Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway

Yang, Keda; Cao, Fangming; Qiu, Shui; Jiang, Wen; Lin, Tao; Zhu, Yue

doi:10.3389/fphar.2022.829830

Cited by 8 publications

(8 citation statements)

References 47 publications

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“…Our previous study also showed that Nrf2 activation attenuated cardiac damage after myocardial infarction injury, whereas AKT inhibition almost abolish the effect of Nrf2 [39]. It is worth noting that metformin is an effective Nrf2 activator, and the effect is tightly related to activation of AKT [40,41]. These results lead us to hypothesize that metformin might elicit similar effect in ethanol-treated cardiomyocytes.…”

Section: Discussionmentioning

confidence: 70%

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner

et al. 2023

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Background Metformin, a rst-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism.Methods and Results H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanolinduced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin suppressed cardiomyocyte apoptosis induced by ethanol exposure. Furthermore, the up-regulated expressions of apoptosis-related proteins (Bax and C-CAS-3) were also reduced by metformin. In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 expression was signi cantly inhibited in ethanol-treated cardiomyocyte, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis,indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner.Conclusions In summary, our study provides the rst evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy.

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Section: Discussionmentioning

confidence: 70%

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner

et al. 2023

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“…Metformin reverses pre-osteoblast mitochondrial dysfunction by attenuating mPTP opening. Based on a previous study by the authors, 0.2 mM was determined to be the optimal concentration of H 2 O 2 to induce oxidative stress in pre-osteoblasts, which reached the maximum apoptotic rate (22). In addition, 0.2 mM metformin was shown to have the strongest ability to reverse oxidative apoptosis (22).…”

Section: Resultsmentioning

confidence: 97%

“…Based on a previous study by the authors, 0.2 mM was determined to be the optimal concentration of H 2 O 2 to induce oxidative stress in pre-osteoblasts, which reached the maximum apoptotic rate ( 22 ). In addition, 0.2 mM metformin was shown to have the strongest ability to reverse oxidative apoptosis ( 22 ). The present study first examined the mechanisms by which metformin prevents pre-osteoblast apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…Encyclopedia of Genes and Genes (KEGG) pathways. The present study analyzed the transcriptome data (GSE198254) of metformin reversing osteoporosis in pre-osteoblasts (22). Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) was carried out using clusterProfiler R statistical software (R, x64, 4.1.3).…”

Section: Enrichment Analysis Of Gene Ontology (Go) and Kyotomentioning

confidence: 99%

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Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway

et al. 2023

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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.

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“…Under physiological conditions, bone tissue is in a dynamic balance between the bone formation effect of osteoblasts and the bone resorption effect of osteoclasts ( Teissier et al, 2022 ). The direct pathogenesis of osteoporosis is that the weakened bone formation is difficult to compensate for the reduced bone mass of bone resorption ( Yang et al, 2022 ). With aging, the prevalence of osteoporosis is increasing year by year ( Dong et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Osteoporosis in Patients With Respiratory Diseases

Qiu

Zhou

2022

Front. Physiol.

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Climate change, environmental pollution, and virus epidemics have sharply increased the number of patients suffering from respiratory diseases in recent years. Prolonged periods of illness and drug use increase the occurrence of complications in these patients. Osteoporosis is the common bone metabolism disease with respiratory disturbance, which affects prognosis and increases mortality of patients. The problem of osteoporosis in patients with respiratory diseases needs more attention. In this review, we concluded the characteristics of osteoporosis in some respiratory diseases including COPD, asthma, COVID-19, tuberculosis, and lung cancer. We revealed that hypoxia was the common pathogenesis of osteoporosis secondary to respiratory diseases, with malnutrition and corticosteroid abuse driving the progression of osteoporosis. Hypoxia-induced ROS accumulation and activated HIF-1α lead to attenuated osteogenesis and enhanced osteoclastogenesis in patients with respiratory diseases. Tuberculosis and cancer also invaded bone tissue and reduced bone strength by direct infiltration. For the treatment of osteoporosis in respiratory patients, oral-optimized bisphosphonates were the best treatment modality. Vitamin D was a necessary supplement, both for calcium absorption in osteogenesis and for improvement of respiratory lesions. Reasonable adjustment of the dose and course of corticosteroids according to the etiology and condition of patients is beneficial to prevent the occurrence and development of osteoporosis. Additionally, HIF-1α was a potential target for the treatment of osteoporosis in respiratory patients, which could be activated under hypoxia condition and involved in the process of bone remodeling.

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Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway

Cited by 8 publications

References 47 publications

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner

Metformin alleviates ethanol-induced cardiomyocyte injury by activating AKT/Nrf2 signaling in an ErbB2-dependent manner

Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway

Osteoporosis in Patients With Respiratory Diseases

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