Targeting of micro<scp>RNA</scp>‐199a‐5p protects against pilocarpine‐induced status epilepticus and seizure damage via <scp>SIRT</scp>1‐p53 cascade

Wang, Dong; Li, Zhenlu; Zhang, Yukun; Wang, Guangzhi; Wei, Minghai; Hu, Yan; Ma, Shuo; Jiang, Yue; Che, Ningwei; Wang, Xiaofeng; Yao, Jihong; Yin, Jian

doi:10.1111/epi.13348

Cited by 66 publications

(35 citation statements)

References 42 publications

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“…p53, a tumor suppressor protein, plays a critical role in cell cycle control and apoptosis. Notably, induction of cell apoptosis is one of the most dramatic responses to p53 activation, which is achieved through the up-regulation of pro-apoptotic molecules [39,40]. Another study has also shown that deacetylation of p53 by overexpression of SIRT 1 exerts a protective effect on H9c2 cardiac myoblasts against hypoxia/reoxygenation injury [41].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

Feng

Liú

et al. 2018

Cell Physiol Biochem

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Background/Aims: Myocardial ischemia/reperfusion (MI/R) injury is a leading factor responsible for damage in myocardial infarction, resulting in additional injury to cardiac tissues involved in oxidative stress, inflammation, and apoptosis. Thymoquinone (TQ), the main constituent of Nigella sativa L. seeds, has been reported to possess various biological activities. However, few reports regarding myocardial protection are available at present. Therefore, this study was conducted aiming to investigate the protective effect of TQ against MI/R injury and to clarify its potential mechanism. Methods: MI/R injury models of isolated rat hearts and neonatal rat cardiomyocytes were established. The Langendorff isolated perfused heart system, triphenyltetrazolium chloride staining, gene transfection, TransLaser scanning confocal microscopy, and western blotting were employed to evaluate the cardioprotection effect of TQ against MI/R injury. Results: Compared with the MI/R group, TQ treatment could remarkably improve left ventricular function, decrease myocardial infarct size and production of lactate dehydrogenase (LDH), and attenuate mitochondrial oxidative damage by elevating superoxide dismutase (SOD) activity and reducing production of hydrogen peroxide (H₂O₂) and malonaldehyde (MDA). Moreover, the cardioprotective effect of TQ was accompanied by up-regulated expression of SIRT1 and inhibition of p53 acetylation. Additionally, TQ treatment could also enhance mitochondrial function and reduce the number of apoptotic cardiomyocytes. Nonetheless, the cardioprotective effect of TQ could be mitigated by SIRT1 inhibitor sirtinol and SIRT1 siRNA, respectively, which was achieved through inhibition of the SIRT1 signaling pathway. Conclusions: The findings in this study demonstrate that TQ is efficient in attenuating MI/R injury through activation of the SIRT1 signaling pathway, which can thus reduce mitochondrial oxidative stress damage and cardiomyocyte apoptosis.

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Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

Feng

Liú

et al. 2018

Cell Physiol Biochem

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“…Pretreating rats with an antagomir targeting miR-199a prior to status epilepticus reduced acute seizure severity and damage. The authors identified the mechanism of the antagomir effect as partly the result of de-repression of Sirtuin1, a transcriptional silencer (37).…”

Section: Micrornas With Potential Seizure-promoting (Proconvulsive) Ementioning

confidence: 99%

Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

Henshall

2017

Epilepsy Curr

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MicroRNAs are small noncoding RNAs that work posttranscriptionally to negatively regulate protein levels. They influence neuronal and glial structure and function, neuroinflammatory signaling, cell death, neurogenesis, and other processes relevant to epileptogenesis. Functional studies using oligonucleotide inhibitors (antagomirs) and mimics (agomirs) to modulate microRNAs in rat and mouse models of epilepsy show effects on evoked and spontaneous seizures and attendant neuropathology. The present review summarizes recent findings and points to gaps in our knowledge of the underlying mechanisms and directions for the future.

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“…Pilocarpine-induced status epilepticus was reported to upregulate miR-199a in the rat hippocampus and antagomirs against miR-199a reduced seizure severity in the model. 35 This was partly mediated by protection of Sirtuin1 levels, a deacetylase and transcriptional silencer. 35 Interestingly, miR-199a also targets inhibitors of the mechanistic target of rapamycin (mTOR) pathway.…”

mentioning

confidence: 99%

MicroRNAs in epilepsy: pathophysiology and clinical utility

Henshall

Hamer

Pasterkamp

et al. 2016

The Lancet Neurology

199

172

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In the past 5 years, studies have found changes in miRNA levels in the hippocampus of patients with temporal lobe epilepsy and in neural tissues from animal models of epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using antisense oligonucleotides (antagomirs) had potent antiseizure effects in animal models, whereas genetic deletion of miR-128 produced fatal epilepsy in mice. Levels of certain miRNAs were also found to be altered in the blood of rodents after seizures. In the past 18 months, functional studies have identified nine novel miRNAs that appear to influence seizures or hippocampal pathology. Their targets include transcription factors, neurotransmitter signalling components, and modulators of neuroinflammation. New approaches to manipulate miRNAs have been tested, including injection of mimics (agomirs) to enhance brain levels of miRNAs. Altered miRNA expression has also been reported in other types of refractory epilepsy and our understanding of how miRNA levels are controlled has grown, with studies on DNA methylation indicating epigenetic regulation. Biofluids (blood) of patients with epilepsy have shown differences in quantity of circulating miRNAs, implying diagnostic biomarker potential. WHERE NEXT?: Recent functional studies need to be replicated to build a robust evidence base. The specific cell types in which miRNAs execute their functions and their primary targets have to be identified, to fully explain the phenotypic effects of modulating miRNAs. Delivery of large molecules such as antisense inhibitors or mimics to the brain poses a challenge, and the multi-targeting effects of miRNAs create additional risks of unanticipated side effects. Potential genetic variation in miRNAs should be explored as the basis for disease susceptibility. The latest findings provide a rich source of new miRNA targets, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of epilepsy can be translated into clinical practice.

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Targeting of microRNA‐199a‐5p protects against pilocarpine‐induced status epilepticus and seizure damage via SIRT1‐p53 cascade

Cited by 66 publications

References 42 publications

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

Manipulating MicroRNAs in Murine Models: Targeting the Multi-Targeting in Epilepsy

MicroRNAs in epilepsy: pathophysiology and clinical utility

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