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Critical Care (London, England) Mar 2023Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its' optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock.
METHODS
In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days.
RESULTS
Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59-83] vs 94 h [IQR 74-141]; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration.
CONCLUSION
In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.
Topics: Humans; Shock, Septic; Methylene Blue; Vasoconstrictor Agents; Sepsis
PubMed: 36915146
DOI: 10.1186/s13054-023-04397-7 -
Cells Dec 2021Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining,... (Review)
Review
Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increaseding oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. This review summarizes the recent studies on the applications of MB in treating age-related conditions, including neurodegeneration, memory loss, skin aging, and a premature aging disease, progeria.
Topics: Aging; Animals; Brain; Humans; Methylene Blue; Models, Biological; Skin Aging
PubMed: 34943887
DOI: 10.3390/cells10123379 -
Methods in Molecular Biology (Clifton,... 2023The 1,9-dimethylmethylene blue (DMMB) assay enables the detection of sulfated glycosaminoglycans (sGAGs). This assay can be used to quickly quantify the sGAG content in...
The 1,9-dimethylmethylene blue (DMMB) assay enables the detection of sulfated glycosaminoglycans (sGAGs). This assay can be used to quickly quantify the sGAG content in a large number of samples using spectrophotometry. While this widespread assay appears straightforward, there are certain pitfalls that need to be considered.
Topics: Glycosaminoglycans; Methylene Blue; Spectrophotometry
PubMed: 36355288
DOI: 10.1007/978-1-0716-2839-3_9 -
Biomolecules Sep 2022It is important for clinicians to consider exposure to toxic substances and nutritional deficiencies when diagnosing and managing cases of vision loss. In these cases,... (Review)
Review
It is important for clinicians to consider exposure to toxic substances and nutritional deficiencies when diagnosing and managing cases of vision loss. In these cases, physiologic damage can alter the function of key components of the visual pathway before morphologic changes can be detected by traditional imaging methods. Electrophysiologic tests can aid in the early detection of such functional changes to visual pathway components, including the retina or optic nerve. This review provides an overview of various electrophysiologic techniques, including multifocal electroretinogram (mfERG), full-field ERG (ffERG), electrooculogram (EOG), pattern electroretinogram (PERG), and visual evoked potential (VEP) in monitoring the retinal and optic nerve toxicities of alcohol, amiodarone, cefuroxime, cisplatin, deferoxamine, digoxin, ethambutol, hydroxychloroquine, isotretinoin, ocular siderosis, pentosane, PDE5 inhibitors, phenothiazines (chlorpromazine and thioridazine), quinine, tamoxifen, topiramate, vigabatrin, and vitamin A deficiency.
Topics: Humans; Evoked Potentials, Visual; Ethambutol; Vigabatrin; Hydroxychloroquine; Thioridazine; Quinine; Cefuroxime; Isotretinoin; Topiramate; Phosphodiesterase 5 Inhibitors; Chlorpromazine; Cisplatin; Deferoxamine; Retina; Optic Nerve; Electrophysiology; Digoxin; Tamoxifen; Amiodarone
PubMed: 36291599
DOI: 10.3390/biom12101390 -
Journal of Biochemical and Molecular... Mar 2024Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on... (Review)
Review
Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of "off-target" effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non-electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non-electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress-mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas.
Topics: Antioxidants; Free Radical Scavengers; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Phenothiazines
PubMed: 38369721
DOI: 10.1002/jbt.23661 -
Anesthesia and Analgesia Jun 2020
Topics: Methylene Blue; Oximetry; Reading
PubMed: 32243292
DOI: 10.1213/ANE.0000000000004757 -
Toxicology Jun 2023The current review focuses on the effect of phenothiazine derivatives, tested in vitro, on necrosis and necroptosis, the latter constitutes one of the kinds of... (Review)
Review
The current review focuses on the effect of phenothiazine derivatives, tested in vitro, on necrosis and necroptosis, the latter constitutes one of the kinds of programmed cell death. Necroptosis is a necrotic and inflammatory type of programmed cell death. Phenothiazines are D1 and D2-like family receptor antagonists, which are used in the treatment of schizophrenia. Necroptosis begins from TNF-α, whose synthesis is stimulated by dopamine receptors, thus it can be concluded that phenothiazine derivatives may modulate necroptosis. We identified 19 papers reporting in vitro assays of necroptosis and necrosis in which phenothiazine derivatives, and both normal and cancer cell lines were used. Chlorpromazine, fluphenazine, levomepromazine, perphenazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate necroptosis and necrosis. The type of a drug, concentration and a cell line have an impact on the ultimate effect. Unfortunately, the authors confirmed both processes on the basis of TNF-α and ATP levels as well as the final steps of necrosis/necroptosis related to membrane permeability (PI staining, LDH release, and HMGB1 amount), which makes it impossible to understand the complete mechanism of phenothiazines impact on necroptosis and necrosis. Studies analyzing the effect of phenothiazines on RIPK1, RIPK3, or MLKL has not been performed yet. Only the analysis of the expression of those proteins as well as necrosis and necroptosis inhibitors can help us to comprehend how phenothiazine derivatives act, and how to improve their therapeutic potential.
Topics: Humans; Tumor Necrosis Factor-alpha; Necroptosis; Phenothiazines; Antipsychotic Agents; Necrosis
PubMed: 37127180
DOI: 10.1016/j.tox.2023.153528 -
Sensors (Basel, Switzerland) Apr 2020Suitable immobilization of a biorecognition element, such as an antigen or antibody, on a transducer surface is essential for development of sensitive and analytically... (Review)
Review
Suitable immobilization of a biorecognition element, such as an antigen or antibody, on a transducer surface is essential for development of sensitive and analytically reliable immunosensors. In this review, we report on (1) methods of antibody prefunctionalization using electroactive probes, (2) methods for immobilization of such conjugates on the surfaces of electrodes in electrochemical immunosensor construction and (3) the use of antibody-electroactive probe conjugates as bioreceptors and sensor signal generators. We focus on different strategies of antibody functionalization using the redox active probes ferrocene (Fc), anthraquinone (AQ), thionine (Thi), cobalt(III) bipyridine (Co(bpy)), Ru(bpy) and horseradish peroxidase (HRP). In addition, new possibilities for antibody functionalization based on bioconjugation techniques are presented. We discuss strategies of specific, quantitative antigen detection based on (i) a sandwich format and (ii) a direct signal generation scheme. Further, the integration of different nanomaterials in the construction of these immunosensors is presented. Lastly, we report the use of a redox probe strategy in multiplexed analyte detection.
Topics: Antibodies; Antibodies, Immobilized; Antigens; Electrochemical Techniques; Electrodes; Ferrous Compounds; Immunoassay; Metallocenes; Nanostructures; Oxidation-Reduction; Phenothiazines
PubMed: 32260217
DOI: 10.3390/s20072014 -
Experimental Neurology Nov 2023Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are...
BACKGROUND
Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are known to prevent the generation of free radicals and uptake of Ca by plasma membrane; they have a potential as a treatment for acute ischemic stroke (AIS). This study aims to investigate the role of endoplasmic reticulum (ER) stress-associated PERK-eIF2α pathway underlying the phenothiazine-induced neuroprotective effects after cerebral ischemia/reperfusion (I/R) injury.
METHODS
A total of 49 male Sprague Dawley rats (280-320 g) were randomly divided into 4 groups (n = 7 per group): (1) sham, (2) I/R that received 2 h of middle cerebral artery occlusion (MCAO), followed by 6 or 24 h of reperfusion, (3) MCAO treated by C + P without temperature control and (4) MCAO treated by C + P with temperature control. Human neuroblastoma (SH-SY5Y) cells were used in 5 groups: (1) control, (2) oxygen-glucose deprivation (OGD) for 2 h followed by reoxygenation (OGD/R), (3) OGD/R with C + P; (4) OGD/R with PERK inhibitor, GSK2656157, and (5) OGD/R with C + P and GSK2656157. The molecules of ER stress, unfolded protein response (UPR) (Bip, PERK, p-PERK, p-PERK/PERK, eIF2α, p-eIF2α, p-eIF2α/eIF2α), autophagy (ATG12, LC3II/I), and apoptosis (BAX, Bcl-XL) were measured at mRNA levels by real time PCR and protein levels by Western blotting.
RESULTS
In ischemic rats followed by reperfusion, expression of Bip, p-PERK/PERK, p-eIF2α/eIF2α, ATG12, and LC3II/I, as well as BAX were all significantly increased. These markers were significantly reduced by C + P at both 6 and 24 h of reperfusion. Anti-apoptotic Bcl-XL expression was increased, while pro-apoptotic BAX expression was decreased by C + P. In SH-SY5Y cell lines, both C + P and GSK2656157 significantly reduced the level of autophagy and apoptosis after I/R, respectively. The combination of GSK2656157 and C + P did not promote the same effect, suggesting that C + P did not induce any neuroprotective effect by inhibiting autophagy and apoptosis through the PERK-eIF2α pathway when this pathway was already blocked by GSK2656157. In general, the reduction in body temperature by phenothiazines was associated with better neuroprotection but it did not reach significant levels.
CONCLUSION
The combined treatment of C + P plays a crucial role in stroke therapy by inhibiting ER stress-mediated autophagy, thereby leading to reduced apoptosis and increased neuroprotection. Our findings highlight the PERK-eIF2α pathway as a central mechanism through which C + P exerts its beneficial effects. The results from this study may pave the way for the development of more targeted and effective treatments for stroke patients.
Topics: Animals; Humans; Male; Rats; Apoptosis; Autophagy; bcl-2-Associated X Protein; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Infarction, Middle Cerebral Artery; Ischemic Stroke; Neuroblastoma; Neuroprotective Agents; Phenothiazines; Rats, Sprague-Dawley; Reperfusion Injury
PubMed: 37673390
DOI: 10.1016/j.expneurol.2023.114524 -
Methods in Molecular Biology (Clifton,... 2023The ommochrome and porphyrin body pigments that give freshwater planarians their brown color are produced by specialized dendritic cells located just beneath the...
The ommochrome and porphyrin body pigments that give freshwater planarians their brown color are produced by specialized dendritic cells located just beneath the epidermis. During embryonic development and regeneration, differentiation of new pigment cells gradually darkens newly formed tissue. Conversely, prolonged light exposure ablates pigment cells through a porphyrin-based mechanism similar to the one that causes light sensitivity in rare human disorders called porphyrias. Here, we describe a novel program using image-processing algorithms to quantify relative pigment levels in live animals and apply this program to analyze changes in bodily pigmentation induced by light exposure. This tool will facilitate further characterization of genetic pathways that affect pigment cell differentiation, ommochrome and porphyrin biosynthesis, and porphyrin-based photosensitivity.
Topics: Animals; Humans; Planarians; Pigmentation; Phenothiazines; Porphyrins
PubMed: 37428383
DOI: 10.1007/978-1-0716-3275-8_16