scholarly journals METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Fanpeng Zhao ◽  
Ying Xu ◽  
Shichao Gao ◽  
Lixia Qin ◽  
Quillan Austria ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Neuronal Damage ◽  
Underlying Mechanism ◽  
Aβ Oligomers ◽  
Aberrant Cell ◽  
Soluble Aβ Oligomers ◽  
The Impact

Abstract Background N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). Methods We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo. Results We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo. Conclusions Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

scholarly journals Neuroprotection by Brazilian Green Propolis againstIn vitroandIn vivoIschemic Neuronal Damage

2005 ◽  
Vol 2 (2) ◽  
pp. 201-207 ◽  
Author(s):  
Masamitsu Shimazawa ◽  
Satomi Chikamatsu ◽  
Nobutaka Morimoto ◽  
Satoshi Mishima ◽  
Hiroichi Nagai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Folk Medicine ◽  
Neuroprotective Function ◽  
Brazilian Green Propolis

We examined whether Brazilian green propolis, a widely used folk medicine, has a neuroprotective functionin vitroand/orin vivo.In vitro, propolis significantly inhibited neurotoxicity induced in neuronally differentiated PC12 cell cultures by either 24 h hydrogen peroxide (H2O2) exposure or 48 h serum deprivation. Regarding the possible underlying mechanism, propolis protected against oxidative stress (lipid peroxidation) in mouse forebrain homogenates and scavenged free radicals [induced by diphenyl-p-picrylhydrazyl (DPPH). In micein vivo, propolis [30 or 100 mg/kg; intraperitoneally administered four times (at 2 days, 1 day and 60 min before, and at 4 h after induction of focal cerebral ischemia by permanent middle cerebral artery occlusion)] reduced brain infarction at 24 h after the occlusion. Thus, a propolis-induced inhibition of oxidative stress may be partly responsible for its neuroprotective function againstin vitrocell death andin vivofocal cerebral ischemia.

scholarly journals Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3216
Author(s):  
Maryvonne Ardourel ◽  
Chloé Felgerolle ◽  
Arnaud Pâris ◽  
Niyazi Acar ◽  
Khaoula Ramchani Ben Othman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Müller Cells ◽  
Nutritional Supplement ◽  
Glutamine Metabolism ◽  
Muller Cells ◽  
Omega 3 ◽  
Glutamine Synthesis ◽  
The Impact

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

scholarly journals α-Tocopherol modifies the expression of genes related to oxidative stress and apoptosis during in vitro maturation and enhances the developmental competence of rabbit oocytes

2018 ◽  
Vol 30 (12) ◽  
pp. 1728 ◽  
Author(s):  
M. Arias-Álvarez ◽  
R. M. García-García ◽  
J. López-Tello ◽  
P. G. Rebollar ◽  
A. Gutiérrez-Adán ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
In Vitro Maturation ◽  
Cumulus Cell ◽  
Rabbit Model ◽  
Developmental Competence ◽  
Antioxidant Agents ◽  
Junction Protein

The developmental competence of in vitro maturation (IVM) oocytes can be enhanced by antioxidant agents. The present study investigated, for the first time in the rabbit model, the effect of adding α-tocopherol (0, 100, 200 and 400 µM) during IVM on putative transcripts involved in antioxidant defence (superoxide dismutase 2, mitochondrial (SOD2), glutathione peroxidase 1 (GPX1), catalase (CAT)), cell cycle regulation and apoptosis cascade (apoptosis tumour protein 53 (TP53), caspase 3, apoptosis-related cysteine protease (CASP3)), cell cycle progression (cellular cycle V-Akt murine thymoma viral oncogene homologue 1 (AKT1)), cumulus expansion (gap junction protein, alpha 1, 43 kDa (GJA1) and prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclo-oxygenase) (PTGS2)) and metabolism (glucose-6-phosphate dehydrogenase (G6PD)). Meiotic progression, mitochondrial reallocation, cumulus cell apoptosis and the developmental competence of oocytes after IVF were also assessed. Expression of SOD2, CAT, TP53, CASP3 and GJA1 was downregulated in cumulus–oocyte complexes (COCs) after IVM with 100 μM α-tocopherol compared with the group without the antioxidant. The apoptotic rate and the percentage of a non-migrated mitochondrial pattern were lower in COCs cultured with 100 μM α-tocopherol, consistent with better-quality oocytes. In fact, early embryo development was improved when 100 μM α-tocopherol was included in the IVM medium, but remained low compared with in vivo-matured oocytes. In conclusion, the addition of 100 μM α-tocopherol to the maturation medium is a suitable approach to manage oxidative stress and apoptosis, as well as for increasing the in vitro developmental competence of rabbit oocytes.

scholarly journals The Rational Design and Biological Mechanisms of Nanoradiosensitizers

Nanomaterials ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 504 ◽  
Author(s):  
Hainan Sun ◽  
Xiaoling Wang ◽  
Shumei Zhai
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Dna Damage ◽  
Rational Design ◽  
Design Strategies ◽  
Biological Mechanisms ◽  
Normal Tissues ◽  
Current State

Radiotherapy (RT) has been widely used for cancer treatment. However, the intrinsic drawbacks of RT, such as radiotoxicity in normal tissues and tumor radioresistance, promoted the development of radiosensitizers. To date, various kinds of nanoparticles have been found to act as radiosensitizers in cancer radiotherapy. This review focuses on the current state of nanoradiosensitizers, especially the related biological mechanisms, and the key design strategies for generating nanoradiosensitizers. The regulation of oxidative stress, DNA damage, the cell cycle, autophagy and apoptosis by nanoradiosensitizers in vitro and in vivo is highlighted, which may guide the rational design of therapeutics for tumor radiosensitization.

scholarly journals In vitro assessment of the cytotoxic, genotoxic and oxidative stress effects of the synthetic cannabinoid JWH-018 in human SH-SY5Y neuronal cells

2020 ◽  
Vol 9 (6) ◽  
pp. 734-740
Author(s):  
Yigit Sezer ◽  
Ayse Tarbin Jannuzzi ◽  
Marilyn A Huestis ◽  
Buket Alpertunga
Keyword(s):  
Oxidative Stress ◽  
Neuronal Cells ◽  
Underlying Mechanism ◽  
Synthetic Cannabinoid ◽  
Stress Effects ◽  
Legal High ◽  
New Generation ◽  
And Oxidative Stress

Abstract Background: JWH-018 was the first synthetic cannabinoid introduced as a legal high and the first of the new generation of novel psychoactive substances that flooded worldwide drug markets. JWH-018 was marketed as “spice,” “herbal incense,” or “herbal blend,” as a popular and legal (at the time) alternative to cannabis (marijuana). JWH-018 is a potent synthetic cannabinoid with considerable toxicity associated with its use. JWH-018 has qualitatively similar but quantitatively greater pharmacological effects than cannabis, leading to intoxications and even deaths. The mechanisms of action of the drug’s toxicity require research, and thus, the aim of the present study was to investigate the toxicological profile of JWH-018 in human SH-SY5Y neuronal cells. Methods: SH-SY5Y neuronal cells were exposed to increasing concentrations from 5 to 150 μM JWH-018 over 24 h. Cytotoxicity, DNA damage, the apoptotic/necrotic rate, and oxidative stress were assessed following SH-SY5Y exposure. Results: JWH-018 did not produce a significant decrease in SH-SY5Y cell viability, did not alter apoptotic/necrotic rate, and did not cause genotoxicity in SH-SY5Y cells with 24-h exposure. Glutathione reductase and catalase activities were significantly reduced; however, there was no significant change in glutathione peroxidase activity. Also, JWH-018 treatment significantly decreased glutathione concentrations, significantly increased protein carbonylation, and significantly increased malondialdehyde (MDA) concentrations. For significance, all P < 0.05. Discussion/Conclusion: JWH-018 produced oxidative stress in SH-SY5Y cells that could be an underlying mechanism of JWH-018 neurotoxicity. Additional in vivo animal and human-based studies are needed to confirm our findings.

scholarly journals Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Youngmun Lee ◽  
Sunyoung Kim ◽  
Yeonsoo Oh ◽  
Young-Mi Kim ◽  
Young-Won Chin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Neuronal Damage ◽  
Biological Activities ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ros Generation ◽  
Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

scholarly journals miR-96 Regulates Liver Tumor-Initiating Cells Expansion and Sorafenib Resistance

2020 ◽  
Author(s):  
Yonggang Huang ◽  
Jin Zhang ◽  
Wei Dong ◽  
Huiping Peng ◽  
Maolin Gu ◽  
...  
Keyword(s):  
Liver Tumor ◽  
Underlying Mechanism ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
Functional Studies ◽  
Optimal Target ◽  
The Impact

Abstract Background Liver tumor-initiating cells (T-ICs) contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Methods Real-time PCR was used to detect the expression of miR-96 in liver tumor-initiating cells (T-ICs). The impact of miR-96 on liver T-ICs expansion was investigated both in vivo and in vitro . The correlation between miR-96 expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results Our finding shows that miR-96 is upregulated in liver T-ICs. Functional studies revealed that forced miR-96 promotes liver T-ICs self-renewal and tumorigenesis. Conversely, knockdown miR-96 inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, miR-96 downregulates SOX6 via its mRNA 3’UTR in liver T-ICs. Furthermore, the miR-96 expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-96 may predict sorafenib benefits in HCC patients. Conclusion Our findings revealed the crucial role of the miR-96 in liver T-ICs expansion and sorafenib response, rendering miR-96 as an optimal target for the prevention and intervention of HCC.

Targeting NOX4 Disrupts the Resistance of Papillary Thyroid Carcinoma to Chemotherapeutic Drugs and Lenvatinib

2021 ◽  
Author(s):  
Ping Tang ◽  
Jianfeng Sheng ◽  
Xiujuan Peng ◽  
Renfei Zhang ◽  
Tao Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Underlying Mechanism ◽  
Serum Starvation ◽  
Chemotherapeutic Drugs ◽  
Nadph Oxidase 4 ◽  
Cell Death Detection Elisaplus

Abstract Background: Advanced differentiated thyroid cancer cells are subjected to extreme nutritional starvation which contributes to develop resistance to treatments; however, the underlying mechanism remains unclear.Methods: We used 0.5% serum to mimic starvation during cell culture. A CCK8 assay, cell death Detection ELISAPLUS kit, PI staining were measured to determine cell viability, cell apoptosis and cell cycle respectively in BCPAP cells and TPC-1 cells expressing shRNA against NOX4. The cells were then treated with etoposide and doxorubicin, two chemotherapeutic drugs, as well as lenvatinib to determine the role of NOX4 in resistance. Lenvatinib-resistant BCPAP cells (LRBCs) were also established to confirm the role. Finally, GLX351322, a chemical inhibitor targeting NOX4, was used to inhibit NOX4-derived ROS and detect the the contribution of NOX4 to resistance in vitro and in vivo. Results: NADPH oxidase 4 (NOX4) is highly expressed under serum starvation in BCPAP or TPC-1 cells. NOX4 knockdown impairs cell viability, increases cell apoptosis, extends G1 phase in cell cycle and modulates the level of energy-associated metabolites in starved cells. When these starved cells or Lenvatinib-resistant BCPAP cells (LRBCs) are treated with chemotherapeutic drugs or Lenvatinib, NOX4 knockdown inhibits cell viability and aggravates cell apoptosis depending on NOX4-derived ROS production. GLX351322, a NOX4-derived ROS inhibitor, has a significantly inhibitory effect on cell growth in vitro and the growth of BPCPA-derived even LRBCs-derived xenografts in vivo.Conclusions: These findings highlight NOX4 and NOX4-derived ROS as a potential therapeutic target in resistance of PTC patients.

scholarly journals Andrographolide Ameliorates Diabetic Cardiomyopathy in Mice by Blockage of Oxidative Damage and NF-κB-Mediated Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ershun Liang ◽  
Xue Liu ◽  
Zhanhui Du ◽  
Ruixue Yang ◽  
Yuxia Zhao
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Myocardial Dysfunction ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Related Factor

Andrographolide (Andro), a major bioactive component obtained from Andrographis paniculata Nees, has exerted wide antioxidant as well as cytoprotective properties. However, whether Andro treatment could retard the progress of diabetic cardiomyopathy (DCM) remains unknown. In this study, we evaluated the effects of Andro against diabetes-induced myocardial dysfunction and explored the underlying mechanism in STZ-induced diabetic mice. As a result, treatment with Andro dose dependently suppressed cardiac inflammation and oxidative stress, accompanied by decreasing cardiac apoptosis, which subsequently ameliorated cardiac fibrosis and cardiac hypertrophy. Further, Andro blocked hyperglycemia-triggered reactive oxygen species (ROS) generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Our results suggest that the cardioprotective effects afforded by Andro treatment involve the modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. The present study unravels the therapeutic potential of Andro in the treatment of DCM by attenuating oxidative stress, inflammation, and apoptosis.

scholarly journals Insight into the Influence of Cultivar Type, Cultivation Year, and Site on the Lignans and Related Phenolic Profiles, and the Health-Promoting Antioxidant Potential of Flax (Linum usitatissimum L.) Seeds

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2636 ◽  
Author(s):  
Laurine Garros ◽  
Samantha Drouet ◽  
Cyrielle Corbin ◽  
Cédric Decourtil ◽  
Thibaud Fidel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Biological Activities ◽  
Yeast Cells ◽  
In Vivo Studies ◽  
Major Influence ◽  
Antioxidant Power ◽  
Accumulation Pattern ◽  
The Impact

Flaxseeds are a functional food representing, by far, the richest natural grain source of lignans, and accumulate substantial amounts of other health beneficial phenolic compounds (i.e., flavonols, hydroxycinnamic acids). This specific accumulation pattern is related to their numerous beneficial effects on human health. However, to date, little data is available concerning the relative impact of genetic and geographic parameters on the phytochemical yield and composition. Here, the major influence of the cultivar over geographic parameters on the flaxseed phytochemical accumulation yield and composition is evidenced. The importance of genetic parameters on the lignan accumulation was further confirmed by gene expression analysis monitored by RT-qPCR. The corresponding antioxidant activity of these flaxseed extracts was evaluated, both in vitro, using ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and iron chelating assays, as well as in vivo, by monitoring the impact of UV-induced oxidative stress on the lipid membrane peroxidation of yeast cells. Our results, both the in vitro and in vivo studies, confirm that flaxseed extracts are an effective protector against oxidative stress. The results point out that secoisolariciresinol diglucoside, caffeic acid glucoside, and p-coumaric acid glucoside are the main contributors to the antioxidant capacity. Considering the health benefits of these compounds, the present study demonstrates that the flaxseed cultivar type could greatly influence the phytochemical intakes and, therefore, the associated biological activities. We recommend that this crucial parameter be considered in epidemiological studies dealing with flaxseeds.

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