Hyperglycemia,
hyperlipidemia, and atherosclerotic lesions may cause
inflammation, which leads to
chemokine production and changes in vascular responses.
Hyperglycemia can impair normal protein folding by producing
reactive oxygen species (ROS) and interacting with various signaling molecules, resulting in the activation of ER stress responses, that stimulates
NF-kB, which regulates the expression of numerous genes involved in
inflammation and
vascular remodeling. Our previous studies have shown that
diosgenin has a protective effect against
streptozotocin (STZ) - induced oxidative damage in rat aorta. However, the therapeutic role of
diosgenin on iRhom2/TACE signaling which has primarily been linked to the endoplasmic reticulum (ER)-stress induced
inflammation is unknown.
Diosgenin was administered (40 mg/kg b. wt, orally, for 4 weeks) to STZ-induced male albino rats. Fasting plasma
glucose, blood pressure,
nitrite level,
lipid profile, and
lipoprotein were assessed. Serum
insulin and pro-inflammatory markers were analyzed using ELISA,
mRNA and
protein expression of iRhom2/TACE signaling molecules were analyzed using RT-PCR and western blotting analysis respectively. In silico study was also performed to find out the possible binding affinity of
diosgenin with the ER stress signaling molecules. Through regulation of the iRhom2/TACE signaling molecules,
diosgenin lowered
dyslipidemia,
hypertension, and pro-inflammatory
cytokines (TNF-α, IL-1, IL-6, and IL-4) in the aorta of STZ induced diabetic rats. Results of molecular docking analysis also confirmed the potential binding interaction with iRhom2/TACE and TNF- α. These in silico and in vivo results indicated that a change in
lipid profile and
hypertension led to diabetes-related
inflammation by promoting ER stress and, as a result, accelerating the aorta by generating proinflammatory
cytokines and
lipid deposition. This study concludes that
diosgenin attenuates ER stress-induced
inflammation in diabetic rat aorta by modulating the expression of pro-inflammatory, iRhom2/TACE mediated mechanism and hence
diosgenin can be a therapeutic
drug for the treatment of diabetes-induced
inflammation.