Dataset Information

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3? Signaling.

ABSTRACT: Osteoblasts derived osteocalcin (OCN) is recently reported to be involved in dopaminergic neuronal development. As dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinson's disease (PD), we investigated whether OCN could exert protective effects on 6-hydroxydopamine (6-OHDA)-induced PD rat model. Our data showed that the OCN level in the cerebrospinal fluid (CSF) in PD rat models was significantly lower than that in controls. Intervention with OCN could improve the behavioral dysfunction in PD rat models and reduce the tyrosine hydroxylase (TH) loss in the nigrostriatal system. In addition, OCN could inhibit the astrocyte and microglia proliferation in the SN of PD rats. In vitro studies showed that OCN significantly ameliorated the neurotoxicity of 6-OHDA through the AKT/GSK3? signaling pathway. In summary, OCN plays a protective role against parkinsonian neurodegeneration in the PD rat model, suggesting a potential therapeutic use of OCN in PD.

SUBMITTER: Guo XZ

PROVIDER: S-EPMC6170617 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3β Signaling.

Guo Xing-Zhi XZ Shan Chang C Hou Yan-Fang YF Zhu Geng G Tao Bei B Sun Li-Hao LH Zhao Hong-Yan HY Ning Guang G Li Sheng-Tian ST Liu Jian-Min JM

Frontiers in molecular neuroscience 20180927

Osteoblasts derived osteocalcin (OCN) is recently reported to be involved in dopaminergic neuronal development. As dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinson's disease (PD), we investigated whether OCN could exert protective effects on 6-hydroxydopamine (6-OHDA)-induced PD rat model. Our data showed that the OCN level in the cerebrospinal fluid (CSF) in PD rat models was significantly lower than that in controls. Intervention with OCN could ...[more]

PMID: 30319352

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Project description:Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3?Ser9, and Nrf2, and suppressed the activation of NF-?B in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-?B pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3?Ser9, and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3?), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-?B signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3?-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3?-Nrf2/NF-?B signaling axis.

Project description:Current knowledge of TMEM17, a recently identified protein of the transmembrane (TMEM) family, is limited, especially with respect to its expression and biological functions in malignant tumors. This study analyzed TMEM17 expression in invasive breast cancer tissue and breast cell lines and its relevance to clinicopathological factors, and investigated the mechanisms underlying the biological effects of TMEM17 on breast cancer cells.TMEM17 protein expression was determined in 20 freshly harvested specimens (tumor and paired normal tissues) by Western blotting. Immunohistochemical analysis was performed to determine the expression and subcellular localization of TMEM17 in samples from 167 patients (mean age, 49 years) diagnosed with invasive ductal carcinoma (38 with triple-negative breast cancer; 129 with non-triple-negative breast cancer) who underwent complete resection in the First Affiliated Hospital of China Medical University between 2011 and 2013. Furthermore, TMEM17 was knocked down by small interfering RNAs in breast cancer cell lines.TMEM17 was found to be significantly upregulated in breast cancer tissues compared to the corresponding normal breast tissues by Western blotting (p=0.015). Immunohistochemical analysis revealed that TMEM was significantly upregulated in invasive breast cancer cells compared to adjacent normal breast duct glandular epithelial cells (10.78% vs 76.05%, p<0.001), and its expression was closely related to the patient's T-stage (p=0.022), advanced TNM stages (p=0.007), and lymph node metastasis (p=0.012). After TMEM17 knockdown or overexpression in breast cancer cell lines, TMEM17 upregulated p-AKT, p-GSK3?, active ?-catenin, and Snail, and downstream target proteins c-myc and cyclin D1, and downregulated E-cadherin, resulting in increased cancer cell proliferation, invasion, and migration. These effects were reversed by the AKT inhibitor LY294002.Our results indicate that TMEM17 is upregulated in breast cancer tissues and can promote malignant progression of breast cancer cells by activating the AKT/GSK3? signaling pathway.

Dataset Information

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3? Signaling.

Publications

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3β Signaling.

Similar Datasets

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