PI3K/Akt and ERK1/2 Signalling Are Involved in Quercetin-Mediated Neuroprotection against Copper-Induced Injury

Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective effects of quercetin. In severely injured neurons, 30 μM quercetin exerted strong prooxidative action and exacerbated cytotoxic effects of copper, whereas 150 μM quercetin failed to affect neuronal survival. These results demonstrate the dual nature of quercetin action in copper-related neurodegeneration. Hence, they are relevant in the context of considering quercetin as a possible therapeutic for neuroprotection and imply that detailed pharmacological and toxicological studies must be carried out for natural compounds capable of acting both as antioxidants and prooxidants.

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Towards Understanding Extracellular ROS Sensory and Signaling Systems in Plants

Advances in Botany ◽

10.1155/2014/538946 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Saijaliisa Kangasjärvi ◽

Jaakko Kangasjärvi

Keyword(s):

Reverse Genetics ◽

Stomatal Closure ◽

Air Pollutant ◽

Cellular Functions ◽

Alarm Signal ◽

Signaling Systems ◽

Signaling Function ◽

Electron Transport Chains ◽

Response To Stress ◽

Ros Formation

Reactive Oxygen Species (ROS) are ubiquitous metabolites in all aerobic organisms. Traditionally ROS have been considered as harmful, accidental byproducts of cellular functions involving electron transport chains or electron transfer. However, it is now recognized that controlled production of ROS has significant signaling functions, for example, in pathogen defense, in the regulation of stomatal closure, or in cell-to-cell signaling. ROS formation in subcellular compartments is critical to act as “alarm” signal in the response to stress, and the concept of ROS as primarily signaling substances has emerged. The involvement of ROS in several developmental and inducible processes implies that there must be coordinated function of signaling network(s) that govern ROS responses and subsequent processes. The air pollutant ozone can be used as a useful tool to elucidate the function of apoplastic ROS: O3 degrades in cell wall into various ROS which are interpreted as ROS with signaling function inducing downstream responses. We have used ozone as a tool in mutant screens and transcript profiling-reverse genetics to identify genes involved in processes related to the signaling function of ROS. We review here our recent findings in the elucidation of apoplastic ROS sensing, signaling, and interaction with various symplastic components.

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Antiproliferative Effects of Hop-derived Prenylflavonoids and Their Influence on the Efficacy of Oxaliplatine, 5-fluorouracil and Irinotecan in Human ColorectalC Cells

Nutrients ◽

10.3390/nu11040879 ◽

2019 ◽

Vol 11 (4) ◽

pp. 879 ◽

Cited By ~ 7

Author(s):

Martin Ambrož ◽

Kateřina Lněničková ◽

Petra Matoušková ◽

Lenka Skálová ◽

Iva Boušová

Keyword(s):

Colorectal Cancer ◽

Reactive Oxygen Species ◽

Cell Lines ◽

Nutritional Value ◽

Antioxidant Properties ◽

Oxygen Species ◽

Antiproliferative Effects ◽

Colorectal Cancer Cell Lines ◽

Potential Benefits ◽

Ros Formation

Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 µM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.

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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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Passiflora cincinnata Extract Delays the Development of Motor Signs and Prevents Dopaminergic Loss in a Mice Model of Parkinson’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/8429290 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Luiz Eduardo Mateus Brandão ◽

Diana Aline Morais Ferreira Nôga ◽

Aline Lima Dierschnabel ◽

Clarissa Loureiro das Chagas Campêlo ◽

Ywlliane da Silva Rodrigues Meurer ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Tyrosine Hydroxylase ◽

Native Species ◽

Biological Effects ◽

Neuroprotective Effect ◽

Substantia Nigra Pars Compacta ◽

Concomitant Treatment ◽

Mice Model ◽

Neuroprotective Effects

Passiflora cincinnata Masters is a Brazilian native species of passionflower. This genus is known in the American continent folk medicine for its diuretic and analgesic properties. Nevertheless, few studies investigated possible biological effects of P. cincinnata extracts. Further, evidence of antioxidant actions encourages the investigation of possible neuroprotective effects in animal models of neurodegenerative diseases. This study investigates the effect of the P. cincinnata ethanolic extract (PAS) on mice submitted to a progressive model of Parkinson’s disease (PD) induced by reserpine. Male (6-month-old) mice received reserpine (0.1 mg/kg, s.c.), every other day, for 40 days, with or without a concomitant treatment with daily injections of PAS (25 mg/kg, i.p.). Catalepsy, open field, oral movements, and plus-maze discriminative avoidance evaluations were performed across treatment, and immunohistochemistry for tyrosine hydroxylase was conducted at the end. The results showed that PAS treatment delayed the onset of motor impairments and prevented the occurrence of increased catalepsy behavior in the premotor phase. However, PAS administration did not modify reserpine-induced cognitive impairments. Moreover, PAS prevented the decrease in tyrosine hydroxylase immunostaining in the substantia nigra pars compacta (SNpc) induced by reserpine. Taken together, our results suggested that PAS exerted a neuroprotective effect in a progressive model of PD.

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Magnesium—Essentials for Anesthesiologists

Anesthesiology ◽

10.1097/aln.0b013e318210483d ◽

2011 ◽

Vol 114 (4) ◽

pp. 971-993 ◽

Cited By ~ 98

Author(s):

Susanne Herroeder ◽

Marianne E. Schönherr ◽

Stefan G. De Hert ◽

Markus W. Hollmann ◽

David S. Warner

Keyword(s):

Clinical Trials ◽

Clinical Medicine ◽

Current Knowledge ◽

Experimental Studies ◽

Torsades De Pointes ◽

Cellular Functions ◽

Neuroprotective Effects ◽

Positive Effects ◽

Disease States ◽

Current Review

Magnesium plays a fundamental role in many cellular functions, and thus there is increasing interest in its role in clinical medicine. Although numerous experimental studies indicate positive effects of magnesium in a variety of disease states, large clinical trials often give conflicting results. However, there is clear evidence for magnesium to benefit patients with eclampsia or torsades de pointes arrhythmias. In addition, magnesium seems to have antinociceptive and anesthetic as well as neuroprotective effects, yet well-designed large clinical trials are required to determine its actual efficacy in pain management or in the state of stroke or subarachnoid hemorrhage. The current review aims to provide an overview of current knowledge and available evidence with respect to physiologic aspects of magnesium and proposed indications and recommendations for its use in the clinical setting.

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High-Intensity Exercise Training Protects The Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-Inflammatory Functions

10.21203/rs.3.rs-116002/v1 ◽

2020 ◽

Author(s):

Yifat Zaychik ◽

Nina Fainstein ◽

Olga Touloumi ◽

Yehuda Goldberg ◽

Liel Hamdi ◽

...

Keyword(s):

T Cells ◽

Exercise Training ◽

High Intensity ◽

Inflammatory Responses ◽

Ex Vivo ◽

Treadmill Running ◽

Clinical Severity ◽

Continuous Training ◽

Neuroprotective Effects ◽

Ros Formation

Abstract Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia.Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)- reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary and HICT healthy mice, as well as 5-days post EAE induction (prior to onset of disease) were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines. Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein in response to PLP-stimulation.Conclusions: HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity and pro-inflammatory responses involved in propagation of autoimmune neuroinflammation.

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Transcriptional Repression by DrosophilaMethyl-CpG-Binding Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.20.19.7401-7409.2000 ◽

2000 ◽

Vol 20 (19) ◽

pp. 7401-7409 ◽

Cited By ~ 32

Author(s):

Karim Roder ◽

Ming-Shiu Hung ◽

Tai-Lin Lee ◽

Tzu-Yang Lin ◽

Hengyi Xiao ◽

...

Keyword(s):

Transcriptional Repression ◽

Binding Proteins ◽

Genomic Structure ◽

Chromatin Condensation ◽

Cellular Functions ◽

Developmentally Regulated ◽

Cpg Dinucleotides ◽

Alternatively Spliced ◽

Mbd Proteins

ABSTRACT C methylation at genomic CpG dinucleotides has been implicated in the regulation of a number of genetic activities during vertebrate cell differentiation and embryo development. The methylated CpG could induce chromatin condensation through the recruitment of histone deacetylase (HDAC)-containing complexes by methyl-CpG-binding proteins. These proteins consist of the methylated-DNA binding domain (MBD). Unexpectedly, however, several studies have identified MBD-containing proteins encoded by genes of Drosophila melanogaster, an invertebrate species supposed to be void of detectable m5CpG. We now report the genomic structure of aDrosophila gene, dMBD2/3, that codes for two MBD-containing, alternatively spliced, and developmentally regulated isoforms of proteins, dMBD2/3 and dMBD2/3Δ. Interestingly, in vitro binding experiments showed that as was the case for vertebrate MBD proteins, dMBD2/3Δ could preferentially recognize m5CpG-containing DNA through its MBD. Furthermore, dMBD2/3Δ as well as one of its orthologs in mouse, MBD2b, could function in human cells as a transcriptional corepressor or repressor. The activities of HDACs appeared to be dispensable for transcriptional repression by dMBD2/3Δ. Finally, dMBD2/3Δ also could repress transcription effectively in transfectedDrosophila cells. The surprisingly similar structures and characteristics of the MBD proteins as well as DNA cytosine (C-5) methyltransferase-related proteins in Drosophila and vertebrates suggest interesting scenarios for their roles in eukaryotic cellular functions.

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Human Co-culture Model of Neurons and Astrocytes to Test Acute Cytotoxicity of Neurotoxic Compounds

International Journal of Toxicology ◽

10.1177/1091581817739428 ◽

2017 ◽

Vol 36 (6) ◽

pp. 463-477 ◽

Cited By ~ 10

Author(s):

Uliana De Simone ◽

Francesca Caloni ◽

Laura Gribaldo ◽

Teresa Coccini

Keyword(s):

Cell Line ◽

Cell Morphology ◽

Cell Model ◽

Culture Conditions ◽

Test Method ◽

Alternative Methods ◽

Mitochondrial Activity ◽

Neuroprotective Effects ◽

Toxicological Studies

Alternative methods and their use in planning and conducting toxicology experiments have become essential for modern toxicologists, thus reducing or replacing living animals. Although in vitro human co-culture models allow the establishment of biologically relevant cell–cell interactions that recapitulate the tissue microenvironment and better mimic its physiology, the number of publications is limited specifically addressing this scientific area and utilizing this test method which could provide an additional valuable model in toxicological studies. In the present study, an in vitro model based on central nervous system (CNS) cell co-cultures was implemented using a transwell system combining human neuronal cells (SH-SY5Y cell line) and glial cells, namely astrocytes (D384 cell line), to investigate neuroprotection of D384 on SH-SY5Y and vice versa. The model was applied to test acute (24-48 hours) cytotoxicity of 3 different neurotoxicants: (1) methyl mercury (1-2.5 μM), (2) Fe3O4 nanoparticles (1-100 μg/mL), and (3) methylglyoxal (0.5-1 mM). Data were compared to mono-cultures evaluating the mitochondrial function and cell morphology. The results clearly showed that all compounds tested affected the mitochondrial activity and cell morphology in both mono-culture and co-culture conditions. However, astrocytes, when cultured together with neurons, diminish the neurotoxicant-induced cytotoxic effects that occurred in neurons cultured alone, and astrocytes become more resistant in the presence of neurons. This human CNS co-culture system seems a suitable cell model to feed high-throughput acute screening platforms and to evaluate both human neuronal and astrocytic toxicity and neuroprotective effects of new and emerging materials (eg, nanomaterials) and new products with improved sensitivity due to the functional neuron–astrocyte metabolic interactions.

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1,6-hexanediol rapidly immobilizes and condenses chromatin in living human cells

Life Science Alliance ◽

10.26508/lsa.202001005 ◽

2021 ◽

Vol 4 (4) ◽

pp. e202001005 ◽

Cited By ~ 2

Author(s):

Yuji Itoh ◽

Shiori Iida ◽

Sachiko Tamura ◽

Ryosuke Nagashima ◽

Kentaro Shiraki ◽

...

Keyword(s):

Liquid Droplet ◽

Chromatin Condensation ◽

Human Cells ◽

Dependent Manner ◽

Liquid Droplets ◽

Cellular Functions ◽

Spatiotemporal Regulation ◽

Dose Dependent ◽

Liquid Liquid Phase Separation

Liquid droplets formed inside the cell by liquid–liquid phase separation maintain membrane-less condensates/bodies (or compartments). These droplets are important for concentrating certain molecules and facilitating spatiotemporal regulation of cellular functions. 1,6-hexanediol (1,6-HD), an aliphatic alcohol, inhibits weak hydrophobic protein–protein/protein-RNA interactions required for the droplet formation (droplet melting activity) and is used here to elucidate the formation process of cytoplasmic/nuclear condensates/bodies. However, the effect of 1,6-HD on chromatin in living cells remains unclear. We found that 1,6-HD drastically suppresses chromatin motion and hyper-condenses chromatin in human cells by using live-cell single-nucleosome imaging, which detects changes in the state of chromatin. These effects were enhanced in a dose-dependent manner. Chromatin was “frozen” by 5%, or higher, concentrations of 1,6-HD. 1,6-HD greatly facilitated cation-dependent chromatin condensation in vitro. This 1,6-HD action is distinct from its melting activity of liquid droplets. Alcohols, such as 1,6-HD, appear to remove water molecules around chromatin and locally condense chromatin. Therefore, liquid droplet results obtained using 1,6-HD should be carefully interpreted or reconsidered when these droplets are associated with chromatin.

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Challenges of Combination Therapies in Alzheimer’s Disease

10.32545/encyclopedia202005.0004.v2 ◽

2020 ◽

Author(s):

Md. Sahab Uddin

Keyword(s):

Single Molecule ◽

Molecular Targets ◽

Symptomatic Treatment ◽

Therapeutic Agents ◽

Combination Therapies ◽

Neuroprotective Effects ◽

Randomized Controlled ◽

Long Duration ◽

Potential Benefits ◽

End Stage

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. It is indeed difficult to combine several pharmacophores into a single molecule.  It is essential to carry out long-duration randomized controlled trials to establish whether CT delays disease progression in early AD stages. Other factors also need to be assessed in CT, such as its potential neuroprotective effects, cost-effectiveness, and a more exhaustive estimation of its potential benefits on the patients at the end-stage of AD.

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