Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Abstract

Purpose: High glucose environment in diabetes mellitus induces the dysfunction of bone marrow-derived mesenchymal stromal cells (BMSCs) and impairs bone regeneration. Chrysin is a natural polyphenol with outstanding anti-inflammation and anti-oxidation ability. However, whether and how chrysin affects BMSCs in high glucose conditions remain poorly understood. The present study aimed to explore the effects and underlying mechanisms of chrysin on the BMSCs exposed to high glucose environment. Materials and Methods: Cell viability was detected by cell counting kit 8 assay and 5ethynyl-2'-deoxyuridine staining, while cell apoptosis was determined through flow cytometry using Annexin V-FITC/PI kit. The oxidative stress in BMSCs was evaluated by detecting the reactive oxygen species production, malondialdehyde content, and superoxide dismutase activity. Alkaline phosphatase staining, Alizarin Red staining, and quantitative real-time PCR were performed to determine the osteogenic differentiation. Western blot was used to examine the expression of the PI3K/ATK/Nrf2 signaling pathway. Furthermore, chrysin was injected into calvarial defects of type 1 diabetic SD rats to assess its in vivo bone formation capability. Results: Chrysin reduced oxidative stress, increased cell viability, and promoted osteogenic differentiation in BMSCs exposed to high glucose. Blocking PI3K/ATK/Nrf2 signaling pathway weakened the beneficial effects of chrysin, indicating that chrysin at least partly worked through the PI3K/ATK/Nrf2 pathway. Conclusion: Chrysin can protect BMSCs from high glucose-induced oxidative stress via the activation of the PI3K/AKT/Nrf2 pathway, and promote bone regeneration in type 1 diabetic rats.

Mapping Knowledge Landscapes and Emerging Trends of the Links Between Bone Metabolism and Diabetes Mellitus: A Bibliometric Analysis From 2000 to 2021

“…an adverse effect on bone quality. In vitro experiments have proven that high glucose environment exerts an inhibitory action on the osteogenic differentiation and growth of osteoblasts and bone marrow stroma cells (BMSCs) (18,56). Glycolysis is a fundamental metabolic pathway for glucose catabolism.…”

“…Furthermore, there is also study showing that sustained hyperglycemia may trigger cellular innate immune responses, activate reactive oxygen species (ROS)-producing enzymes localized on the outer mitochondrion, resulting in overproduction of ROS and cell dysfunction (59). Therefore, in recent years, a large number of studies have focused on how to rescue the impaired osteogenesis differentiation ability of BMSCs and osteoblasts (56,57,60,61). That is very critical and meaningful way to find novel therapeutic targets for diabetic osteoporosis.…”

Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging

“…A more beneficial way would be activating innate pathways that promote endogenous antioxidants production in vivo, such as the nuclear factor erythroid 2-related factor 2 (NRF2) pathway [ 194 , 195 ]. Chrysin is reported to promote bone regeneration in type 1 diabetic rats and protect BMSCs from high glucose-induced oxidative stress by PI3K/AKT/Nrf2 pathway [ 196 ]. Nevertheless, as older people have a higher risk of cancer development, another significant concern may be raised because of the potential effect of antioxidants on cancer promotion.…”

An update of Nrf2 activators and inhibitors in cancer prevention/promotion

“…According to the literature reports, the most reliable pharmacological activities of chrysin are antioxidant, anti-inflammatory, anti-diabetic, hepatoprotective, neuroprotective, anti-aging, and anticancer effects [ 213 – 215 ]. In many studies, it has been reported that chrysin occupies an axial role in many biological process for example suppression the pro-inflammatory cytokines expression, down-regulation of nuclear factor kappa B (NF-kB), tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β), up-regulation of apoptotic pathways, and inhibition of angiogenesis and metastasis formation [ 216 – 218 ]. Gao and colleagues have been reported a higher level of Nrf2 expression in BEL-7402/ADM cells.…”