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Combating atherosclerosis with targeted Diosmin nanoparticles-treated experimental diabetes


Diabetes with poor glycemic control is accompanying with an increased risk of disease namely atherosclerotic cardiovascular. Diosmin (DSN), which is obtained from citrus fruit used to assist the treatment of hemorrhoids or chronic venous atherosclerosis diseases, has an antioxidant, anti-hyperglycemic and anti-inflammatory effect. DSN is characterized by poor water solubility which limits its absorption by the gastrointestinal tract. To overcome this limitation, this study was designed to increase DSN bioavailability and solubility, through its loading on polymeric matrix; hydroxypropyl starch (HPS) and Poly lactide–glycolide-chitin (PLGA/chitin) to prepare Diosmin nanoparticles (DSN-NPs). Two methods were used to prepare DSN- NPs; Emulsion–solvent evaporation and Acid–base neutralization followed by further assessment on diabetes induced atherosclerosis The study was conducted on 50 animals assigned into 5 groups with 10 animals in each group: Group I: Normal rats received only normal saline, Group II: Diabetic rats, Group III: diabetic rats received oral DSN, Group IV: diabetic rats received DSN loaded HPS, Group V: diabetic rats received DSN loaded PLGA/chitin. Levels of total cholesterol, triglycerides, HDL-cholesterol, insulin, MDA and NO. plasminogen activator inhibitor-1 PAI-1), Paraoxonase-1(PON1), transforming growth factor-β1 (TGF-β1), NF-ҡB and Ang II were estimated. Our study revealed that, there was statistically significant difference between DSN treated group compared with DSN loaded HPS treated group and DSN loaded PLGA/chitin. Furthermore, the results obtained clearly disclosed no statistically significant difference between DSN loaded PLGA/chitin and control group exhibited DSN loaded PLGA/chitin has the higher ability to counteract the atherosclerosis factors induced by diabetes in all rats.

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  1. 1.

    Bullon P, Newman HN (2000) Battino M (2014) obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? Periodontol 64:139–153

    Google Scholar 

  2. 2.

    Lind M, Svensson A-M, Kosiborod M et al (2014) Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 371:1972–1982

    PubMed  Google Scholar 

  3. 3.

    Al-Mashhadi RH, Bjørklund MM, Mortensen MB et al (2015) Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs. Diabetologia 58:1926–1936

    CAS  PubMed  Google Scholar 

  4. 4.

    Berneis KK, Krauss RM (2002) Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 43:1363–1379

    CAS  PubMed  Google Scholar 

  5. 5.

    Katakami N (2017) Mechanism of development of atherosclerosis and cardiovascular disease in diabetes mellitus. J Atheroscler Thromb:RV17014

  6. 6.

    Carr ME (2001) Diabetes mellitus: a hypercoagulable state. J Diabetes Complicat 15:44–54

    CAS  PubMed  Google Scholar 

  7. 7.

    Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561

    CAS  PubMed  Google Scholar 

  8. 8.

    VERMA S, ANDERSON TJ (2001) The ten most commonly asked questions about endothelial function in cardiology. Cardiol Rev 9:250–252

    CAS  PubMed  Google Scholar 

  9. 9.

    Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. Jama 287:2570–2581

    CAS  PubMed  Google Scholar 

  10. 10.

    Schmidt AM, Stern D (2000) Atherosclerosis and diabetes: the RAGE connection. Curr Atheroscler Rep 2:430–436

    CAS  PubMed  Google Scholar 

  11. 11.

    Zhang L, Gu FX, Chan JM et al (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83:761–769

    CAS  PubMed  Google Scholar 

  12. 12.

    Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 70:1–20

    CAS  PubMed  Google Scholar 

  13. 13.

    Imam F, Al-Harbi NO, Al-Harbi MM et al (2015) Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice. Pharmacol Res 102:1–11

    CAS  PubMed  Google Scholar 

  14. 14.

    Feldo M, Woźniak M, Wójciak-Kosior M et al (2018) Influence of diosmin treatment on the level of oxidative stress markers in patients with chronic venous insufficiency. Oxid Med Cell Longev 2018

  15. 15.

    Anwer MK (2014) Development of diosmin loaded eudragit s100 polymeric nanoparticles: an investigation of antioxidant effect. IJBPAS 3:2015–2026

    CAS  Google Scholar 

  16. 16.

    Hebeish A, El-Rafie MH, Ramadan MA, El-Naggar ME (2013) Investigation into the synthesis and characterization of silver nanoparticles. Res J Text Appar 17:83–97.

    CAS  Article  Google Scholar 

  17. 17.

    Kohli R, Meininger CJ, Haynes TE et al (2004) Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr 134:600–608

    CAS  PubMed  Google Scholar 

  18. 18.

    Arab HH, Salama SA, Omar HA et al (2015) Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One 10:e0122417

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Mannaa F, Ahmed HH, Estefan SF et al (2005) Saccharomyces cerevisiae intervention for relieving flutamide-induced hepatotoxicity in male rats. Die Pharm Int J Pharm Sci 60:689–695

    CAS  Google Scholar 

  20. 20.

    JUDZEWITSCH RG, PFEIFER MA, BEST JD et al (1982) Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose. J Clin Endocrinol Metab 55:321–328

    CAS  PubMed  Google Scholar 

  21. 21.

    Richmond W (1973) Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 19:1350–1356

    CAS  PubMed  Google Scholar 

  22. 22.

    Fossati P, Prencipe L (1982) Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 28:2077–2080

    CAS  PubMed  Google Scholar 

  23. 23.

    Lopes-Virella MF, Stone P, Ellis S, Colwell JA (1977) Cholesterol determination in high-density lipoproteins separated by three different methods. Clin Chem 23:882–884

    CAS  PubMed  Google Scholar 

  24. 24.

    Glatter TR (1984) Hyperlipidemia: What is ‘normal,‘who should be treated and how. Postgrad Med 76:49–59

    CAS  PubMed  Google Scholar 

  25. 25.

    Ruiz-Larrea MB, Leal AM, Liza M et al (1994) Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 59:383–388

    CAS  PubMed  Google Scholar 

  26. 26.

    Ellman (1959) GL. Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    CAS  PubMed  Google Scholar 

  27. 27.

    Hussein J, Refaat E, Morsy S et al (2013) Green tea attenuates experimental hepatitis in context of oxidative stress. J Appl Pharm Sci 3:124

    Google Scholar 

  28. 28.

    Mohamed NA, El-Naggar ME (2018) Amifostine-based nanoemulsion as promising protective agent for nephrotoxicity. J Innov Pharm Biol Sci 5:38–45

    CAS  Google Scholar 

  29. 29.

    Hussein J, El-Naggar ME, Anwar M et al (2019) Synthesis of docosahexaenoic acid–loaded zinc oxide nanoparticles as a promising treatment in neurotoxicity. Comp Clin Pathol 28:1455–1464.

    CAS  Article  Google Scholar 

  30. 30.

    Hussein JS, Rasheed W, Ramzy T et al (2019) Synthesis of docosahexaenoic acid–loaded silver nanoparticles for improving endothelial dysfunctions in experimental diabetes. Hum Exp Toxicol 38:962–973.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Hamad SR, El-Naggar ME (2019) Blocking of gastric acid induced histopathological alterations, enhancing of DNA content and proliferation of goblet cells in the acute lung injury mice models by nano-fenugreek oral administration. Toxicol Mech Methods.

  32. 32.

    El-Naggar ME, Al-Joufi F, Anwar M et al (2019) Curcumin-loaded PLA-PEG copolymer nanoparticles for treatment of liver inflammation in streptozotocin-induced diabetic rats. Colloids Surf B: Biointerfaces 177:389–398.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    El-Naggar ME, El-Rafie MH, El-sheikh MA et al (2015) Synthesis, characterization, release kinetics and toxicity profile of drug-loaded starch nanoparticles. Int J Biol Macromol 81:718–729.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    El-Feky GS, E-R MH, El-Sheikh MA et al (2015) Utilization of Crosslinked starch nanoparticles as a carrier for indomethacin and acyclovir drugs. Nanomedicine Nanotechnol 6:254

    Google Scholar 

  35. 35.

    Shaheen TI, El-Naggar ME, Hussein JS et al (2016) Antidiabetic assessment; in vivo study of gold and core-shell silver-gold nanoparticles on streptozotocin-induced diabetic rats. Biomed Pharmacother Biomed Pharmacother 83:865

    CAS  PubMed  Google Scholar 

  36. 36.

    Abdelgawad AM, El-Naggar ME, Eisa WH, Rojas OJ (2017) Clean and high-throughput production of silver nanoparticles mediated by soy protein via solid state synthesis. J Clean Prod:144.

  37. 37.

    Hussein J, El-Bana M, Refaat E, El-Naggar ME (2017) Synthesis of carvacrol-based nanoemulsion for treating neurodegenerative disorders in experimental diabetes. J Funct Foods 37:441–448.

    CAS  Article  Google Scholar 

  38. 38.

    Al-Taweel A, Alqasoumi S, Alam P, Abdel-Kader M (2013) Densitometric-high-performance thin-layer chromatographic estimation of diosmin, hesperidin, and ascorbic acid in pharmaceutical formulations. JPC-Journal Planar Chromatogr TLC 26:336–342

    CAS  Google Scholar 

  39. 39.

    Xiao J, Kai G (2012) A review of dietary polyphenol-plasma protein interactions: characterization, influence on the bioactivity, and structure-affinity relationship. Crit Rev Food Sci Nutr 52:85–101

    CAS  PubMed  Google Scholar 

  40. 40.

    Giannouli M, Karagkiozaki V, Pappa F et al (2018) Fabrication of quercetin-loaded PLGA nanoparticles via electrohydrodynamic atomization for cardiovascular disease. Mater Today Proc 5:15998–16005

    CAS  Google Scholar 

  41. 41.

    Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50:537–546

    CAS  PubMed  Google Scholar 

  42. 42.

    Ritarwan K, Lelo A, Pane YS, Nerdy N (2018) Increasing atherosclerosis in Streptozotocin-induced diabetes into four groups of mice. Open access Maced J Med Sci 6:287

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Srinivasan S, Pari L (2012) Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chem Biol Interact 195:43–51

    CAS  PubMed  Google Scholar 

  44. 44.

    Husain K, Hernandez W, Ansari RA, Ferder L (2015) Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem 6:209

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    van Dijk DJ, Boner G, Giler S, Erman A (2001) Increased serum angiotensin-converting enzyme activity and plasma angiotensin II levels during pregnancy and postpartum in the diabetic rat. J Renin-Angiotensin-Aldosterone Syst 2:193–198

    PubMed  Google Scholar 

  46. 46.

    Ogata Y, Nemoto W, Nakagawasai O et al (2016) Involvement of spinal angiotensin II system in streptozotocin-induced diabetic neuropathic pain in mice. Mol Pharmacol 90:205–213

    CAS  PubMed  Google Scholar 

  47. 47.

    Ali FEM, Azouz AA, Bakr AG et al (2018) Hepatoprotective effects of diosmin and/or sildenafil against cholestatic liver cirrhosis: the role of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS signaling pathway. Food Chem Toxicol 120:294–304

    CAS  PubMed  Google Scholar 

  48. 48.

    Chapman MJ, Ginsberg HN, Amarenco P et al (2011) Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 32:1345–1361

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Schofield JD, Liu Y, Rao-Balakrishna P et al (2016) Diabetes dyslipidemia. Diabetes Ther 7:203–219

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Taskinen M-R (2003) Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46:733–749

    PubMed  Google Scholar 

  51. 51.

    Queenthy SS, John B (2013) Diosmin exhibits anti-hyperlipidemic effects in isoproterenol induced myocardial infarcted rats. Eur J Pharmacol 718:213–218

    CAS  PubMed  Google Scholar 

  52. 52.

    El-Fawal R, El Fayoumi HM, Mahmoud MF (2018) Diosmin and crocin alleviate nephropathy in metabolic syndrome rat model: effect on oxidative stress and low grade inflammation. Biomed Pharmacother 102:930–937

    CAS  PubMed  Google Scholar 

  53. 53.

    Petersen KE, Lykkesfeldt J, Raun K, Rakipovski G (2017) Brief communication: plasma lipid oxidation predicts atherosclerotic status better than cholesterol in diabetic apolipoprotein E deficient mice. Exp Biol Med 242:88–91

    CAS  Google Scholar 

  54. 54.

    Yoon J-H, Kim J-Y, Park J-K, Ko S-B (2015) Oxidative damage markers are significantly associated with the carotid artery intima-media thickness after controlling for conventional risk factors of atherosclerosis in men. PLoS One 10:e0119731

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Yang R-L, Shi Y-H, Hao G et al (2008) Increasing oxidative stress with progressive hyperlipidemia in human: relation between malondialdehyde and atherogenic index. J Clin Biochem Nutr 43:154–158

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Gupta S, Sharma SB, Singh UR, Bansal SK (2011) Salutary effect of Cassia auriculata L. leaves on hyperglycemia-induced atherosclerotic environment in streptozotocin rats. Cardiovasc Toxicol 11:308

  57. 57.

    Gomathi P, Iyer AC, Murugan PS et al (2018) Association of paraoxonase-1 gene polymorphisms with insulin resistance in south Indian population. Gene 650:55–59

    CAS  PubMed  Google Scholar 

  58. 58.

    Kunutsor SK, Kieneker LM, Bakker SJL et al (2017) Incident type 2 diabetes is associated with HDL, but not with its anti-oxidant constituent-paraoxonase-1: the prospective cohort PREVEND study. Metabolism 73:43–51

    CAS  PubMed  Google Scholar 

  59. 59.

    Viktorinova A, Jurkovicova I, Fabryova L et al (2018) Abnormalities in the relationship of paraoxonase 1 with HDL and apolipoprotein A1 and their possible connection to HDL dysfunctionality in type 2 diabetes. Diabetes Res Clin Pract 140:174–182

    CAS  PubMed  Google Scholar 

  60. 60.

    Campanero MA, Escolar M, Perez G et al (2010) Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography–atmospheric pressure chemical ionization tandem mass spectrometry: application to a clinical pharmacokinetic study. J Pharm Biomed Anal 51:875–881

    CAS  PubMed  Google Scholar 

  61. 61.

    Kohler HP, Grant PJ (2000) Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 342:1792–1801

    CAS  PubMed  Google Scholar 

  62. 62.

    Moustapha M, Chadhli-Chaieb M, Mahjoub T, Chaieb L (2017) Genetic and metabolic determinants of plasminogen activator inhibitor 1 (PAI-1) in Tunisian type 2 diabetes patients. Open J Endocr Metab Dis 7:141

    CAS  Google Scholar 

  63. 63.

    Mahmoud AM (2017) Exercise amaliorates metabolic disturbances and oxidative stress in diabetic cardiomyopathy: possible underlying mechanisms. In: Exercise for Cardiovascular Disease Prevention and Treatment. Springer, pp 207–230

  64. 64.

    Gilmore TD (2006) Introduction to NF-κB: players, pathways, perspectives. Oncogene 25:6680

    CAS  PubMed  Google Scholar 

  65. 65.

    Tedgui A, Mallat Z (2001) Anti-inflammatory mechanisms in the vascular wall. Circ Res 88:877–887

    CAS  PubMed  Google Scholar 

  66. 66.

    Shrikhande GV, Scali ST, da Silva CG et al (2010) O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice. PLoS One 5:e14240

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Saad AS, Mohamed KAA (2017) Diosmin versus cabergoline for prevention of ovarian hyperstimulation syndrome. Middle East Fertil Soc J 22:206–210

    Google Scholar 

  68. 68.

    Soufy H, Lin TS, Das S, Zakaria Z (2012) Histological changes in the heart and the proximal aorta in experimental diabetic rats fed with Piper sarmentsoum. African J Tradit Complement Altern Med 9:396–404

    Google Scholar 

  69. 69.

    Aronson D, Rayfield EJ (2002) How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 1:1

    PubMed  PubMed Central  Google Scholar 

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This work was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.

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Correspondence to Mehrez E. El-Naggar or Moustafa M. G. Fouda.

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Hendawy OM declares that he has no conflict of interest. Mehrez E. El-Naggar declares that he has no conflict of interest. Mona El-Banna declares that he has no conflict of interest. Moustafa M. G. Fouda declares that he has no conflict of interest. Sarah I. Othman. declares that he has no conflict of interest. Ahmed A. Allam declares that he has no conflict of interest and Osama M. Morsy declares that he has no conflict of interest.

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OM, H., El-Naggar, M.E., El-Banna, M. et al. Combating atherosclerosis with targeted Diosmin nanoparticles-treated experimental diabetes. Invest New Drugs 38, 1303–1315 (2020).

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  • Diosmin
  • Emulsion–solvent evaporation
  • Acid–base neutralization
  • Nanoparticles
  • Atherosclerotic cardiovascular