Baicalin alleviates hyperglycemia-induced endothelial impairment via Nrf2

Abstract

Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine, which exhibits strong anti-inflammatory, anti-viral and anti-tumor activities. The present work was devoted to elucidate the molecular and cellular mechanisms underlying the protective effects of Baicalin against diabetes-induced oxidative damage, inflammation and endothelial dysfunction. Diabetic mice, induced by streptozotocin (STZ), were treated with intraperitoneal Baicalin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of Baicalin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature by Baicalin, along with restoration of hyperglycemia-impaired nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway activity. However, the protective effects of Baicalin almost completely abolished in HUVECs transduced with shRNA against Nrf2, but not with nonsense shRNA. Mechanistic studies demonstrated that HG decreased Akt and GSK3B phosphorylation, restrained nuclear export of Fyn and nuclear localization of Nrf2, blunted Nrf2 downstream target genes and subsequently induced oxidative stress in HUVECs. However, those destructive cascades were well prevented by Baicalin in HUVECs. Furthermore, LY294002 and ML385 (inhibitor of PI3K and Nrf2) attenuated Baicalin-mediated Nrf2 activation and the ability of facilitates angiogenesis in vivo and ex vivo. Taken together, the endothelial protective effect of Baicalin under hyperglycemia condition could be partly attributed to its role in downregulating reactive oxygen species (ROS) and inflammation via the Akt/GSK3B/Fyn-mediated Nrf2 activation.

Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

“…Several chemical compounds can also indirectly regulate endothelial function through the Keap1‐Nrf2 pathway. The protective effects of Baicalin in inhibiting hyperglycemia‐triggered oxidative damage and inflammation in HUVECs and diabetic aortal vasculature could be partially attributed to its role in downregulating ROS and inflammation via Nrf2 activation mediated by the Akt/Glycogen synthase kinase‐3β (GSK‐3β)/Fyn axis (G. Chen et al, 2018). More intriguingly, the rejuvenative effects of ameliorating vascular EC senescence and recovering the compromised proliferation, migration, and tube formation capabilities in exosomes derived from human embryonic stem cells were largely impaired after cotreatment with the Nrf2 inhibitor, brusatol (B. Chen et al, 2019).…”

The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches

“…Interestingly, the entire dose-response curves of berberine was shown to be shifted down in the presence of baicalin (100 µmol/L), and baicalin antagonised the effect of berberine on glucose uptake in 3T3-L1 adipocytes. Since the antioxidant flavonoid baicalein is known to improve a range of abnormalities associated with diabetes [80][81][82][83][84][85], its coadministration with berberine appear to have a favourable outcome in the specified dose range.…”

Baicalin Improves Cardiac Outcome and Survival by Suppressing Drp1‐Mediated Mitochondrial Fission after Cardiac Arrest‐Induced Myocardial Damage

“…Herein, our results show that daily administration of baicalin for 28 days before CA attenuates myocardial injury induced by CA, supporting that long-term daily use of baicalin can serve as a promising therapeutic strategy to lower myocardial injury in CA. This intervention could be practicable in future clinical application because baicalin has been demonstrated to provide good validity in treating obesity [ 32 ], hyperglycemia [ 33 ], and hyperglycemia-induced vascular complications such as endothelial dysfunction [ 34 ], which are all vital factors of increased risk for sudden CA. In addition, short-term intervention of baicalin for 7 days has been shown to be cardioprotective in myocardial infarction [ 35 ]; however, further study is required to determine whether short-term administration of baicalin is effective in reducing myocardial injury after CA.…”