Isosamidin from Peucedanum japonicum Roots Prevents Methylglyoxal-Induced Glucotoxicity in Human Umbilical Vein Endothelial Cells via Suppression of ROS-Mediated Bax/Bcl-2

Abstract

Methylglyoxal (MGO) is a highly reactive metabolite of glucose. Elevated levels of MGO induce the generation of reactive oxygen species (ROS) and cause cell death in endothelial cells. Vascular endothelial cell damage by ROS has been implicated in the progression of diabetic vascular complications, cardiovascular diseases, and atherosclerosis. In this study, the protective effect of isosamidin, isolated from Peucedanum japonicum roots, on MGO-induced apoptosis was investigated using human umbilical vein endothelial cells (HUVECs). Among the 20 compounds isolated from P. japonicum, isosamidin showed the highest effectiveness in inhibiting MGO-induced apoptosis of HUVECs. Pretreatment of HUVECs with isosamidin significantly prevented the generation of ROS and cell death induced by MGO. Isosamidin prevented MGO-induced apoptosis in HUVECs by downregulating the expression of Bax and upregulating the expression of Bcl-2. MGO treatment activated mitogen-activated protein kinases (MAPKs), such as p38, c-Jun N terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). In contrast, pretreatment with isosamidin strongly inhibited the activation of p38 and JNK. Furthermore, isosamidin caused the breakdown of the crosslinks of the MGO-derived advanced glycation end products (AGEs). These findings suggest that isosamidin from P. japonicum may be used as a preventive agent against MGO-mediated endothelial dysfunction in diabetes. However, further study of the therapeutic potential of isosamidin on endothelial dysfunction needs to explored in vivo models.

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

“…MGO is a highly reactive dicarbonyl metabolite of glucose known to induce cellular apoptosis, oxidative stress, inflammation, and AGE formation in ECs [40,41]. The accumulation of MGO has been associated with organ dysfunction contributing to the pathogenesis of diabetes and vascular complications [42,43].…”

In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration

“…In another study, MGO exposed HUVECs showed increased ROS production and apoptosis accompanied by an increase in Bax protein expression and a decrease in Bcl-2, increased phosphorylation of the MAPKS (p38, JNK, ERK), and decreased NF-κB activation [240,241]. In addition, Glyoxalase-1 (GLO-1) protein levels decreased while Nrf-2 remained unchanged (isosamidin counteracted all the effects) [241]. HUVECs incubated with MGO showed a significant increase in ROS production, monolayer permeability, actin stress fibers, and a decrease in gene and protein expression of ZO-1, Cx43, and the gap junctional intercellular communication (GJIC) [237].…”

“…In both cases, MGO modified BSA induced the most significant decrease in GSH activity and increase in GPx activity compared to the other glycated proteins, whereas, in the presence of N-acetyl-cysteine (NAC) and aminoguanidine, the effects were reversed [167]. In another study, MGO exposed HUVECs showed increased ROS production and apoptosis accompanied by an increase in Bax protein expression and a decrease in Bcl-2, increased phosphorylation of the MAPKS (p38, JNK, ERK), and decreased NF-κB activation [240,241]. In addition, Glyoxalase-1 (GLO-1) protein levels decreased while Nrf-2 remained unchanged (isosamidin counteracted all the effects) [241].…”

Cudrania tricuspidata Root Extract Prevents Methylglyoxal‐Induced Inflammation and Oxidative Stress via Regulation of the PKC‐NOX4 Pathway in Human Kidney Cells

“…MGO- and MGO-mediated AGEs are increased in DN patients, and they are important factors in DN progression [ 58 – 60 ]. It is well established that MGO increases oxidative stress and cell damage/death in endothelial cells [ 61 ] and several kidney cells including mesangial cells [ 62 , 63 ], podocytes [ 64 ], and tubular epithelial cells [ 26 , 27 , 65 ]. According to several studies [ 26 – 28 , 35 ], including the present study, MGO-induced oxidative stress activates MAPK/NF κ B signaling and induces an inflammatory response in renal tubular epithelial cells.…”