Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats

Chem Biol Interact. 2014 Aug 5;219:101-12. doi: 10.1016/j.cbi.2014.05.012. Epub 2014 May 29.


Chronic, unhealed diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus (DM). Naringin, a flavanone glycoside antioxidant, was reported to have antidiabetic and anti-apoptotic properties. In the present study DM was induced experimentally by streptozotocin (STZ, 55 mg/kg, i.p.). In surgically introduced wounds on the dorsal surface of the hind paw of rats, the healing potential of naringin was investigated. Rats were treated with naringin (20, 40 and 80 mg/kg, p.o.), insulin (10 IU/kg, s.c.) and tetrachlorodecaoxide (TCDO) (1 drop, twice a day, topically) for 16 days. The wound area was measured every second day, and on day 17 various biochemical parameters were determined in serum, wound tissue, and histopathological examination of the wound was performed. Naringin (40 and 80 mg/kg) significantly (P<0.05) improved wound area, serum glucose level, glycated Hb and serum insulin. Naringin treatment at 40 and 80 mg/kg resulted in significant (P<0.05) up-regulation of mRNA expression of growth factor (IFG-1, TGF-β and VEGF-c), Ang-1 and collagen-1 whereas mRNA expression of inflammatory mediators (TNF-α, IL-1β and IL-6) was down-regulated. Furthermore, naringin significantly (P<0.05) attenuated STZ-induced apoptosis and stimulated angiogenesis in the wound tissue. Further results suggest that angiogenesis was improved via naringin-mediated inhibition of hyperglycemia, oxidative stress, down-regulation of inflammatory mediator expression and up-regulation of growth factor expression, leading to improved wound healing of DFU.

Keywords: Ang-1; Collagen-1; Diabetic foot ulcer; IFG-1; Naringin; VEGF-c.

MeSH terms

  • Angiotensin I / genetics
  • Angiotensin I / metabolism
  • Animals
  • Apoptosis / physiology*
  • Blood Glucose / analysis
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Diabetic Foot / drug therapy*
  • Diabetic Foot / pathology
  • Flavanones / administration & dosage
  • Flavanones / pharmacology*
  • Flavanones / therapeutic use
  • Gene Expression Regulation / physiology*
  • Glycated Hemoglobin / analysis
  • Histocytochemistry
  • Insulin / blood
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Male
  • Neovascularization, Physiologic / physiology*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Random Allocation
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / drug effects
  • Wound Healing / physiology*


  • Blood Glucose
  • Collagen Type I
  • Flavanones
  • Glycated Hemoglobin A
  • Insulin
  • Interleukin-1beta
  • Interleukin-6
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Insulin-Like Growth Factor I
  • Angiotensin I
  • naringin