Upregulation of MDH1 acetylation by HDAC6 inhibition protects against oxidative stress-derived neuronal apoptosis following intracerebral hemorrhage

Wang, Miao; Zhou, Chao; Yu, Lu; Kong, Delian; Ma, Wei-jing; Lv, Bingchen; Wang, Yan; Wu, Weifeng; Zhou, Mingyue; Cui, Guiyun

doi:10.1007/s00018-022-04341-y

Cited by 27 publications

(24 citation statements)

References 42 publications

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“…In addition, treatment with Tat-MDH1, but not with MDH1, significantly ameliorated H 2 O 2 -induced DNA fragmentation and ROS production in HT22 cells. This result is consistent with that of a previous study showing that MDH1 significantly reduced ROS production in hemin-stimulated HT22 cells 37 .…”

Section: Discussionsupporting

confidence: 94%

“…In addition, treatment with Tat-MDH1 significantly ameliorated ischemiainduced hydroperoxide levels, MDA levels, and DHE fluorescence in the hippocampus 2 d after ischemia. This result was supported by a previous study showing that MDH1 overexpression significantly reduced MDA levels induced by intracranial hemorrhage 37 . In the present study, we focused on the GSH status after ischemia because it protects neurons from oxidative or ischemic damage as a major intracellular antioxidant 40,41 .…”

Section: Discussionsupporting

confidence: 84%

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Tat-malate dehydrogenase fusion protein protects neurons from oxidative and ischemic damage by reduction of reactive oxygen species and modulation of glutathione redox system

Kwon

Hahn

Kang

et al. 2023

Sci Rep

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Malate dehydrogenase (MDH) plays an important role in the conversion of malate to oxaloacetate during the tricarboxylic acid cycle. In this study, we examined the role of cytoplasmic MDH (MDH1) in hydrogen peroxide (H2O2)-induced oxidative stress in HT22 cells and ischemia-induced neuronal damage in the gerbil hippocampus. The Tat-MDH1 fusion protein was constructed to enable the delivery of MDH1 into the intracellular space and penetration of the blood–brain barrier. Tat-MDH1, but not MDH1 control protein, showed significant cellular delivery in HT22 cells in a concentration- and time-dependent manner and gradual intracellular degradation in HT22 cells. Treatment with 4 μM Tat-MDH1 significantly ameliorated 200 μM H2O2-induced cell death, DNA fragmentation, and reactive oxygen species formation in HT22 cells. Transient increases in MDH1 immunoreactivity were detected in the hippocampal CA1 region 6–12 h after ischemia, but MDH1 activity significantly decreased 2 days after ischemia. Supplementation of Tat-MDH1 immediately after ischemia alleviated ischemia-induced hyperlocomotion and neuronal damage 1 and 4 days after ischemia. In addition, treatment with Tat-MDH1 significantly ameliorated the increases in hydroperoxides, lipid peroxidation, and reactive oxygen species 2 days after ischemia. Tat-MDH1 treatment maintained the redox status of the glutathione system in the hippocampus 2 days after ischemia. These results suggest that Tat-MDH1 exerts neuroprotective effects by reducing oxidative stress and maintaining glutathione redox system in the hippocampus.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 84%

Tat-malate dehydrogenase fusion protein protects neurons from oxidative and ischemic damage by reduction of reactive oxygen species and modulation of glutathione redox system

Kwon

Hahn

Kang

et al. 2023

Sci Rep

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“…Histone deacetylase 6 (HDAC6) is a special histone deacetylase with two deacetylation domains and one ubiquitination domain. HDAC6 plays a center role in several processes, including positive regulation of peptidyl-serine phosphorylation, protein deacetylation, protein destabilization, microtubule stability (Olzmann et al, 2007;Wang et al, 2018;Wang et al, 2020a;Osseni et al, 2020;Wang et al, 2022). Our study showed that histone deacetylase HDAC6 was expressed heterogeneously in different primordial follicles.…”

Section: Hdac6mentioning

confidence: 52%

Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients

Zhang

He²,

Zhang³

et al. 2023

Front. Physiol.

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Primordial follicles are the starting point of follicular development and the basic functional unit of female reproduction. Primordial follicles are formed around birth, and most of the primordial follicles then enter a dormant state. Since primordial follicles are limited in number and can’t be renewed, dormant primordial follicles cannot be reversed once they enter the growing state. Thus, the orderly occurrence of primordial follicles selective activation directly affects the rate of follicle consumption and thus determines the length of female reproductive lifespan. Studies have found that appropriately inhibiting the activation rate of primordial follicles can effectively slow down the rate of follicle consumption, maintain fertility and delay ovarian aging. Based on the known mechanisms of primordial follicle activation, primordial follicle in vitro activation (IVA) technique has been clinically developed. IVA can help patients with premature ovarian failure, middle-aged infertile women, or infertile women due to gynecological surgery treatment to solve infertility problems. The study of the mechanism of selective activation of primordial follicles can contribute to the development of more efficient and safe IVA techniques. In this paper, recent mechanisms of primordial follicle activation and its clinical application are reviewed.

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“…We also confirmed that HDAC6 inhibition can improve neuronal apoptosis in an ICH model. A recent study by Wang et al (2022) found that HDAC6 knockout can up-regulate the acetylation of MDH1, which may play an anti-apoptotic role by alleviating oxidative stress in ICH. Our research further confirms the ability of pharmacological inhibitor TubA to up-regulate α-tubulin acetylation and its anti-apoptotic effect in neurons.…”

Section: Discussionmentioning

confidence: 99%

Selective HDAC6 inhibitor TubA offers neuroprotection after intracerebral hemorrhage via inhibiting neuronal apoptosis

Peng¹,

Gong²,

Hu³

et al. 2023

PeerJ

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A large body of evidence has demonstrated that neuronal apoptosis is involved in the pathological process of secondary brain injury following intracerebral hemorrhage (ICH). Additionally, our previous studies determined that the inhibition of HDAC6 activity by tubacin or specific shRNA can attenuate neuronal apoptosis in an oxygen-glucose deprivation reperfusion model. However, whether the pharmacological inhibition of HDAC6-attenuated neuronal apoptosis in ICH remains unclear. In this study, we used hemin-induced SH-SY5Y cells to simulate a hemorrhage state in vitro and adopted a collagenase-induced ICH rat model in vivo to assess the effect of the HDAC6 inhibition. We found a significant increase in HDAC6 during the early stages of ICH. As expected, the acetylated α-tubulin significantly decreased in correlation with the expression of HDAC6. Medium and high doses (25, 40 mg/kg) of TubA, a selective inhibitor of HDAC6, both reduced neurological impairments, histological impairments, and ipsilateral brain edema in vivo. TubA or HDAC6 siRNA both alleviated neuronal apoptosis in vivo and in vitro. Finally, HDAC6 inhibition increased the level of acetylated α-tubulin and Bcl-2 and lowered the expression of Bax and cleaved caspase-3 post-ICH. In general, these results suggested that the pharmacological inhibition of HDAC6 may act as a novel and promising therapeutic target for ICH therapy by up-regulating acetylated α-tubulin and reducing neuronal apoptosis.

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Upregulation of MDH1 acetylation by HDAC6 inhibition protects against oxidative stress-derived neuronal apoptosis following intracerebral hemorrhage

Cited by 27 publications

References 42 publications

Tat-malate dehydrogenase fusion protein protects neurons from oxidative and ischemic damage by reduction of reactive oxygen species and modulation of glutathione redox system

Tat-malate dehydrogenase fusion protein protects neurons from oxidative and ischemic damage by reduction of reactive oxygen species and modulation of glutathione redox system

Mechanisms of primordial follicle activation and new pregnancy opportunity for premature ovarian failure patients

Selective HDAC6 inhibitor TubA offers neuroprotection after intracerebral hemorrhage via inhibiting neuronal apoptosis

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