediators in lipopolysaccharide-induced RAW264.7 macrophages via NF-κB and MAPKs signal pathways. Gen Physiol Biophys. 2019; 38(4): 315–324.
- Bai HW, Zhu BT. Strong activation of cyclooxygenase I and II catalytic activity by dietary bioflavonoids. J Lipid Res. 2008; 49(12): 2557–2570.
- López-Posadas R, Ballester I, Mascaraque C, et al. Flavonoids exert distinct modulatory actions on cyclooxygenase 2 and NF-kappaB in an intestinal epithelial cell line (IEC18). Br J Pharmacol. 2010; 160(7): 1714–1726.