Rhodiola crenulata Suppresses High Glucose-Induced Matrix Metalloproteinase Expression and Inflammatory Responses by Inhibiting ROS-Related HMGB1-TLR4 Signaling in Endothelial Cells

Abstract

Rhodiola crenulata, a popular folk medicine for anti-altitude sickness in Tibet, has been shown to have protective effects against high glucose (HG)-induced endothelial cell dysfunction in human umbilical vein endothelial cells (HUVECs). However, its mechanisms of action are unclear. Here, we aimed to examine the effects and the mechanisms of action of Rhodiola crenulata extract (RCE) on matrix metalloproteinases (MMPs) and inflammatory responses under HG conditions. HUVECs were pretreated with RCE or untreated and then exposed to 33[Formula: see text]mM glucose medium for 24[Formula: see text]h. The levels of oxidative stress markers, MMPs, endogenous tissue inhibitors of MMPs (TIMPs), and adhesion molecules were determined. Zymography assays were also carried out. We found that RCE significantly decreased HG-induced increases in reactive oxygen species (ROS) and activation of MAPK and NF-[Formula: see text]B pathways. In addition, RCE not only significantly reduced the expression and activities of MMPs but also upregulated TIMP protein levels. Consistently, HG-induced activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein (MyD88) signaling pathway, intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and high mobility group box 1 (HMGB1) as well as endothelial cell apoptosis was inhibited by RCE treatment. RCE exerts protective effects on endothelial cells against HG insult, partially by suppressing the HMGB1/TLR4 axis. These findings indicate that Rhodiola crenulata may be a potential therapeutic agent for diabetes-associated vascular diseases.

Impact of High-Altitude Hypoxia on Bone Defect Repair: A Review of Molecular Mechanisms and Therapeutic Implications

“…As far as traditional Chinese medicine (TCM) is concerned, the anti-altitude sickness drug rhodiola has the obvious effect of inhibiting bone resorption. Studies have found that rhodiola reduces ROS production, significantly decreases the expression and activity of MMPs, and upregulates the TIMP protein ( 125 ). Salidroside, the major bioactive compound of rhodiola, has various pharmacological effects and acts through HIF-1α-VEGF ( 126 ) and BMP ( 127 ) pathways, simultaneously promoting angiogenesis and osteogenesis, thereby accelerating bone defect healing.…”

Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway

“…In addition to their anti-fatigue and anti-hypoxia roles in traditional medicine, Rhodiola extract, and salidroside also displayed medicinal properties as anti-cardiovascular diseases agents, which was mainly attributed to their antioxidant effects (Li et al, 2017;Zhao et al, 2021). Rhodiola crenulata exerts protective effects on hypoxia/high glucose-induced endothelial dysfunction and CIHinduced cardiac apoptosis (Lai et al, 2015;Chang et al, 2018;Huang et al, 2020). Rhodiola rosea extract attenuated pulmonary hypertension in chronic hypoxic rats (Kosanovic et al, 2013) and inhibited atherosclerosis formation in high fat diet-fed rabbits (Shen et al, 2008).…”

Vitamin D3 preserves blood retinal barrier integrity in an in vitro model of diabetic retinopathy

“…Vitamin D 3 could exert a pleiotropic anti-inflammatory activity considering its capability to counteract different pathways; this point would certainly need further investigation. We cannot rule out the hypothesis that vitamin D 3 could interfere with the activation of ROSrelated HMGB1-TLR4 signaling, described to induce endothelial dysfunction in presence of HG (Rao et al, 2017;Zhang et al, 2018;Fernandez-Robredo et al, 2020;Huang et al, 2020). Moreover, our results could be consistent with a putative contribution of vitamin D 3 in calcium homeostasis through the involvement of the purinergic system (P2X7R) that we found involved in high glucose-induced retinal endothelial damage (Platania et al, 2017).…”