Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

Yang, Qianjie; Zhou, Yunxiang; Sun, Yuting; Luo, Yi; Shen, Ye; Shao, Anwen

doi:10.3389/fnins.2020.00791

Cited by 22 publications

(15 citation statements)

References 152 publications

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“…We observed alterations in numerous mitochondrial proteins including ATP synthase, cytochrome c oxidase, NADH dehydrogenase, and ubiquinol-cytochrome c oxidoreductase proteins, all associated with increased oxidative phosphorylation and in agreement with previous reports . Sirtuin signaling plays an important role in aging, metabolism, cancer, inflammation, DNA repair, and cellular responses to stress . Here, we observed numerous proteins throughout this pathway that were altered in NMRs including superoxide dismutase [Cu-Zn] (SOD1) and NAD-dependent protein deacetylase sirtuin-2 (SIRT2).…”

Section: Resultssupporting

confidence: 91%

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation

et al. 2021

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Naked mole-rats (NMRs) are a long-lived animal that do not develop age-related diseases including neurodegeneration and cancer. Additionally, NMRs have a profound ability to consume reactive oxygen species (ROS) and survive long periods of oxygen deprivation. Here, we evaluated the unique proteome across selected brain regions of NMRs at different ages. Compared to mice, we observed numerous differentially expressed proteins related to altered mitochondrial function in all brain regions, suggesting that the mitochondria in NMRs may have adapted to compensate for energy demands associated with living in a harsh, underground environment. Keeping in mind that ROS can induce polyunsaturated fatty acid peroxidation under periods of neuronal stress, we investigated docosahexaenoic acid (DHA) and arachidonic acid (AA) peroxidation under oxygen-deprived conditions and observed that NMRs undergo DHA and AA peroxidation to a far less extent compared to mice. Further, our proteomic analysis also suggested enhanced peroxisome proliferator-activated receptor (PPAR)-retinoid X receptor (RXR) activation in NMRs via the PPARα-RXR and PPARγ-RXR complexes. Correspondingly, we present several lines of evidence supporting PPAR activation, including increased eicosapetenoic and omega-3 docosapentaenoic acid, as well as an upregulation of fatty acid-binding protein 3 and 4, known transporters of omega-3 fatty acids and PPAR activators. These results suggest enhanced PPARα and PPARγ signaling as a potential, innate neuroprotective mechanism in NMRs.

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Section: Resultssupporting

confidence: 91%

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation

et al. 2021

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“…Neurodegenerative diseases are generally accepted as sequelae of TBI. The key pathological features of chronic traumatic encephalopathy, including inflammation, oxidative stress, excitotoxicity, protein aggregation, cell death and generation, metabolic disorder and physiological dysfunction, with a high probability sustain for months or years post‐TBI, which are similar to that in many neurodegenerative diseases (Yang et al, 2020). Microglia, served as the principal neuroimmune sentinels of the brain, are involved in all these pathologies at each stage of TBI, and also play a unique role in neurodegenerative disease pathogenesis (Glass, Saijo, Winner, Marchetto, & Gage, 2010).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration

Cong

Dai

Shi

et al. 2021

Glia

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Neurotrauma has been recognized as a risk factor for neurodegenerative diseases, and sex difference of the incidence and outcome of neurodegenerative diseases has long been recognized. Past studies suggest that microglia could play a versatile role in both health and disease. So far, the microglial mechanisms underlying neurodegeneration and potentially lead to sex‐specific therapies are still very open. Here we applied whole transcriptome analysis of microglia acutely isolated at different timepoints after a cortical stab wound injury to gain insight into genes that might be dysregulated and transcriptionally different between males and females after cortical injury. We found that microglia displayed distinct temporal and sexual molecular signatures of transcriptome after cortical injury. Hypotheses and gene candidates that we presented in the present study could be worthy to be examined to explore the roles of microglia in neurotrauma and in sex‐biased neurodegenerative diseases.

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“…In addition, SIRT-1 is also involved in the pathogenesis of diseases such as acute kidney injury, craniocerebral trauma, and aortic sclerosis [ 28 ]. In these diseases, the SIRT-1 expression is reduced, while in some cancers, the SIRT-1 expression is significantly increased, suggesting that it may be used for cancer treatment [ 29 ]. Vorinostat (SAHA), as a natural HDAC inhibitor, has been shown to inhibit IL-1β-induced MMP-13 expression [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

The protective mechanism of SIRT1 on cartilage through regulation of LEF-1

Feng

Meng

et al. 2021

BMC Musculoskelet Disord

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Background Osteoarthritis (OA) is a chronic degenerative disease that suppresses middle-aged and older people worldwide. Silent information regulator 1(SIRT-1) is associated with several age-related diseases, such as cardiovascular diseases, neurodegenerative diseases and tumors, etc. The protective role of SIRT-1 in bone and joint diseases has become increasingly well known. Objective To explore the relationship between SIRT-1 and its related factors in OA. Methods Fresh tibial plateau specimens were collected from 30 patients with knee OA who underwent total knee arthroplasty. According to the results of Safranin O Fast Green Staining, hematoxylin–eosin staining and the OARSI grade developed by the International Association for the Study of Osteoarthropathy, the specimens were divided into the mild group, moderate group and severe group, and the damage of cartilage was evaluated. SIRT-1 protein levels in cartilage samples were analyzed by immunohistochemistry. Then, take 60 8-week-old female C57BL/6 J mice and apply the Destabilization of the medial meniscus (DMM) to induce OA. Mice were randomly divided into normal group (sham), model group (model), and post-modeling drug administration group (srt), and each group was further divided into 2 weeks after modeling (2 W) and 8 weeks after modeling (8 W) according to the time after surgery. The degenerative degree of a knee joint in mouse knee cartilage samples was evaluated using Safranin O Fast Green Staining and OARSI grade. Immunohistochemical techniques assessed the protein levels of SIRT-1, β-catenin, LEF-1, MMP-13 and Collagen II in cartilage samples. The protein levels of β-catenin, LEF-1 and MMP-13 in the samples were assessed by the immunohistofluorescence technique. The mRNA expression of SIRT-1 and LEF-1 in mouse cartilage samples was evaluated by real-time quantitative polymerase chain reaction (qPCR). Results In the human cartilage samples, according to the results of Safranin O Fast Green Staining, compared with the mild group, the moderate group and the severe group showed damage cartilage layer structure, the number of chondrocytes decreased, the cell hypertrophic, the cartilage surface discontinuous, and the OARSI grade increased. The severe group had severe cartilage injury and the highest OARSI grade. In the mice cartilage samples, according to immunohistochemical analysis, the protein levels of β-catenin, LEF-1 and MMP-13 in cartilage specimens of model 2 W and model 8 W groups were significantly increased than the sham 2 W and sham 8 W groups. The protein levels of SIRT-1 and Collagen II were significantly decreased (P < 0.05), the results of srt 2 W and srt 8 W groups were between the sham group and the model group. According to immunofluorescence analysis, the protein levels of β-catenin, LEF-1 and MMP-13 in model 2 W and model 8 W groups were significantly increased than sham 2 W and sham 8 W groups. The results of srt 2w and srt 8w groups were between the sham group and the model group. According to the real-time qPCR results: Compared with sham 2 W and sham 8 W groups, the mRNA expression of SIRT-1 in model 2 W and model 8 W groups was significantly decreased, while the mRNA expression of LEF-1 was significantly increased. In contrast, the results of srt 2 W and srt 8 W groups were between the sham group and the model group. Conclusion SRT-1720, as a specific activator of SIRT-1, does increase the protein level of SIRT-1. SIRT-1 may play a protective role in cartilage by regulating the expression of LEF-1 and related inflammatory factors in OA.

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Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

Cited by 22 publications

References 152 publications

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation

Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration

The protective mechanism of SIRT1 on cartilage through regulation of LEF-1

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