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Rhodiola crenulata root extract (RCE), a traditional Chinese medicine, has been shown to regulate glucose and lipid metabolism via the AMPK pathway in high glucose (HG) conditions. However, the effect of RCE on HG-induced endothelial dysfunction remains unclear. The present study was designed to examine the effects and mechanisms of RCE against hyperglycemic insult in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without RCE and then exposed to 33mM HG medium. The cell viability, nitrite production, oxidative stress markers, and vasoactive factors, as well as the mechanisms underlying RCE action, were then investigated. We found that RCE significantly improved cell death, nitric oxide (NO) defects, and oxidative stress in HG conditions. In addition, RCE significantly decreased the HG-induced vasoactive markers, including endothelin-1 (ET-1), fibronectin, and vascular endothelial growth factor (VEGF). However, the RCE-restored AMPK-Akt-eNOS-NO axis and cell viability were abolished by the presence of an AMPK inhibitor. These findings suggested that the protective effects of RCE were associated with the AMPK-Akt-eNOS-NO signaling pathway. In conclusion, we showed that RCE protected endothelial cells from hyperglycemic insult and demonstrated its potential for use as a treatment for endothelial dysfunction in diabetes mellitus.

Skin injury is a major complication during radiation therapy and is associated with oxidative damage to skin cells. An effective and safe radioprotectant to prevent this skin damage is still unavailable. The Rhodiola crenulata root extract (RCE) has been reported to be a free radical scavenger and a potent anti-oxidant in both in vitro and in vivo models. In the current study, we investigated the effects of RCE on ionizing radiation-induced skin injury and its underlying mechanisms. HaCaT cells — a non-cancerous skin cell line together with HepG2, Caco2, A549, and OECM cancer cell lines — were pre-treated with RCE for 24h followed by exposure to 15 Gy using Caesium-137 as a γ-ray source. The cell viability was measured. In HaCaT cells, oxidative stress markers, cellular apoptosis pathways, matrix metalloproteinases (MMPs), and pro-inflammatory cytokine gene expression were studied. We found that RCE significantly protected HaCaT cells, but not cancer cells from the loss of viability induced by exposure to ionizing radiation. RCE attenuated radiation-induced oxidative stress markers, cell apoptosis, MMP levels, and expression of cytokine genes. RCE also limited the induction of p53 and p21 by radiation exposure. These findings indicate that RCE may selectively protect the skin cells from ionizing radiation without altering its ability to kill cancer cells. Therefore, we suggest that RCE or its derivatives could serve as a novel radioprotective therapy.

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 33mM glucose medium for 24h. 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-$\kappa$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.

The medicinal plant Rhodiola crenulata grows at high altitudes in the Arctic and mountainous regions and is commonly used in phytotherapy in Eastern European and Asian countries. In the present study, we investigated the anti-apoptotic effect of Rhodiola crenulata and its neuroprotective mechanism of action in a rat model of D-galactose-induced aging. Two groups of twelve-week-old male Wistar rats received a daily injection of D-galactose (150mg/kg/day, i.p.) and orally administered Rhodiola crenulata (0, 248mg/kg/day) for eight weeks, while a control group received a saline injection (1ml/kg/day, i.p.). We examined apoptosis in the cortex and hippocampus of three groups of rats based on a terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL) positive assay. The expression levels of apoptotic and anti-apoptotic proteins in excised brains were analyzed by Western blotting. Our findings indicated that D-galactose caused marked neuronal apoptosis via activation of both extrinsic-dependent and mitochondrial-dependent apoptotic pathways. When compared to the control group, the protein levels of Fas receptor, Fas ligand, Fas-associated death domain (FADD), and activated caspase-8 (Fas-dependent apoptotic pathways), as well as those of t-Bid, Bax, cytochrome $c$, activated caspase-9, and activated caspase-3 (mitochondrial-dependent apoptotic pathways), were significantly increased in the D-galactose treated group. In addition, D-galactose impaired the phosphorylation of PI3K/Akt, an important survival signaling event in neurons. Rhodiola crenulata, however, protected against all these neurotoxicities in aging brains. The present study suggests that neuronal survival promoted by Rhodiola crenulata may be a potentially effective method to enhance the resistance of neurons to age-related disorders.