scholarly journals LncRNA-T199678 Mitigates α-Synuclein-Induced Dopaminergic Neuron Injury via miR-101-3p

2020 ◽  
Vol 12 ◽  
Author(s):  
Lu-Lu Bu ◽  
Ying-Yu Xie ◽  
Dan-Yu Lin ◽  
Ying Chen ◽  
Xiu-Na Jing ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Dopaminergic Neuron ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Molecular Target ◽  
Neuron Death ◽  
Abnormal Accumulation ◽  
Neuron Injury

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by dopaminergic neuron death and the abnormal accumulation and aggregation of α-synuclein (α-Syn) in the substantia nigra (SN). Although the abnormal accumulation of α-Syn can solely promote and accelerate the progress of PD, the underlying molecular mechanisms remain unknown. Mounting evidence confirms that the abnormal expression of long non-coding RNA (lncRNA) plays an important role in PD. Our previous study found that exogenous α-Syn induced the downregulation of lncRNA-T199678 in SH-SY5Y cells via a gene microarray analysis. This finding suggested that lncRNA-T199678 might have a potential pathological role in the pathogenesis of PD. This study aimed to explore the influence of lncRNA-T199678 on α-Syn-induced dopaminergic neuron injury. Overexpression of lncRNA-T199678 ameliorated the neuron injury induced by α-Syn via regulating oxidative stress, cell cycle, and apoptosis. Studies indicate lncRNAs could regulate posttranscriptional gene expression via regulating the downstream microRNA (miRNA). To discover the downstream molecular target of lncRNA-T199678, the following experiment found out that miR-101-3p was a potential target for lncRNA-T199678. Further study showed that the upregulation of lncRNA-T199678 reduced α-Syn-induced neuronal damage through miR-101-3p in SH-SY5Y cells and lncRNA-T199678 was responsible for the α-Syn-induced intracellular oxidative stress, dysfunction of the cell cycle, and apoptosis. All in all, lncRNA-T199678 mitigated the α-Syn-induced dopaminergic neuron injury via targeting miR-101-3p, which contributed to promote PD. Our results highlighted the role of lncRNA-T199678 in mitigating dopaminergic neuron injury in PD and revealed a new molecular target for PD.

scholarly journals Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson’s Disease: An Insight Into Role of Pharmacological Interventions

2020 ◽  
Vol 8 ◽  
Author(s):  
Bhupesh Vaidya ◽  
Shyam Sunder Sharma
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Neurodegenerative Disorder ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Transient Receptor

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the symptoms of motor deficits and cognitive decline. There are a number of therapeutics available for the treatment of PD, but most of them suffer from serious side effects such as bradykinesia, dyskinesia and on-off effect. Therefore, despite the availability of these pharmacological agents, PD patients continue to have an inferior quality of life. This has warranted a need to look for alternate strategies and molecular targets. Recent evidence suggests the Transient Receptor Potential (TRP) channels could be a potential target for the management of motor and non-motor symptoms of PD. Though still in the preclinical stages, agents targeting these channels have shown immense potential in the attenuation of behavioral deficits and signaling pathways. In addition, these channels are known to be involved in the regulation of ionic homeostasis, which is disrupted in PD. Moreover, activation or inhibition of many of the TRP channels by calcium and oxidative stress has also raised the possibility of their paramount involvement in affecting the other molecular mechanisms associated with PD pathology. However, due to the paucity of information available and lack of specificity, none of these agents have gone into clinical trials for PD treatment. Considering their interaction with oxidative stress, apoptosis and excitotoxicity, TRP channels could be considered as a potential future target for the treatment of PD.

scholarly journals The Neuroprotective Effects ofRatanasampilon Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Aiqin Zhu ◽  
Zhou Wu ◽  
Jie Meng ◽  
Patrick L. McGeer ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Mitogen Activated Protein Kinase ◽  
Tibetan Medicine ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma ◽  
Traditional Tibetan Medicine

We previously found thatRatanasampil(RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress-induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 μg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2′-deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2associated (100 μM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD.

scholarly journals COMMENTARY: COMBINATION THERAPY FOR ALZHEIMER’S DISEASE – THE NEXT STEP

2019 ◽  
pp. 1-1
Author(s):  
F. Jessen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Combination Therapy ◽  
Effect Size ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Molecular Target ◽  
Positive Signal ◽  
Clinical Worsening

Over the last several years, many clinical trials in Alzheimer’s disease (AD) have failed and in those with a positive signal, the effect size was of limited magnitude. It has become clear that the molecular mechanisms, which underlie neuronal damage and clinical worsening in AD are complex; maybe even too complex to be sufficiently impacted upon by a single molecular target approach. As in many other diseases, combination therapy might be a way forward to in achieve effects, which eventually are large enough to robustly prove efficacy and to provide patient related benefit.

scholarly journals Power of Proteomics in Linking Oxidative Stress and Female Infertility

2014 ◽  
Vol 2014 ◽  
pp. 1-26 ◽  
Author(s):  
Sajal Gupta ◽  
Jana Ghulmiyyah ◽  
Rakesh Sharma ◽  
Jacques Halabi ◽  
Ashok Agarwal
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Unexplained Infertility ◽  
Female Infertility ◽  
Related Disease ◽  
Large Numbers ◽  
The One ◽  
Related Proteins ◽  
Potential Biomarkers

Endometriosis, PCOS, and unexplained infertility are currently the most common diseases rendering large numbers of women infertile worldwide. Oxidative stress, due to its deleterious effects on proteins and nucleic acids, is postulated to be the one of the important mechanistic pathways in differential expression of proteins and in these diseases. The emerging field of proteomics has allowed identification of proteins involved in cell cycle, as antioxidants, extracellular matrix (ECM), cytoskeleton, and their linkage to oxidative stress in female infertility related diseases. The aim of this paper is to assess the association of oxidative stress and protein expression in the reproductive microenvironments such as endometrial fluid, peritoneal fluid, and follicular fluid, as well as reproductive tissues and serum. The review also highlights the literature that proposes the use of the fertility related proteins as potential biomarkers for noninvasive and early diagnosis of the aforementioned diseases rather than utilizing the more invasive methods used currently. The review will highlight the power of proteomic profiles identified in infertility related disease conditions and their linkage with underlying oxidative stress. The power of proteomics will be reviewed with regard to eliciting molecular mechanisms for early detection and management of these infertility related conditions.

scholarly journals MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian Lan ◽  
Ye Li ◽  
Cuiqin Fan ◽  
Liyan Wang ◽  
Wenjing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Immunofluorescence Assay ◽  
Electrophysiological Recording ◽  
Protein Signaling ◽  
Oxidative Markers ◽  
Electron Microscopy Analysis ◽  
Stress Damage ◽  
Related Proteins

Abstract Background Neuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. However, the underlying molecular mechanisms of neuroinflammation associated with neuronal injury in depression remain largely uncharacterized. Therefore, identifying potential molecular mechanisms and therapeutic targets would serve to better understand the progression of this condition. Methods Chronic unpredictable stress (CUS) was used to induce depression-like behaviors in rats. RNA-sequencing was used to detect the differentially expressed microRNAs. Stereotactic injection of AAV virus to overexpress or knockdown the miR-204-5p. The oxidative markers and inflammatory related proteins were verified by immunoblotting or immunofluorescence assay. The oxidative stress enzyme and products were verified using enzyme-linked assay kit. Electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Finally, electrophysiological recording was used to analyze the synaptic transmission. Results Here, we found that the expression of miR-204-5p within the hippocampal dentate gyrus (DG) region of rats was significantly down-regulated after chronic unpredicted stress (CUS), accompanied with the oxidative stress-induced neuronal damage within DG region of these rats. In contrast, overexpression of miR-204-5p within the DG region of CUS rats alleviated oxidative stress and neuroinflammation by directly targeting the regulator of G protein signaling 12 (RGS12), effects which were accompanied with amelioration of depressive-like behaviors in these CUS rats. In addition, down-regulation of miR-204-5p induced neuronal deterioration in DG regions and depressive-like behaviors in rats. Conclusion Taken together, these results suggest that miR-204-5p plays a key role in regulating oxidative stress damage in CUS-induced pathological processes of depression. Such findings provide evidence of the involvement of miR-204-5p in mechanisms underlying oxidative stress associated with depressive phenotype. Graphical Abstract

scholarly journals MicroRNAs, Parkinson’s Disease, and Diabetes Mellitus

2021 ◽  
Vol 22 (6) ◽  
pp. 2953
Author(s):  
Hsiuying Wang
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Cell Cycle ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Differentiation ◽  
Neurodegenerative Disorder ◽  
Glucose Absorption ◽  
Therapeutic Opportunity ◽  
The Common

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.

scholarly journals The Mitochondrial Metabolic Checkpoint and Reversing Stem Cell Aging

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-34-SCI-34
Author(s):  
Danica Chen
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Mitochondrial Protein ◽  
Cell Aging ◽  
Quiescent State ◽  
Mitochondrial Oxidative Stress ◽  
Hematopoietic Stem

Abstract Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced, which is associated with increased mitochondrial protein folding stress and mitochondrial oxidative stress. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. Other mitochondrial maintenance mechanisms include mitophagy and asymmetric segregation of aged mitochondria. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and heightened susceptibility to ROS-induced cell death

2020 ◽  
Author(s):  
Bailey Balouch ◽  
Halle Nagorsky ◽  
Truc Pham ◽  
Thai LaGraff ◽  
Quynh Chu-LaGraff
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Endoplasmic Reticulum Stress Response ◽  
Compound Heterozygous ◽  
Storage Material ◽  
Cellular Environment ◽  
And Oxidative Stress

AbstractInfantile Neuronal Ceroid Lipofuscinosis (INCL) is a pediatric neurodegenerative disorder characterized by progressive retinal and central nervous system deterioration during infancy. This lysosomal storage disorder results from a deficiency in the Palmitoyl Protein Thioesterase 1 (PPT1) enzyme - a lysosomal hydrolase which cleaves fatty acid chains such as palmitate from lipid-modified proteins. In the absence of PPT1 activity, these proteins fail to be degraded, leading to the accumulation of autofluorescence storage material in the lysosome. The underlying molecular mechanisms leading to INCL pathology remain poorly understood. A role for oxidative stress has been postulated, yet little evidence has been reported to support this possibility. Here we present a comprehensive cellular characterization of human PPT1-deficient fibroblast cells harboring Met1Ile and Tyr247His compound heterozygous mutations. We detected autofluorescence storage material and observed distinct organellar abnormalities of the lysosomal and mitochondrial structures, which supported previous postulations about the role of ER, mitochondria and oxidative stress in INCL. An increase in the number of lysosomal structures was found in INCL patient fibroblasts, which suggested an upregulation of lysosomal biogenesis, and an association with endoplasmic reticulum stress response. The mitochondrial network also displayed abnormal spherical punctate morphology instead of normal elongated tubules with extensive branching, supporting the involvement of mitochondrial and oxidative stress in INCL cell death. Autofluorescence accumulation and lysosomal pathologies can be mitigated in the presence of conditioned wild type media suggesting that a partial restoration via passive introduction of the enzyme into the cellular environment may be possible. We also demonstrated, for the first time, that human INCL fibroblasts have a heightened susceptibility to exogenous reactive oxygen species (ROS)-induced cell death, which suggested an elevated basal level of endogenous ROS in the mutant cell. Collectively, these findings support the role of intracellular organellar networks in INCL pathology, possibly due to oxidative stress.

scholarly journals The Sources of Reactive Oxygen Species and Its Possible Role in the Pathogenesis of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Minrui Weng ◽  
Xiaoji Xie ◽  
Chao Liu ◽  
Kah-Leong Lim ◽  
Cheng-wu Zhang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neuron ◽  
Neurodegenerative Disorder ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Oxygen Species ◽  
Neuron Death ◽  
Neuron Damage

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. The precise mechanism underlying pathogenesis of PD is not fully understood, but it has been widely accepted that excessive reactive oxygen species (ROS) are the key mediator of PD pathogenesis. The causative factors of PD such as gene mutation, neuroinflammation, and iron accumulation all could induce ROS generation, and the later would mediate the dopaminergic neuron death by causing oxidation protein, lipids, and other macromolecules in the cells. Obviously, it is of mechanistic and therapeutic significance to understand where ROS are derived and how ROS induce dopaminergic neuron damage. In the present review, we try to summarize and discuss the main source of ROS in PD and the key pathways through which ROS mediate DA neuron death.

scholarly journals Neuroprotective Activity of Mentha Species on Hydrogen Peroxide-Induced Apoptosis in SH-SY5Y Cells

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1366 ◽  
Author(s):  
Doaa M. Hanafy ◽  
Paul D. Prenzler ◽  
Geoffrey E. Burrows ◽  
Saliya Gurusinghe ◽  
Bashar M. Thejer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Cell Model ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Neuroprotective Activity ◽  
Caspase Activity ◽  
Apoptotic Protein ◽  
Aβ Aggregation

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unclear cause. It appears that multiple factors participate in the process of neuronal damage including oxidative stress and accumulation of the protein amyloid β (Aβ) in the brain. The search for a treatment for this disorder is essential as current medications are limited to alleviating symptoms and palliative effects. The aim of this study is to investigate the effects of mint extracts on selected mechanisms implicated in the development of AD. To enable a thorough investigation of mechanisms, including effects on β-secretase (the enzyme that leads to the formation of Aβ), on Aβ aggregation, and on oxidative stress and apoptosis pathways, a neuronal cell model, SH-SY5Y cells, was selected. Six Mentha taxa were investigated for their in vitro β-secretase (BACE) and Aβ-aggregation inhibition activities. Moreover, their neuroprotective effects on H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells were evaluated through caspase activity. Real-time PCR and Western blot analysis were carried out for the two most promising extracts to determine their effects on signalling pathways in SH-SY5Y cells. All mint extracts had strong BACE inhibition activity. M. requienii extracts showed excellent inhibition of Aβ-aggregation, while other extracts showed moderate inhibition. M. diemenica and M. requienii extracts lowered caspase activity. Exposure of SH-SY5Y cells to M. diemenica extracts resulted in a decrease in the expression of pro-apoptotic protein, Bax, and an elevation in the anti-apoptotic protein, Bcl-xL, potentially mediated by down-regulation of the ASK1-JNK pathway. These results indicate that mint extracts could prevent the formation of Aβ and also could prevent their aggregation if they had already formed. M. diemenica and M. requienii extracts have potential to suppress apoptosis at the cellular level. Hence, mint extracts could provide a source of efficacious compounds for a therapeutic approach for AD.

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