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BMC Neurology Jun 2024Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the...
BACKGROUND
Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient.
METHODS
All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1β) within 14 days after stroke onset.
RESULTS
Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1β, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05).
CONCLUSIONS
Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www.
CLINICALTRIALS
gov/ct2/show/NCT04175691 .
Topics: Humans; Edaravone; Male; Ischemic Stroke; Female; Aged; Middle Aged; Cytokines; Neuroprotective Agents; Treatment Outcome; Inflammation
PubMed: 38902691
DOI: 10.1186/s12883-024-03712-1 -
Microbiome Research Reports 2024The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report...
The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report on the added value of combining a microbiome screening model, the i-screen, with fresh intestinal tissue explants in a microfluidic gut-on-a-chip model, the Intestinal Explant Barrier Chip (IEBC). Adult human gut microbiome (fecal pool of 6 healthy donors) was cultured anaerobically in the i-screen platform for 24 h, without and with exposure to 4 mg/mL inulin. The i-screen cell-free culture supernatant was subsequently applied to the luminal side of adult human colon tissue explants ( = 3 donors), fixed in the IEBC, for 24 h and effects were evaluated. The supplementation of the media with inulin promoted the growth of , , , and in the i-screen, and triggered an elevated production of butyrate by the microbiota. Human colon tissue exposed to inulin-treated i-screen cell-free culture supernatant or control i-screen cell-free culture supernatant with added short-chain fatty acids (SCFAs) showed improved tissue barrier integrity measured by a 28.2%-34.2% reduction in FITC-dextran 4000 (FD4) leakage and 1.3 times lower transport of antipyrine. Furthermore, the release of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α was reduced under these circumstances. Gene expression profiles confirmed these findings, but showed more profound effects for inulin-treated supernatant compared to SCFA-supplemented supernatant. The combination of i-screen and IEBC facilitates the study of complex intestinal processes such as host-microbial metabolite interaction and gut health.
PubMed: 38841408
DOI: 10.20517/mrr.2023.79 -
International Journal of Molecular... May 2024Polyurethanes are among the most significant types of polymers in development; these materials are used to produce construction products intended for work in various... (Review)
Review
Polyurethanes are among the most significant types of polymers in development; these materials are used to produce construction products intended for work in various conditions. Nowadays, it is important to develop methods for fire load reduction by using new kinds of additives or monomers containing elements responsible for materials' fire resistance. Currently, additive antipyrines or reactive flame retardants can be used during polyurethane material processing. The use of additives usually leads to the migration or volatilization of the additive to the surface of the material, which causes the loss of the resistance and aesthetic values of the product. Reactive flame retardants form compounds containing special functional groups that can be chemically bonded with monomers during polymerization, which can prevent volatilization or migration to the surface of the material. In this study, reactive flame retardants are compared. Their impacts on polyurethane flame retardancy, combustion mechanism, and environment are described.
Topics: Flame Retardants; Polyurethanes; Green Chemistry Technology
PubMed: 38791552
DOI: 10.3390/ijms25105512 -
Chemistry & Biodiversity May 2024The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing...
The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing (4-arylazo-3-hydroxy-2-thienyl) 4-antipyrine ketones 1a, 1b and 1c and (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketones (2a, 2b and 2c) further replaced with six other coupling components, a broad spectrum of hybrid molecules have been created. Mass spectra, NMR, FTIR, and elemental analyses have all been used to confirm the structures of the synthesised compounds. The antimicrobial screening was investigated by agar well diffusion and diluting the broth technique against both Gram-negative and positive-tested bacterial strains. (3-methyl-5-(phenylamino)-4-(4-tolylazo)-2-thienyl) 4-antipyrine ketone (2a) was found to be superior to Ciprofloxacin against test strains: Acinetobacter sp (34.33 ±1.15 mm), Listeria monocytogenes (29.33 ±1.15 mm) and Streptococcus sp. (19.33 ±1.15 mm). Also, good to moderate activities were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) which were recorded at 9±1 to 59.67±4.51 µg/mL and 16±4 to > 512 µg/mL, respectively, using compounds 2a, 2b, and 2c. MBC/MIC ratio showed, that only, 2a and 2b have a bactericidal effect but other antipyrines with bacteriostatic strength. It was suggested that the use of these novel synthesized (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketone derivatives molecules as a new chemical class of antimicrobial agents.
PubMed: 38787357
DOI: 10.1002/cbdv.202400894 -
Neuropharmacology Sep 2024Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to...
Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aβ deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further in vitro investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.
Topics: Animals; Toll-Like Receptor 4; Mice; Male; Cognitive Dysfunction; Receptors, Immunologic; Membrane Glycoproteins; Edaravone; Up-Regulation; Mice, Transgenic; Neuroprotective Agents; MAP Kinase Signaling System; Hippocampus; Amyloid beta-Protein Precursor; Mice, Inbred C57BL; Alzheimer Disease; Disease Models, Animal; Presenilin-1
PubMed: 38763325
DOI: 10.1016/j.neuropharm.2024.110006 -
Talanta Aug 2024Hypoxanthine is a promising index for evaluating the freshness of various aquatic products. Combined the hydrogels containing upconversion nanoparticles (UCNPs), CoO...
Hypoxanthine is a promising index for evaluating the freshness of various aquatic products. Combined the hydrogels containing upconversion nanoparticles (UCNPs), CoO NPs, and N-ethyl-N-(3-sulfopropyl)-3-methylaniline sodium salt/4-amino-antipyrine (TOPS/4-AAP) with a smartphone, a portable sensor was developed for the convenient, sensitive detection of hypoxanthine. With the HO from xanthine oxidase (XOD)-catalyzed reactions of hypoxanthine, the fluorescence of UCNPs was effectively quenched by the purple product produced from the oxidization of TOPS/4-AAP catalyzed by CoO NPs exhibiting peroxidase activity, among which the color change could be transformed into digital signals for quantification of hypoxanthine. The Green value in the RGB analysis of the fluorescence image was negatively proportional to hypoxanthine concentration in the range of 2.5-20 mg/L with a detection limit of 0.69 mg/L and a quantitation limit of 2.30 mg/L. Finally, this sensor was applied for hypoxanthine detection in real aquatic products, showing potential application for freshness evaluation of aquatic products.
Topics: Smartphone; Hypoxanthine; Hydrogels; Oxides; Cobalt; Fluorescence; Limit of Detection; Nanoparticles; Animals; Spectrometry, Fluorescence; Hydrogen Peroxide
PubMed: 38761664
DOI: 10.1016/j.talanta.2024.126259 -
Journal of Pharmaceutical Sciences May 2024The olfactory and trigeminal pathways are direct delivery pathways between the nose and brain. To determine the effect of direct delivery on drug distribution in the...
The olfactory and trigeminal pathways are direct delivery pathways between the nose and brain. To determine the effect of direct delivery on drug distribution in the brain, two model drugs with different physical properties, antipyrine (ANP), with high membrane permeability, and ranitidine (RNT), with low membrane permeability, were selected. For ANP, direct delivery from the nose to the brain was observed only in the olfactory bulb beside the nasal cavity, with a direct transport percentage (DTP) of approximately 45 %, whereas in the frontal and occipital brains, the contribution from the systemic circulation to the brain was observed as the primary route of brain distribution. No significant variations were observed in the pharmacokinetics of ANP in the left and right brain, whereas RNT was distributed in all brain regions with a DTP of > 95 %. The closer the brain region is to the nasal cavity, the higher the DTP. Furthermore, the left brain, the same nostril site (left nostril) of administration, had a larger level of drug delivery than the right brain. These findings imply that the influence of the administered nostril site differs based on the physicochemical properties and amount of the drug.
PubMed: 38734208
DOI: 10.1016/j.xphs.2024.05.003 -
Journal of Stroke and Cerebrovascular... Jul 2024Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain...
OBJECTIVES
Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain unclear. We evaluated whether edaravone dexborneol has a neuroprotective effect in intracerebral hemorrhage, and its underlying mechanisms.
MATERIALS AND METHODS
Bioinformatics were used to predict the pathway of action of edaravone dexborneol. An intracerebral hemorrhage model was established using type IV collagenase in edaravone dexborneol, intracerebral hemorrhage, Sham, adeno-associated virus + edaravone dexborneol, and adeno-associated virus + intracerebral hemorrhage groups. The modified Neurological Severity Score was used to evaluate neurological function in rats. Brain water content was measured using the dry-wet weight method. Tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and γ-aminobutyric acid levels were determined by enzyme-linked immunosorbent assay. The expression levels of neurofilament light chain and γ-aminobutyric acid transaminase were determined by western blot. Nissl staining was used to examine neuronal morphology. Cognitive behavior was evaluated using a small-animal treadmill.
RESULTS
Edaravone dexborneol alleviated neurological defects, improved cognitive function, and reduced cerebral edema, neuronal degeneration, and necrosis in rats with cerebral hemorrhage. The expression levels of neurofilament light chain, tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and γ-aminobutyric acid were decreased, while γ-aminobutyric acid transaminase expression was up-regulated.
CONCLUSIONS
Edaravone dexborneol regulates γ-aminobutyric acid content by acting on the γ-aminobutyric acid transaminase signaling pathway, thus alleviating oxidative stress, neuroinflammation, neuronal degeneration, and death caused by excitatory toxic injury of neurons after intracerebral hemorrhage.
Topics: Animals; Edaravone; Disease Models, Animal; Male; Rats, Sprague-Dawley; Neuroprotective Agents; Interleukin-1beta; Brain Edema; 4-Aminobutyrate Transaminase; Behavior, Animal; Cerebral Hemorrhage; Anti-Inflammatory Agents; Cognition; Brain; Nitric Oxide Synthase Type II; Signal Transduction; Tumor Necrosis Factor-alpha; Inflammation Mediators
PubMed: 38701940
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107738 -
American Journal of TherapeuticsAmyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include... (Review)
Review
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.
MECHANISM OF ACTION
The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.
PHARMACOKINETICS
Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.
CLINICAL TRIALS
The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.
THERAPEUTIC ADVANCE
Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.
Topics: Edaravone; Humans; Amyotrophic Lateral Sclerosis; Neuroprotective Agents; Administration, Oral; Suspensions; Biological Availability
PubMed: 38691665
DOI: 10.1097/MJT.0000000000001742 -
Biomolecules Apr 2024A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS)....
A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions.
Topics: Animals; Humans; Mice; Antioxidants; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Edaravone; Molecular Docking Simulation; Molecular Dynamics Simulation; NF-E2-Related Factor 2; Receptors, Aryl Hydrocarbon; Signal Transduction; Zebrafish
PubMed: 38672460
DOI: 10.3390/biom14040443