Dataset Information

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts.

ABSTRACT: The widespread use of therapeutic glucocorticoids has increased the frequency of glucocorticoid-induced osteoporosis (GIOP). One of the potential pathological processes of GIOP is an increased level of oxidative stress and mitochondrial dysfunction, which eventually leads to osteoblast apoptosis. Proanthocyanidins (PAC) are plant-derived antioxidants that have therapeutic potential against GIOP. In our study, a low dose of PAC was nontoxic to healthy osteoblasts and restored osteogenic function in dexamethasone- (Dex-) treated osteoblasts by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PAC neutralized Dex-induced damage in the osteoblasts by activating the Nrf2 pathway, since silencing Nrf2 partly eliminated the protective effects of PAC. Furthermore, PAC injection restored bone mass and promoted the expression of Nrf2 in the distal femur of Dex-treated osteoporotic rats. In summary, PAC protect osteoblasts against Dex-induced oxidative stress and mitochondrial dysfunction via the Nrf2 pathway activation and may be a promising drug for treating GIOP.

SUBMITTER: Chen L

PROVIDER: S-EPMC7533007 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts.

Chen Liang L Hu Sun-Li SL Xie Jun J Yan De-Yi DY Weng She-Ji SJ Tang Jia-Hao JH Wang Bing-Zhang BZ Xie Zhong-Jie ZJ Wu Zong-Yi ZY Yang Lei L Yang Lei L

Oxidative medicine and cellular longevity 20200925

The widespread use of therapeutic glucocorticoids has increased the frequency of glucocorticoid-induced osteoporosis (GIOP). One of the potential pathological processes of GIOP is an increased level of oxidative stress and mitochondrial dysfunction, which eventually leads to osteoblast apoptosis. Proanthocyanidins (PAC) are plant-derived antioxidants that have therapeutic potential against GIOP. In our study, a low dose of PAC was nontoxic to healthy osteoblasts and restored osteogenic function ...[more]

PMID: 33062149

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Project description:Aim: Sirtuin3 (sirt3) plays a pivotal role in improving oxidative stress and mitochondrial dysfunction which directly induced neuronal apoptosis after intracerebral hemorrhage (ICH). Reactive oxygen species (ROS) is also a critical activator in triggering NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes activation which can regulate inflammatory responses in brain. Moreover, hyperglycemia can aggravate the ICH-induced damage. Hence, this study was designed to investigate the mechanisms of neuroprotection of sirt3 in hyperglycemic ICH. Methods: ICH model was established by autologous blood injection. Hyperglycemia was induced by intraperitoneal injection with streptozotocin. Honokiol (HKL, a pharmacological agonist of sirt3) was injected intraperitoneally at doses of 2.5, 5, or 10 mg/kg. Sirt3 small interfering RNA transfection was implemented through intracerebroventricular injection. The expression of sirt3 and its downstream signaling molecules were detected using Western blotting or immunofluorescence staining. Morphological changes of mitochondria were detected by electron microscopy. SH-SY5Y cells were incubated with 10 μM oxyhemoglobin for 48 h to establish an in vitro ICH model, and then JC-1 staining was used to determine mitochondrial membrane potential (Δψm). Results: Hyperglycemia could suppress sirt3 expression after ICH when compared with non-diabetic rats. Sirt3 protein expression was decreased to the minimum at 24 h in perihematoma tissues. Electron microscope analysis indicated that hyperglycemic ICH induced extensive mitochondrial vacuolization. HKL attenuated ROS accumulation, adenosine triphosphate reduction, and Δψm through Sirt3-superoxide dismutase 2 (SOD2) and Sirt3-NRF1-TFAM pathway. Sirt3 knockdown could exacerbate the neuronal apoptosis and reverse the positive effects of HKL. Sirt3 activation could decrease NLRP3 and interleukin-1β levels through deacetylating SOD2 and scavenging ROS. Conclusion: HKL protects against hyperglycemic ICH-induced neuronal injury via a sirt3-dependent manner.

Project description:Oxidative stress is one of the main causes of osteoblast apoptosis induced by post‑menopausal osteoporosis. The authors previously found that metformin can reverse the loss of bone mass in post‑menopausal osteoporosis. The present study aimed to further clarify the effects and mechanisms of action of metformin in post‑menopausal osteoporosis under conditions of oxidative stress. Combined with an in‑depth investigation using the transcriptome database, the association between oxidative stress and mitochondrial dysfunction in post‑menopausal osteoporosis was confirmed. A pre‑osteoblast model of oxidative stress was constructed, and the apoptotic rate following the addition of hydrogen peroxide and metformin was detected using CCK‑8 assay and Annexin V‑FITC/PI staining. Mitochondrial membrane potential was detected using the JC‑1 dye, the intracellular calcium concentration was detected using Fluo‑4 AM, the intracellular reactive oxygen species (ROS) level was observed using DCFH‑DA, and the mitochondrial superoxide level was observed using MitoSOX Red. Bay K8644 was used to increase the level of intracellular calcium. siRNA was used to interfere with the expression of glycogen synthase kinase (GSK)‑3β. Western blot analysis was used to detect the expression of mitochondrial dysfunction‑related proteins. The results revealed that oxidative stress decreased mitochondrial membrane potential and increased intracellular ROS, mitochondrial superoxide and cytoplasmic calcium levels in pre‑osteoblasts; however, metformin improved mitochondrial dysfunction and reversed oxidative stress‑induced injury. Metformin inhibited mitochondrial permeability transition pore opening, suppressed the cytoplasmic calcium influx and reversed pre‑osteoblast apoptosis by promoting GSK‑3β phosphorylation. Moreover, it was found that EGFR was the cell membrane receptor of metformin in pre‑osteoblasts, and the EGFR/GSK‑3β/calcium axis played a key role in metformin reversing the oxidative stress response of pre‑osteoblasts in post‑menopausal osteoporosis. On the whole, these findings provide a pharmacological basis for the use of metformin for the treatment of post‑menopausal osteoporosis.

Dataset Information

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts.

Publications

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts.

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