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Background: Osteonecrosis of the femoral head caused by glucocorticoids (GIONFH) is a significant issue resulting from prolonged or excessive clinical glucocorticoid use. Astaxanthin, an orange-red carotenoid present in marine organisms, has been the focus of this study to explore its impact and mechanism on osteoblast apoptosis induced by dexamethasone (Dex) and GIONFH., Methods: In this experiment, bioinformatic prediction, molecular docking and dynamics simulation, cytotoxicity assay, osteogenic differentiation, qRT-PCR analysis, terminal uridine nickend labeling (TUNEL) assay, determination of intracellular ROS, mitochondrial function assay, immunofluorescence, GIONFH rat model construction, micro-computed tomography (micro-CT) scans were performed., Results: Our research demonstrated that a low dose of astaxanthin was non-toxic to healthy osteoblasts and restored the osteogenic function of Dex-treated osteoblasts by reducing oxidative stress, mitochondrial dysfunction, and apoptosis. Furthermore, astaxanthin rescued the dysfunction in poor bone quality, bone metabolism and angiogenesis of GIONFH rats. The mechanism behind this involves astaxanthin counteracting Dex-induced osteogenic damage by activating the Nrf2 pathway., Conclusion: Astaxanthin shields osteoblasts from glucocorticoid-induced oxidative stress and mitochondrial dysfunction via Nrf2 pathway activation, making it a potential therapeutic agent for GIONFH treatment., (© 2024. The Author(s).)

Glucocorticoid‐induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long‐term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway. We conducted qRT‐PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin–eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX‐induced osteoblast apoptosis, as evidenced by qRT‐PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX‐mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH. [ABSTRACT FROM AUTHOR]

Osteoporosis is characterized by a decrease in bone mass and destruction of the bone microarchitecture, and it commonly occurs in postmenopausal women and the elderly. Overactivation of osteoclasts caused by the inflammatory response or oxidative stress leads to osteoporosis. An increasing number of studies have suggested that intracellular reactive oxygen species (ROS) are strongly associated with osteoclastogenesis. As a novel angiotensin (Ang) II receptor blocker (ARB), azilsartan was reported to be associated with the inhibition of intracellular oxidative stress processes. However, the relationship between azilsartan and osteoclastogenesis is still unknown. In this study, we explored the effect of azilsartan on ovariectomy-induced osteoporosis in mice. Azilsartan significantly inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and downregulated the expression of osteoclast-associated markers (Nfatc1, c-Fos, and Ctsk) in vitro. Furthermore, azilsartan reduced RANKL-induced ROS production by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, azilsartan inhibited the activation of MAPK/NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of azilsartan on MAPK/NF-κB signaling pathways. Consistent with the in vitro data, azilsartan administration ameliorated ovariectomy (OVX)-induced osteoporosis, and decreased ROS levels in vivo. In conclusion, azilsartan inhibited oxidative stress and may be a novel treatment strategy for osteoporosis caused by osteoclast overactivation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Asiatic Acid (AA) has therapeutic potential for glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). • AA prevents GIONFH may related to anti-apoptosis and alleviation of oxidative stress. • AA can inhibit GIONFH by modulating the PI3K/AKT signaling pathway. Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) represents a predominant etiology of non-traumatic osteonecrosis, imposing substantial pain, restricting hip mobility, and diminishing overall quality of life for affected individuals. Centella asiatica (L.) Urb. (CA), an herbal remedy deeply rooted in traditional oriental medicine, has exhibited noteworthy therapeutic efficacy in addressing inflammation and facilitating wound healing. Drawing from CA's historical applications, its anti-inflammatory, anti-apoptotic, and antioxidant attributes may hold promise for managing GIONFH. Asiatic acid (AA), a primary constituent of CA, has been substantiated as a key contributor to its anti-apoptotic, antioxidant, and anti-inflammatory capabilities, showcasing a close association with orthopedic conditions. For the investigation of whether AA could alleviate GIONFH through suppressing oxidative stress, apoptosis, and to delve into its potential cellular and molecular mechanisms, the connection between AA and disease was analyzed through network pharmacology. DEX-induced apoptosis in rat osteoblasts and GIONFH in rat models, got utilized for the verification in vitro/vivo, on underlying mechanism of AA in GIONFH. Network pharmacology analysis reveals a robust correlation between AA and GIONFH in multiple target genes. AA has demonstrated the inhibition of DEX-induced osteoblast apoptosis by modulating apoptotic factors like BAX, BCL-2, Cleaved-caspase3, and cleaved-caspase9. Furthermore, it effectively diminishes the ROS overexpression and regulates oxidative stress through mitochondrial pathway. Mechanistic insights suggest that AA's therapeutic effects involve phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) pathway activation. Additionally, AA has exhibited its potential to ameliorate GIONFH progression in rat models. Our findings revealed that AA mitigated DEX-induced osteoblast apoptosis and oxidative stress through triggering PI3K/AKT pathway. Also, AA can effectively thwart GIONFH occurrence and development in rats. [ABSTRACT FROM AUTHOR]