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Cells Feb 2023Ferroptosis induced by erastin (an inhibitor of cystine transport) and butionine sulfoximine (an inhibitor of glutathione biosynthesis) was prevented by the...
Ferroptosis induced by erastin (an inhibitor of cystine transport) and butionine sulfoximine (an inhibitor of glutathione biosynthesis) was prevented by the mitochondria-targeted antioxidants SkQ1 and MitoTEMPO. These effects correlate with the prevention of mitochondrial lipid peroxidation, which precedes cell death. Methylene blue, a redox agent that inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, also inhibits ferroptosis and mitochondrial lipid peroxidation. Activation of ROS production in complex I with rotenone in the presence of ferrous iron stimulates lipid peroxidation in isolated mitochondria, while ROS produced by complex III are ineffective. SkQ1 and methylene blue inhibit lipid peroxidation. We suggest that ROS formed in complex I promote mitochondrial lipid peroxidation and ferroptosis.
Topics: Lipid Peroxidation; Ferroptosis; Reactive Oxygen Species; Methylene Blue; Mitochondria
PubMed: 36831278
DOI: 10.3390/cells12040611 -
Molecules (Basel, Switzerland) May 2022The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the...
The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-'-arylaminophenothiazines and asymmetrical 3,7-di('-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-'-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-'-arylaminophenothiazines and asymmetrical 3,7-di('-arylamino)phenothiazines containing ester, -butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields.
Topics: Antipsychotic Agents; Methylene Blue; Phenothiazines
PubMed: 35566375
DOI: 10.3390/molecules27093024 -
International Journal of Molecular... May 2021The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new...
The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride () and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds and with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of , two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of , sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents.
Topics: Amines; DNA; Dimerization; Intercalating Agents; Magnetic Resonance Spectroscopy; Methylene Blue; Models, Molecular; Molecular Conformation; Molecular Structure; Spectrometry, Fluorescence; Structure-Activity Relationship
PubMed: 34072560
DOI: 10.3390/ijms22115847 -
Medicine Jan 2022Septic shock is a lethal disease responsible for a large proportion of deaths in the Intensive Care Unit (ICU), even with therapy centered on fluid resuscitation, use of...
INTRODUCTION
Septic shock is a lethal disease responsible for a large proportion of deaths in the Intensive Care Unit (ICU), even with therapy centered on fluid resuscitation, use of vasopressors and empirical antibiotic therapy applied within the first hour of diagnosis. Considering the multifactorial pathophysiology of septic shock and the mechanism of action of vasopressors, some patients may not respond adequately, which can lead to the maintenance of vasodilatation, hypotension and increased morbidity, and mortality. This protocol aims to verify whether the use of methylene blue in septic patients with an early diagnosis can contribute to an earlier resolution of a shock compared to standard treatment.
METHODS AND ANALYSIS
This is a study protocol for a single-center randomized clinical trial design in an ICU of a tertiary university hospital. In this study, we intend to include 64 patients aged between 18 and 80 years with a diagnosis of septic shock, of any etiology, with up to 72 hours of evolution after volume restoration, using norepinephrine at a dose ≥0.2 μg/kg/min and vasopressin at a dose of 0.04 IU/min. After the initial approach, we will randomize patients into two groups, standard care, and standard care plus methylene blue. The sample size was calculated in order to show 30% differences in septic shock resolution between groups. The Research Ethics Committee approved the study, and all patients included will sign an informed consent form (Clinical registration: RBR-96584w4).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Hemodynamics; Humans; Hypotension; Methylene Blue; Middle Aged; Norepinephrine; Randomized Controlled Trials as Topic; Shock, Septic; Vasoconstrictor Agents; Young Adult
PubMed: 35060528
DOI: 10.1097/MD.0000000000028599 -
PloS One 2022Adhesion is a primary challenge following surgery, and the anti-adhesive effect of methylene blue (MB) has been investigated. This systematic review and meta-analysis... (Meta-Analysis)
Meta-Analysis
Adhesion is a primary challenge following surgery, and the anti-adhesive effect of methylene blue (MB) has been investigated. This systematic review and meta-analysis aimed to evaluate the effect of MB on postoperative adhesions in experimental studies. We initially searched OVID-MEDLINE, EMBASE, and Google Scholar in February 2021, and then in May 2021. The anti-adhesive efficacy of MB was compared with that of the control (either placebo or nothing) after the surgical procedure. The primary and secondary outcomes were the macroscopic and microscopic adhesion scores, respectively. Traditional meta-analysis, meta-regression, and trial sequential analysis (TSA) were performed to analyze the retrieved outcomes. We included 13 experimental studies of 367 rats (200 rats received MB and 167 rats received placebo or nothing). The macroscopic adhesion scores were significantly lower in the MB-administered group than in the control group (standardized mean difference, 2.313; 95% confidence interval, 1.104 to3.523; I2 = 94.0%, Tau = 2.059). Meta-regression analysis showed that macroscopic adhesion tended to decrease with an increase in MB dose. TSA demonstrated that the cumulative Z curve crossed both the conventional test and trial sequential monitoring boundary for the macroscopic adhesion score. MB had a beneficial effect on intraperitoneal adhesion following laparotomy, and adhesions decreased with increase in dose.
Topics: Animals; Laparotomy; Methylene Blue; Rats; Tissue Adhesions
PubMed: 35588404
DOI: 10.1371/journal.pone.0268178 -
Pediatric Critical Care Medicine : a... Jun 2020Shock refractory to fluid and catecholamine therapy has significant morbidity and mortality in children. The use of methylene blue to treat refractory shock in children...
OBJECTIVES
Shock refractory to fluid and catecholamine therapy has significant morbidity and mortality in children. The use of methylene blue to treat refractory shock in children is not well described. We aim to collect and summarize the literature and define physicians' practice patterns regarding the use of methylene blue to treat shock in children.
DESIGN
We conducted a systematic search of MEDLINE, Embase, PubMed, Web of Science, Cochrane for studies involving the use of methylene blue for catecholamine-refractory shock from database inception to 2019. Collected studies were analyzed qualitatively. To describe practice patterns of methylene blue use, we electronically distributed a survey to U.S.-based pediatric critical care physicians. We assessed physician knowledge and experience with methylene blue. Survey responses were quantitatively and qualitatively evaluated.
SETTING
Pediatric critical and cardiac care units.
PATIENTS OR SUBJECTS
Patients less than or equal to 25 years old with refractory shock treated with methylene blue.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
One-thousand two-hundred ninety-three abstracts met search criteria, 139 articles underwent full-text review, and 24 studies were included. Studies investigated refractory shock induced by a variety of etiologies and found that methylene blue was generally safe and increased mean arterial blood pressure. There is overall lack of studies, low number of study patients, and low quality of studies identified. Our survey had a 22.5% response rate, representing 125 institutions. Similar proportions of physicians reported using (40%) or never even considering (43%) methylene blue for shock. The most common reasons for not using methylene blue were unfamiliarity with this drug, its proper dosing, and lack of evidentiary support.
CONCLUSIONS
Methylene blue appears safe and may benefit children with refractory shock. There is a stark divide in familiarity and practice patterns regarding its use among physicians. Studies to formally assess safety and efficacy of methylene blue in treating pediatric shock are warranted.
Topics: Adult; Catecholamines; Child; Humans; Methylene Blue; Shock; Surveys and Questionnaires
PubMed: 32453920
DOI: 10.1097/PCC.0000000000002295 -
Progress in Neurobiology Jan 2012This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have... (Review)
Review
This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue's action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.
Topics: Animals; Antioxidants; Brain; Dose-Response Relationship, Drug; Humans; Memory; Methylene Blue; Molecular Structure; Neuroprotective Agents; Nootropic Agents; Oxidation-Reduction; Oxidative Stress
PubMed: 22067440
DOI: 10.1016/j.pneurobio.2011.10.007 -
Bioconjugate Chemistry Nov 2018We recently reported a real-time method to measure heparin in human whole blood based on the photoacoustic change of methylene blue (MB). Intriguingly, the MB behaved...
We recently reported a real-time method to measure heparin in human whole blood based on the photoacoustic change of methylene blue (MB). Intriguingly, the MB behaved unlike other "turn on" photoacoustic probes-the absorbance decreased as the photoacoustic signal increased. The underlying mechanism was not clear and motivated this study. We studied the binding mechanism of MB and heparin in water and phosphate buffer saline (PBS) with both experimental and computational methods. We found that the photoacoustic enhancement of the MB-heparin mixture was a result of MB-heparin aggregation due to charge neutralization and resulting sequestration of MB in these aggregates. The sequestration of MB in the MB-heparin aggregates led to decreased absorbance-there was simply less free dye in solution to absorb light. The highest photoacoustic signal and aggregation occurred when the number of negatively charged sulfate groups on heparin was approximately equal to the number of positively charged MB molecule. The MB-heparin aggregates dissociated when there were more sulfated groups from heparin than MB molecules because of the electrostatic repulsion between negatively charged sulfate groups. PBS facilitated MB dimer formation regardless of heparin concentration and reprecipitated free MB in aggregates due to ionic strength and ionic shielding. Further molecular dynamics experiments found that binding of heparin occurred at the sulfates and glucosamines in heparin. Phosphate ions could interact with the heparin via sodium ions to impair the MB-heparin binding. Finally, our model found 3.7-fold more MB dimerization upon addition of heparin in MB solution confirming that heparin facilitates MB aggregation. We conclude that the addition of heparin in MB decreases the absorbance of the sample because of MB-heparin aggregation leading to fewer MB molecules in solution; however, the aggregation also increases the PA intensity because the MB molecules in the MB-heparin aggregate have reduced degrees of freedom and poor heat transfer to solvent.
Topics: Anticoagulants; Binding Sites; Coloring Agents; Dimerization; Heparin; Kinetics; Methylene Blue; Molecular Docking Simulation; Photoacoustic Techniques
PubMed: 30281976
DOI: 10.1021/acs.bioconjchem.8b00639 -
Drug Delivery and Translational Research Oct 2020Following skin injury, the overproduction of reactive oxygen species (ROS) during the inflammatory phase can cause tissue damage and delay in wound healing. Methylene...
Following skin injury, the overproduction of reactive oxygen species (ROS) during the inflammatory phase can cause tissue damage and delay in wound healing. Methylene blue (MB) decreases mitochondrial ROS production and has antioxidant effects. The authors aimed to prepare MB-loaded niosomes using the ultra-sonication technique as a green formulation method. A Box-Behnken design was selected to optimize formulation variables. The emulsifier to cholesterol ratio, HLB of mixed surfactants (Span 60 and Tween 60), and sonication time were selected as independent variables. Vesicle size, zeta potential (ZP), and drug entrapment capacity percentage were studied as dependent variables. The optimized formulation of niosomes showed spherical shape with optimum vesicle size of 147.8 nm, ZP of - 18.0 and entrapment efficiency of 63.27%. FTIR study showed no observable interaction between MB and other ingredients. In vivo efficacy of optimized formulation was evaluated using an excision wound model in male Wistar rat. Superoxide dismutase (SOD, an endogenous antioxidant) and malondialdehyde (MDA, an end product of lipid peroxidation) levels in skin tissue samples were evaluated. After 3 days, MDA was significantly decreased in niosomal gel-treated group, whereas SOD level was increased. Histological results indicate rats that received niosomal MB were treated effectively faster than other ones. Graphical abstract.
Topics: Animals; Drug Delivery Systems; Green Chemistry Technology; Liposomes; Male; Methylene Blue; Particle Size; Rats; Rats, Wistar; Skin; Wound Healing
PubMed: 32100265
DOI: 10.1007/s13346-020-00715-6 -
Medicinal Research Reviews Jan 2011Methylene Blue (MB), following its introduction to biology in the 19th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the... (Review)
Review
Methylene Blue (MB), following its introduction to biology in the 19th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the first line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide-induced encephalopathy, and is routinely employed as a diagnostic tool in surgical procedures. Furthermore, recent studies suggest that MB has beneficial effects in Alzheimer's disease and memory improvement. Although the modulation of the cGMP pathway is considered the most significant effect of MB, mediating its pharmacological actions, recent studies indicate that it has multiple cellular and molecular targets. In the majority of cases, biological effects and clinical applications of MB are dictated by its unique physicochemical properties including its planar structure, redox chemistry, ionic charges, and light spectrum characteristics. In this review article, these physicochemical features and the actions of MB on multiple cellular and molecular targets are discussed with regard to their relevance to the nervous system.
Topics: Alzheimer Disease; Animals; Humans; Ifosfamide; Methemoglobinemia; Methylene Blue; Neurons
PubMed: 19760660
DOI: 10.1002/med.20177