P3-315: Neuroprotective effects of oxazine derivative against LPS-induced oxidative stress via attenuation of NF-κB pathway and regulation of cellular redox status in PC12 cells

Aim & Objectives: Curcuminoids are characteristic constituents in Curcuma, displaying obviously neuroprotective activities against oxidative stress. As one of the Traditional Chinese Medicines from Curcuma, the radix of Curcuma aromatica is also rich in those chemicals, but its neuroprotective activity and mechanism remain unknown. The aim of the current study is to evaluate the neuroprotective effects of extracts from the radix of C. aromatica (ECAs) on H2O2-damaged PC12 cells. Material and Methods: The model of oxidative stress damage was established by treatment of 400 µM H2O2 on PC12 to induce cell damage. After the treatment of ECWs for 24 h, the cell viability, LDH, SOD, CAT and GSH were measured to evaluate the neuroprotection of ECAs on that model. The potential action mechanism was studied by measurement of level of ROS, cell apoptosis rate, mitochondrial membrane potential (MMP), morphologic change, the intracellular Ca2+ content (F340/F380) and the expressions of Bcl-2, Bax and Caspase-3. Additionally, the constituents from tested extracts were analyzed by HPLC-DAD-Q-TOF-MS method. Results: Compared with a positive control, Vitamin E, 10 µg/ml of 95% EtOH extract (HCECA) and 75% EtOH extract (MCECA) can markedly increase the rate of cell survival and enhance the antioxidant enzyme activities of SOD, CAT, increase the levels of GSH, decrease LDH release and the level of ROS, attenuate the intracellular Ca2+ overloading, reduce the cell apoptotic rate and stabilize MMP, down-regulate Bcl-2 expression, up-regulate Bax and caspase-3 expression, and improve the change of cell morphology. The chemical analysis showed that diarylheptanoids and sesquiterpenoids are the major chemicals in tested extracts and the former were richer in HCECA and MCECA than others. Conclusions: These findings indicated that the effects of HCECA and MCECA on inhibiting the cells damage induced by H2O2 in PC12 are better than other extracts from the radix of C. aromatica, and the active constituents with neuroprotective effects consisting in those two active extracts are diarylheptanoids.

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NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats

Antioxidants ◽

10.3390/antiox10030489 ◽

2021 ◽

Vol 10 (3) ◽

pp. 489

Author(s):

Lauren E. Adams ◽

Hunter G. Moss ◽

Danielle W. Lowe ◽

Truman Brown ◽

Donald B. Wiest ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin D ◽

Redox Status ◽

Therapeutic Window ◽

Post Injury ◽

Artery Ligation ◽

Cellular Redox ◽

Carotid Artery Ligation ◽

Drug Concentrations

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

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Uncovering the beginning of diabetes: the cellular redox status and oxidative stress as starting players in hyperglycemic damage

Molecular and Cellular Biochemistry ◽

10.1007/s11010-012-1555-9 ◽

2013 ◽

Vol 376 (1-2) ◽

pp. 103-110 ◽

Cited By ~ 24

Author(s):

João Soeiro Teodoro ◽

Ana Patrícia Gomes ◽

Ana Teresa Varela ◽

Filipe Valente Duarte ◽

Anabela Pinto Rolo ◽

...

Keyword(s):

Oxidative Stress ◽

Redox Status ◽

Cellular Redox ◽

And Oxidative Stress

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Icariin Inhibits AGE-Induced Injury in PC12 Cells by Directly Targeting Apoptosis Regulator Bax

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7940808 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Shao-Yang Zhao ◽

Li-Xi Liao ◽

Peng-Fei Tu ◽

Wei-Wei Li ◽

Ke-Wu Zeng

Keyword(s):

Oxidative Stress ◽

Pc12 Cells ◽

Pc12 Cell ◽

Cell Apoptosis ◽

Diabetic Patients ◽

Neuroprotective Effects ◽

Apoptosis Pathway ◽

Bax Protein ◽

Pulldown Assay ◽

And Migration

Diabetic encephalopathy (DE) is a serious complication caused by long-term cognitive impairment in diabetic patients. At present, there is no effective treatment for DE. Icariin (ICA) is a bioactive ingredient isolated from Epimedium. Previous research indicated that ICA was neuroprotective against Aβ-induced PC12 cell insult; however, the effect of ICA on an advanced glycosylation end product- (AGE-) induced neural injury model has not been studied. In this study, we investigated the neuroprotective effects of ICA on AGE-induced injury in PC12 cells. Our findings revealed that ICA could effectively protect PC12 cells from AGE-induced cell apoptosis by suppressing oxidative stress. Moreover, we observed that ICA could significantly protect against mitochondrial depolarization following AGE stimulation and inactivate the mitochondria-dependent caspase-9/3 apoptosis pathway. Most notably, we identified the direct target protein of ICA as apoptosis regulator Bax by a pulldown assay. We found that ICA could specifically target Bax protein and inhibit Bax dimer formation and migration to mitochondria. Furthermore, a siRNA knockdown experiment revealed that ICA could inhibit PC12 cell apoptosis and oxidative stress through targeting Bax. Taken together, our findings demonstrated that ICA could attenuate AGE-induced oxidative stress and mitochondrial apoptosis by specifically targeting Bax and further regulating the biological function of Bax on mitochondria.

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Amarogentin from Gentiana rigescens Franch Exhibits Antiaging and Neuroprotective Effects through Antioxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3184019 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Dejene Disasa ◽

Lihong Cheng ◽

Majid Manzoor ◽

Qian Liu ◽

Ying Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Antioxidant Activity ◽

Natural Products ◽

Survival Rate ◽

Pc12 Cells ◽

Neuroprotective Effects ◽

Replicative Lifespan ◽

Antioxidative Stress ◽

Gentiana Rigescens

In the present study, the replicative lifespan assay of yeast was used to guide the isolation of antiaging substance from Gentiana rigescens Franch, a traditional Chinese medicine. A compound with antiaging effect was isolated, and the chemical structure of this molecule as amarogentin was identified by spectral analysis and compared with the reported data. It significantly extended the replicative lifespan of K6001 yeast at doses of 1, 3, and 10 μM. Furthermore, amarogentin improved the survival rate of yeast under oxidative stress by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), and these enzymes’ gene expression. In addition, this compound did not extend the replicative lifespan of sod1, sod2, uth1, and skn7 mutants with K6001 background. These results suggested that amarogentin exhibited antiaging effect on yeast via increase of SOD2, CAT, GPx gene expression, enzyme activity, and antioxidative stress. Moreover, we evaluated antioxidant activity of this natural products using PC12 cell system, a useful model for studying the nervous system at the cellular level. Amarogentin significantly improved the survival rate of PC12 cells under H2O2-induced oxidative stress and increased the activities of SOD and SOD2, and gene expression of SOD2, CAT, GPx, Nrf2, and Bcl-x1. Meanwhile, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) of PC12 cells were significantly reduced after treatment of the amarogentin. These results indicated that antioxidative stress play an important role for antiaging and neuroprotection of amarogentin. Interestingly, amarogentin exhibited neuritogenic activity in PC12 cells. Therefore, the natural products, amarogentin from G. rigescens with antioxidant activity could be a good candidate molecule to develop drug for treating neurodegenerative diseases.

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Modulation of Apoptotic Cell Death and Neuroprotective Effects of Glutathione—L-Dopa Codrug Against H2O2-Induced Cellular Toxicity

Antioxidants ◽

10.3390/antiox8080319 ◽

2019 ◽

Vol 8 (8) ◽

pp. 319 ◽

Cited By ~ 1

Author(s):

Sara Franceschelli ◽

Paola Lanuti ◽

Alessio Ferrone ◽

Daniela Maria Pia Gatta ◽

Lorenza Speranza ◽

...

Keyword(s):

Cell Lines ◽

Apoptotic Cell ◽

Redox Status ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Standard Drug ◽

Cellular Redox ◽

Cellular Toxicity ◽

Ros Formation ◽

Induced Apoptosis

The L-3,4-dihydroxyphenylalanine (LD) is the gold standard drug currently used to manage Parkinson’s disease (PD) and to control its symptoms. However, LD could cause disease neurotoxicity due to the generation of pro-oxidant intermediates deriving from its autoxidation. In order to overcome this limitation, we have conjugated LD to the natural antioxidant glutathione (GSH) to form a codrug (GSH-LD). Here we investigated the effect of GSH-LD on H2O2-induced cellular toxicity in undifferentiated and differentiated lymphoma U-937 and dopaminergic neuroblastoma SH-SY5Y cell lines, used respectively as models to study the involvement of macrophages/microglia and dopaminergic neurons in PD. We analyzed the effect of GSH-LD on apoptosis and cellular oxidative stress, both considered strategic targets for the prevention and treatment of neurodegenerative diseases. Compared to LD and GSH, GSH-LD had a stronger effect in preventing hydrogen peroxide (H2O2) induced apoptosis in both cell lines. Moreover, GSH-LD was able to preserve cell viability, cellular redox status, gluthation metabolism and prevent reactive oxygen species (ROS) formation, in a phosphinositide 3-kinase (PI3K)/kinase B (Akt)-dependent manner, in a neurotoxicity cellular model. Our findings indicate that the GSH-LD codrug offers advantages deriving from the additive effect of LD and GSH and it could represent a promising candidate for PD treatment.

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A combination of curcumin, vorinostat and silibinin reverses Aβ-induced nerve cell toxicity via activation of AKT-MDM2-p53 pathway

PeerJ ◽

10.7717/peerj.6716 ◽

2019 ◽

Vol 7 ◽

pp. e6716 ◽

Cited By ~ 5

Author(s):

Jia Meng ◽

Yan Li ◽

Mingming Zhang ◽

Wenjing Li ◽

Lin Zhou ◽

...

Keyword(s):

Oxidative Stress ◽

Pc12 Cells ◽

Nerve Cell ◽

Drug Combination ◽

Therapeutic Option ◽

Oxidative Stress Marker ◽

Cell Toxicity ◽

Neuroprotective Effects ◽

Cell Viability Assay ◽

P53 Pathway

Alzheimer’s disease (AD) is a significant health issue for the elderly and becoming increasingly common as the global population ages. Although many efforts have been made to elucidate its pathology, there is still a lack of effective clinical anti-AD agents. Previous research has shown the neuroprotective properties of a combination of curcumin and vorinostat. In this study, nine other neuroprotective agents were investigated to examine whether a three-drug combination of curcumin, vorinostat, and a new drug is more advantageous than the previous two-drug combination in alleviating amyloid beta (Aβ)-induced nerve cell toxicity. Cell viability assay was performed to screen these agents, and further validation tests, including determination of cellular oxidative stress, apoptosis, and activity of the AKT/MDM2/p53 pathway, were performed. Among the nine candidate compounds, only silibinin at 1 µM reduced Aβ25–35-induced toxicity in PC12 cells. The neuroprotective effects of 1 µM silibinin in combination with 5 µM curcumin and 0.5 µM vorinostat (CVS) was shown in PC12 cells, in which it decreased apoptosis and oxidative stress marker levels that were increased by 20 µM Aβ25–35. Western blotting results showed that CVS pretreatment significantly increased the phosphorylation of AKT, BAD, and MDM2, which resulted in decreased intracellular expression of p53. Further, immunofluorescence results showed reduced p53 levels in the nuclei of PC12 cells following CVS pretreatment, indicating a reduction in the p53-mediated transcriptional activity associated with Aβ25–35 exposure. In conclusion, our findings suggested that pretreatment with CVS protected PC12 cells from Aβ25–35-induced toxicity through modulation of the AKT/MDM2/p53 pathway. Thus, CVS may present a new therapeutic option for treating AD.

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Redox Potential of Antioxidants in Cancer Progression and Prevention

Antioxidants ◽

10.3390/antiox9111156 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1156

Author(s):

Sajan George ◽

Heidi Abrahamse

Keyword(s):

Oxidative Stress ◽

Cancer Progression ◽

Natural Antioxidants ◽

Redox Balance ◽

Redox Status ◽

Enzyme Activation ◽

Metabolic Reprogramming ◽

Cellular Functions ◽

Cellular Redox ◽

The Right

The benevolent and detrimental effects of antioxidants are much debated in clinical trials and cancer research. Several antioxidant enzymes and molecules are overexpressed in oxidative stress conditions that can damage cellular proteins, lipids, and DNA. Natural antioxidants remove excess free radical intermediates by reducing hydrogen donors or quenching singlet oxygen and delaying oxidative reactions in actively growing cancer cells. These reducing agents have the potential to hinder cancer progression only when administered at the right proportions along with chemo-/radiotherapies. Antioxidants and enzymes affect signal transduction and energy metabolism pathways for the maintenance of cellular redox status. A decline in antioxidant capacity arising from genetic mutations may increase the mitochondrial flux of free radicals resulting in misfiring of cellular signalling pathways. Often, a metabolic reprogramming arising from these mutations in metabolic enzymes leads to the overproduction of so called ’oncometabolites’ in a state of ‘pseudohypoxia’. This can inactivate several of the intracellular molecules involved in epigenetic and redox regulations, thereby increasing oxidative stress giving rise to growth advantages for cancerous cells. Undeniably, these are cell-type and Reactive Oxygen Species (ROS) specific, which is manifested as changes in the enzyme activation, differences in gene expression, cellular functions as well as cell death mechanisms. Photodynamic therapy (PDT) using light-activated photosensitizing molecules that can regulate cellular redox balance in accordance with the changes in endogenous ROS production is a solution for many of these challenges in cancer therapy.

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Oxidative Stress-Mediated Skeletal Muscle Degeneration: Molecules, Mechanisms, and Therapies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/6842568 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Min Hee Choi ◽

Jin Rong Ow ◽

Nai-Di Yang ◽

Reshma Taneja

Keyword(s):

Oxidative Stress ◽

Molecular Level ◽

Redox Homeostasis ◽

Redox Status ◽

Muscle Degeneration ◽

Dystrophic Muscle ◽

Telomere Shortening ◽

Cellular Redox ◽

Pathological Conditions

Oxidative stress is a loss of balance between the production of reactive oxygen species during cellular metabolism and the mechanisms that clear these species to maintain cellular redox homeostasis. Increased oxidative stress has been associated with muscular dystrophy, and many studies have proposed mechanisms that bridge these two pathological conditions at the molecular level. In this review, the evidence indicating a causal role of oxidative stress in the pathogenesis of various muscular dystrophies is revisited. In particular, the mediation of cellular redox status in dystrophic muscle by NF-κB pathway, autophagy, telomere shortening, and epigenetic regulation are discussed. Lastly, the current stance of targeting these pathways using antioxidant therapies in preclinical and clinical trials is examined.

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