Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage via the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway

Liang, Wenqi; Zhao, Chunli; Chen, Zhong-Rui; Zhan, Yɑnɡ; Liu, Ke; Gong, Shusheng

doi:10.3389/fcell.2021.766512

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…The SIRT3-SOD2 linked pathway is critical for regulating ROS production. To maintain ROS homeostasis, SIRT3 activates SOD2 via deacetylation and converts superoxide radicals to harmless oxygen or hydrogen peroxide [ 45 ]. However, whether the SIRT3-SOD2 linked pathway or any other signal is involved in the TMAO-induced ROS production in osteoclast differentiation needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway

Wang

Hao

2022

Nutrients

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Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100–400 μM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway

Wang

Hao

2022

Nutrients

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“…Similarly, SIRT3 decreased palmitate-induced inflammation in proximal tubular cells ( Koyama et al, 2011 ). In previous study, 3-TYP, a SIRT3-selective inhibitor, has been reported to aggravate oxidative damage and reduce enzymatic activity of MnSOD2 in the hair cells of mice ( Liang et al, 2021 ). 3-TYP can not only eliminate the cardioprotective effects of melatonin ( Zhai et al, 2017 ), but also activate NF-κB and NLRP3 pathways, reducing survival rate in mice ( Lv et al, 2021 ).…”

Section: Discussionmentioning

confidence: 96%

SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice

et al. 2022

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The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1β) were measured by ELISA and Western blotting. The cell type expression of IL-1β in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.

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“…The method of ABR testing has been described previously (Liang et al 2021 ; Sergeyenko et al 2013 ). Briefly, it was conducted in sound-proof room using BioSigRZ software (Tucker-Davis Technologies, USA).…”

Section: Methodsmentioning

confidence: 99%

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo

Zhao

Zhan

Chen

et al. 2022

Mol Med

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Background Uncoupling protein 2 (UCP2), activated by excessive reactive oxygen species (ROS) in vivo, has the dual effect of reducing ROS to protect against oxidative stress and reducing ATP production to regulate cellular metabolism. Both the UCP2 and ROS are increased in cochleae in age-related hearing loss (ARHL). However, the role of UCP2 in sensory hair cells in ARHL remains unclear. Methods Male C57BL/6 J mice were randomly assigned to an 8-week-old group (Group 1), a 16-week-old group (Group 2), a 16-week-old + adeno-associated virus-inner ear (AAV-ie) group (Group 3), and a 16-week-old + AAV-ie-UCP2 group (Group 4). Mice aged 8 weeks were administrated with AAV-ie-GFP or AAV-ie-UCP2 via posterior semicircular canal injection. Eight weeks after this viral intervention, hearing thresholds and wave-I amplitudes were tested by auditory brainstem response (ABR). Subsequently, the cochlear basilar membrane was dissected for investigation. The number of hair cells and inner hair cell (IHC) synapses, the level of ROS, and the expression of AMP-activated protein kinase α (AMPKα), were assessed by immunofluorescence staining. In addition, mitochondrial function was determined, and the expression of AMPKα and UCP2 proteins was further evaluated using western blotting. Results Mice with early-onset ARHL exhibited enhanced oxidative stress and loss of outer hair cells and IHC synapses, while UCP2 overexpression aggravated hearing loss and cochlear pathophysiological changes in mice. UCP2 overexpression resulted in a notable decrease in the number of IHCs and IHC synapses, caused ATP depletion and excessive ROS generation, increased AMPKα protein levels, and promoted IHC apoptosis, especially in the apical and middle turns of the cochlea. Conclusion Collectively, our data suggest that UCP2 overexpression may cause mitochondrial dysfunction via energy metabolism, which activates mitochondrion-dependent cellular apoptosis and leads to IHC loss, ultimately exacerbating ARHL.

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Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage via the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway

Cited by 17 publications

References 42 publications

Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway

Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway

SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice

AAV-ie-mediated UCP2 overexpression accelerates inner hair cell loss during aging in vivo

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