Pinacidil protects osteoblastic cells against antimycin A-induced oxidative damage

Choi, Eun Mi; Jung, Woon Won; Suh, Kwang Sik

doi:10.3892/mmr.2014.2721

Cited by 2 publications

(3 citation statements)

References 41 publications

(41 reference statements)

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“…The second-ranked drug pinacidil is an oral antihypertensive drug that relaxes vascular smooth muscle and is a K + channel opener ( 73 ). Several studies have shown that it prevents damage to osteoblast function from reactive oxygen species and may have a positive effect on bone ( 74 , 75 ). The third-ranked PD-184352 is a MEK inhibitor, and the MEK/ERK pathway enhances the production of several pro-inflammatory cytokines ( 76 , 77 ).…”

Section: Discussionmentioning

confidence: 99%

Inflammation produced by senescent osteocytes mediates age-related bone loss

et al. 2023

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PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.

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Section: Discussionmentioning

confidence: 99%

Inflammation produced by senescent osteocytes mediates age-related bone loss

et al. 2023

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“…AntA does not inhibit superoxide generation with NADH, but dose partially with succinate (Purvis, Shewfelt, & Gegogeine, 1995). Theoretically, AntA should not inhibit mitoflashes triggered by PMA, but it interrupted the electron flow (Choi, Jung, & Suh, 2014; King, 2005), which were the dependable factor of mitoflash occurrence. Although FCCP stimulates maximal electron flow, it also dissipates the proton gradient across the inner membrane, which is a critical component of the membrane potential.…”

Section: Discussionmentioning

confidence: 99%

“…Theoretically, AntA should not inhibit mitoflashes triggered by PMA, but it interrupted the electron flow (Choi, Jung, & Suh, 2014;King, 2005), which were the dependable factor of mitoflash occurrence.…”

Section: Mitoflash Generation Is Augmented By the Deficiency Of Compl...mentioning

confidence: 95%

Mitoflash generated at the Qo site of mitochondrial Complex III

Gao

Qin

et al. 2020

Journal Cellular Physiology

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The previous research has shown that mitochondrial flash (mitoflash) genesis are functionally and mechanistically integrated with mitochondrial electron transport chain (ETC) energy metabolism. However, the response of mitoflash to superoxide is not entirely consistent with the response of MitoSOX Red. The generation mechanism of mitoflash is still unclear. Here, we investigated mitoflash activities, using the different combinations of ETC substrates and inhibitors, in permeabilized cardiomyocytes or hearts. We found that blocking the complete electron flow, from Complex I to IV, with any one of ETC inhibitors including rotenone (Rot), antimycin A (AntA), myxothiazol (Myxo), stigmatellin, and sodium cyanide, will lead to the abolishment of mitoflashes triggered by substrates in adult permeabilized cardiomyocytes. However, Myxo boosted mitoflashes triggered by the reverse electron of N,N,N′,N′‐tetramethyl‐p‐phenylenediamine/ascorbate. Moreover, Rot and AntA furtherly enhanced mitoflash activity rather than depressed it, suggesting that mitoflashes generated at the Complex III Qo site. Meanwhile, the inhibition of Complex III protein expression resulted in the activity of Complex III decrease, which decreased mitoflash frequency. The function defect (no change of protein level) of the Qo site of Complex III in aging hearts augmented mitoflash generation confirmed the Qo site function was critical to mitoflash genesis. Thus, our results indicate that mitoflash detected by circularly permuted yellow fluorescent protein is generated at the Qo site of Complex III.

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Pinacidil protects osteoblastic cells against antimycin A-induced oxidative damage

Cited by 2 publications

References 41 publications

Inflammation produced by senescent osteocytes mediates age-related bone loss

Inflammation produced by senescent osteocytes mediates age-related bone loss

Mitoflash generated at the Qo site of mitochondrial Complex III

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