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CNS Neuroscience & Therapeutics Sep 2023Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared...
INTRODUCTION
Previous research has suggested that vanishing white matter disease (VWMD) astrocytes fail to fully differentiate and respond differently to cellular stresses compared to healthy astrocytes. However, few studies have investigated potential VWMD therapeutics in monoculture patient-derived cell-based models.
METHODS
To investigate the impact of alterations in astrocyte expression and function in VWMD, astrocytes were differentiated from patient and control induced pluripotent stem cells and analyzed by proteomics, pathway analysis, and functional assays, in the absence and presence of stressors or potential therapeutics.
RESULTS
Vanishing white matter disease astrocytes demonstrated significantly reduced expression of astrocyte markers and markers of inflammatory activation or cellular stress relative to control astrocytes. These alterations were identified both in the presence and absence of polyinosinic:polycytidylic acid stimuli, which is used to simulate viral infections. Pathway analysis highlighted differential signaling in multiple pathways in VWMD astrocytes, including eukaryotic initiation factor 2 (EIF2) signaling, oxidative stress, oxidative phosphorylation (OXPHOS), mitochondrial function, the unfolded protein response (UPR), phagosome regulation, autophagy, ER stress, tricarboxylic acid cycle (TCA) cycle, glycolysis, tRNA signaling, and senescence pathways. Since oxidative stress and mitochondrial function were two of the key pathways affected, we investigated whether two independent therapeutic strategies could ameliorate astrocyte dysfunction: edaravone treatment and mitochondrial transfer. Edaravone treatment reduced differential VWMD protein expression of the UPR, phagosome regulation, ubiquitination, autophagy, ER stress, senescence, and TCA cycle pathways. Meanwhile, mitochondrial transfer decreased VWMD differential expression of the UPR, glycolysis, calcium transport, phagosome formation, and ER stress pathways, while further modulating EIF2 signaling, tRNA signaling, TCA cycle, and OXPHOS pathways. Mitochondrial transfer also increased the gene and protein expression of the astrocyte marker, glial fibrillary acidic protein (GFAP) in VWMD astrocytes.
CONCLUSION
This study provides further insight into the etiology of VWMD astrocytic failure and suggests edaravone and mitochondrial transfer as potential candidate VWMD therapeutics that can ameliorate disease pathways in astrocytes related to oxidative stress, mitochondrial dysfunction, and proteostasis.
Topics: Humans; Astrocytes; Edaravone; Eukaryotic Initiation Factor-2; Leukoencephalopathies; Mitochondria; White Matter
PubMed: 36971196
DOI: 10.1111/cns.14190 -
Chemosphere Nov 2023In recent years, heterogeneous electro-Fenton processes have gained considerable attention as an alternative to homogeneous processes. In this context, the aim of this...
In recent years, heterogeneous electro-Fenton processes have gained considerable attention as an alternative to homogeneous processes. In this context, the aim of this study is the use of a commercial iron metal-organic framework (Fe-MOF), Basolite® F-300, as a base material for the design of a heterogeneous electro-Fenton treatment system for the removal of antipyrine. Initially, the catalyst was applied as powder in aqueous solution and three key parameters of the electro-Fenton process (pH, Fe-MOF concentration and current density) were evaluated and optimized by a Central Composite Design Face Centred (CCD-FC) using antipyrine removal and energy consumption as response functions. Near complete antipyrine removal (94%) was achieved under optimal conditions: pH 3, Fe-MOF 157.78 mg/L and current density 6.67 mA/cm, obtaining an energy consumption of 0.29 W·h per mg of antipyrine removed. Later, two electrocatalysts (Fe-MOF functionalized cathodes), prepared by different Fe-MOF immobilisation approaches (composite of carbon black/polytetrafluoroethylene or by electrospinning on Ni foam), were synthesized. Their characterisation showed notable Fe-MOF incorporation into the material and favourable properties as electrocatalysts. Both Fe-MOF functionalized cathodes were evaluated in the removal of antipyrine at different pH (acidic and natural) and current density (27.78 and 55.56 mA/cm), achieving in the best conditions removal levels around 80% in 1 h without any operational problems. In addition, several intermediates generated during the treatment were identified and their toxicity estimated. According to the obtained results, the degradation compounds have less toxicity than the parent compounds, confirming the effectiveness of the treatment.
Topics: Antipyrine; Electrodes; Iron; Metal-Organic Frameworks; Powders
PubMed: 37634590
DOI: 10.1016/j.chemosphere.2023.139942 -
The Journal of Antimicrobial... Sep 2023Resistance genes can be genetically transmitted and exchanged between commensal and pathogenic bacterial species, and in different compartments including the...
OBJECTIVES
Resistance genes can be genetically transmitted and exchanged between commensal and pathogenic bacterial species, and in different compartments including the environment, or human and animal guts (One Health concept). The aim of our study was to evaluate whether subdosages of antibiotics administered in veterinary medicine could enhance plasmid transfer and, consequently, resistance gene exchange in gut microbiota.
METHODS
Conjugation frequencies were determined with Escherichia coli strains carrying IncL- (blaOXA-48) or IncI1-type (blaCTX-M-1) plasmids subjected to a series of subinhibitory concentrations of antibiotics used in veterinary medicine, namely amoxicillin, ceftiofur, apramycin, neomycin, enrofloxacin, colistin, erythromycin, florfenicol, lincomycin, oxytetracycline, sulfamethazine, tiamulin and the ionophore narasin. Treatments with subinhibitory dosages were performed with and without supplementation with the antioxidant edaravone, known as a mitigator of the inducibility effect of several antibiotics on plasmid conjugation frequency (PCF). Expression of SOS-response associated genes and fluorescence-based reactive oxygen species (ROS) detection assays were performed to evaluate the stress oxidative response.
RESULTS
Increased PCFs were observed for both strains when treating with florfenicol and oxytetracycline. Increased expression of the SOS-associated recA gene also occurred concomitantly, as well as increased ROS production. Addition of edaravone to the treatments reduced their PCF and also showed a decreasing effect on SOS and ROS responses for both plasmid scaffolds.
CONCLUSIONS
We showed here that some antibiotics used in veterinary medicine may induce transfer of plasmid-encoded resistance and therefore may contribute to the worldwide spread of antibiotic resistance genes.
Topics: Animals; Humans; Anti-Bacterial Agents; Oxytetracycline; Edaravone; Reactive Oxygen Species; Escherichia coli; Plasmids; Drug Resistance, Microbial; Gene Transfer, Horizontal
PubMed: 37486104
DOI: 10.1093/jac/dkad226 -
International Immunopharmacology Mar 2024Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells....
Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1β, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.
Topics: Animals; Mice; Male; Microglia; Edaravone; Astrocytes; Brain Ischemia; Neuroinflammatory Diseases; Mice, Inbred C57BL; Stroke; Infarction, Middle Cerebral Artery; Inflammation; Leukocytes
PubMed: 38382262
DOI: 10.1016/j.intimp.2024.111700 -
Journal of Enzyme Inhibition and... Dec 2023A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (, 1,3,4-thiadiazoles (-, and pyrimidines (-, was preparedand assessed for its potential COX-2...
Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents.
A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (, 1,3,4-thiadiazoles (-, and pyrimidines (-, was preparedand assessed for its potential COX-2 inhibitors. Compared to Celecoxib, compounds and were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds and were chosen among these most potent derivatives for further investigation. The ability of compounds and to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.
Topics: Humans; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antipyrine; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Design; Edema; Molecular Docking Simulation; Structure-Activity Relationship
PubMed: 36633257
DOI: 10.1080/14756366.2022.2162511 -
International Journal of Molecular... Jan 2024Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances... (Review)
Review
Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.
Topics: Humans; Edaravone; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Antioxidants; Neoplasms; Free Radical Scavengers
PubMed: 38338912
DOI: 10.3390/ijms25031633 -
Chemosphere Sep 2023Bifunctional perovskite/carbon-black(CB)/polytetrafluoroethylene(PTFE) electrodes for electro-generation and catalytic decomposition of hydrogen peroxide to oxidizing...
Bifunctional perovskite/carbon-black(CB)/polytetrafluoroethylene(PTFE) electrodes for electro-generation and catalytic decomposition of hydrogen peroxide to oxidizing hydroxyl radicals have been fabricated. These electrodes were tested for electroFenton (EF) removal of antipyrine (ANT) as a model antipyretic and analgesic drug. The influence of the binder loading (20 and 40 wt % PTFE) and type of solvent (1,3-dipropanediol and water) was studied for the preparation of CB/PTFE electrodes. The electrode prepared with 20 wt % PTFE and water exhibited a low impedance and remarkable HO electro-generation (about 1 g/L after 240 min, a production rate of ca. 6.5 mg/h·cm). The incorporation of perovskite on CB/PTFE electrodes was also studied following two different methods: i) direct deposition on the CB/PTFE electrode surface and ii) addition in the own CB/PTFE/water paste used for the fabrication. Physicochemical and electrochemical characterization techniques were used for the electrode's characterization. The dispersion of perovskite particles in the own electrode matrix (method ii) exhibited a higher EF performance than the immobilisation onto the electrode surface (method i). EF experiments at 40 mA/cm and pH 7 (non-acidified conditions) showed ANT and TOC removals of 30% and 17%, respectively. The increase of current intensity up to 120 mA/cm achieved the complete removal of ANT and 92% of TOC mineralisation in 240 min. The bifunctional electrode also proved high stability and durability after 15 h of operation.
Topics: Carbon; Antipyrine; Hydrogen Peroxide; Oxidation-Reduction; Water Pollutants, Chemical; Water; Electrodes; Polytetrafluoroethylene
PubMed: 37178935
DOI: 10.1016/j.chemosphere.2023.138858 -
Medicina (Kaunas, Lithuania) Feb 2024Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation... (Review)
Review
Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.
Topics: Humans; Edaravone; Antioxidants; Oxidative Stress; Eye Diseases; Retinal Diseases; Ophthalmic Solutions
PubMed: 38541080
DOI: 10.3390/medicina60030354 -
Behavioural Neurology 2023Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades....
Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.
Topics: Rats; Male; Mice; Animals; Edaravone; Streptozocin; Antioxidants; Memantine; Rats, Wistar; Donepezil; Oxidative Stress; Memory Disorders; Alzheimer Disease; Inflammation; Maze Learning; Disease Models, Animal
PubMed: 37476485
DOI: 10.1155/2023/9652513 -
Molecules (Basel, Switzerland) Oct 2023Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate...
Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues - showing three substitution patterns -, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate , 4'-ester 2c and N-carbamate-4'-ester were further characterized, justifying their in vitro effects and selecting as a putative EDA 1 prodrug suitable for in vivo testing.
Topics: Humans; Edaravone; Antioxidants; Amyotrophic Lateral Sclerosis; Oxidative Stress; Esters
PubMed: 37836771
DOI: 10.3390/molecules28196928