Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death

Abstract

Although didymin, a flavonoid-O-glycosides compound naturally found in the citrus fruits, has been reported to be a potent anticancer agent in the prevention of various cancers, its role in the prevention of cardiovascular complications is unclear. Most importantly, its effect in the prevention of endothelial dysfunction, a pathological process involved in the atherogenesis, is unknown. We have examined the efficacy of didymin in preventing the high glucose (HG; 25 mM)-induced human umbilical vein endothelial cells (HUVECs) dysfunction. Our results indicate that incubation of HUVECs with HG resulted in the loss of cell viability, and pre-incubation of didymin prevented it. Further, didymin prevented the HG-induced generation of reactive oxygen species (ROS) as well as lipid peroxidation product, malondialdehyde. Pretreatment of HUVECs with didymin also prevented the HG-induced decrease in eNOS and increase in iNOS expressions. Further, didymin prevented the HG-induced monocytes cell adhesion to endothelial cells, expressions of ICAM-1 and VCAM-1 and activation of NF-κB. Didymin also prevented the release of various inflammatory cytokines and chemokines in HG-treated HUVECs. In conclusion, our results demonstrate that didymin with its anti-oxidative and anti-inflammatory actions prevents hyperglycemia-induced endothelial dysfunction and death. Thus, it could be developed as a potential natural therapeutic agent for the prevention of cardiovascular complications in diabetes.

Network Pharmacology Analysis of the Therapeutic Mechanisms Underlying Beimu-Gualou Formula Activity against Bronchiectasis with In Silico Molecular Docking Validation

“…Molecularly, this compound can successively inhibit NF- κ B signaling and ICAM-1 and VCAM-1 expressions in cell adhesion and ultimately downregulate the levels of inflammatory cytokines and chemokines. In terms of sputum production, it is able to decrease the phosphorylation of JNK, ERK, and p38 (i.e., partially inhibiting the MAPK signaling) and further downregulate MUC5AC expression to attenuate mucus hypersecretion [ 60 , 61 ]. Likewise, luteolin (derived from P. Grandiflora ) plays an anti-inflammatory role by targeting such core regulators of the host immune cascades as Src in the NF- κ B pathway, MAPK in the AP-1 pathway, and SOCS3 in the STAT3 pathway [ 62 ].…”

Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies

“…Although it has great antioxidant potential, didymin is mainly mentioned in the literature in relation to its potent anticancer capacity, having an antiproliferative effect and preventing the growth of cancer cells [ 74 , 75 , 76 ]. The effects of didymin against endothelial dysfunction, a pathological process involved in atherogenesis, were described by Shukla, Sonowal, Saxena, and Ramana [ 61 ], who demonstrated the role of this flavanone in inhibiting the apoptosis of human umbilical vein endothelial cells induced by high glucose, via modulating oxidative stress signals, leading to the generation of ROS as well as the activation of caspase-3 and Erk1/2 and regulation of the Bcl2 protein. Moreover, didymin also alleviated high glucose-induced endothelial dysfunction by preventing monocyte adhesion to endothelial cells, restoring endothelial nitric oxide synthase (eNOS) and NO levels, reducing the levels of several inflammatory cytokines, such as TNF-α, interferon gamma (INF-γ), IL-1β, IL-2, and IL-6.…”

Total Synthesis, Discovery and Biological Evaluation of Daldinin A Derivatives for Improving Hyperglycemia-Induced Endothelial Cell Death

“…Excessive OS can induce apoptosis by disrupting the normal function of mitochondria. [6][7][8] An increased ROS content induces the opening of mitochondrial permeability transition pores and the decoupling of the mitochondrial electron transport chain, which leads to the initiation of the intrinsic apoptotic cascade. 9) Eventually, this induces the rupture of the outer membrane of the mitochondria and apoptosis.…”