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Journal of Photochemistry and... Mar 2021Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through...
Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through the generation of reactive oxygen species (ROS). Even after radiation, ROS generation may continue through activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme. Long-term exposure can progress to premature skin aging and photocarcinogenesis. To prevent damage that is caused by UVB radiation, several studies have focused on the topical administration of compounds that have antioxidant properties. 2-Acetylphenothiazine (ML171) is a potent and selective inhibitor of NOX1. The present study investigated the antioxidant potential and photoprotective ability of ML171 in UVB-irradiated L929 fibroblasts. ML171 had considerable antioxidant activity in both the DPPH and xanthine/luminol/xanthine oxidase assays. ML171 did not induce cytotoxicity in L929 fibroblasts and increased the viability of UVB-irradiated cells. ML171 also inhibited ROS production, the enzymatic activity of NOX, depolarization of the mitochondrial membrane, and DNA damage. Additionally, ML171 protected cell membrane integrity and induced fibroblast migration. These results suggest that the incorporation of ML171 in topical administration systems may be a promising strategy to mitigate UVB-induced oxidative damage in L929 fibroblasts.
Topics: Antioxidants; Apoptosis; Cell Line; DNA Damage; Fibroblasts; Humans; Lipid Peroxidation; NADPH Oxidases; Oxidants, Photochemical; Oxidation-Reduction; Oxidative Stress; Phenothiazines; Reactive Oxygen Species; Skin; Ultraviolet Rays
PubMed: 33561688
DOI: 10.1016/j.jphotobiol.2021.112130 -
Cells Nov 2019Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the... (Review)
Review
Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.
Topics: Adenocarcinoma; Animals; Basic Helix-Loop-Helix Transcription Factors; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Proteins; Pancreatic Neoplasms; Phenothiazines; Protein Transport; Xenograft Model Antitumor Assays
PubMed: 31744261
DOI: 10.3390/cells8111453 -
PLoS Computational Biology Oct 2022Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many...
Calmodulin (CaM) is a calcium sensor which binds and regulates a wide range of target-proteins. This implicitly enables the concentration of calcium to influence many downstream physiological responses, including muscle contraction, learning and depression. The antipsychotic drug trifluoperazine (TFP) is a known CaM inhibitor. By binding to various sites, TFP prevents CaM from associating to target-proteins. However, the molecular and state-dependent mechanisms behind CaM inhibition by drugs such as TFP are largely unknown. Here, we build a Markov state model (MSM) from adaptively sampled molecular dynamics simulations and reveal the structural and dynamical features behind the inhibitory mechanism of TFP-binding to the C-terminal domain of CaM. We specifically identify three major TFP binding-modes from the MSM macrostates, and distinguish their effect on CaM conformation by using a systematic analysis protocol based on biophysical descriptors and tools from machine learning. The results show that depending on the binding orientation, TFP effectively stabilizes features of the calcium-unbound CaM, either affecting the CaM hydrophobic binding pocket, the calcium binding sites or the secondary structure content in the bound domain. The conclusions drawn from this work may in the future serve to formulate a complete model of pharmacological modulation of CaM, which furthers our understanding of how these drugs affect signaling pathways as well as associated diseases.
Topics: Calmodulin; Trifluoperazine; Antipsychotic Agents; Calcium; Protein Binding; Binding Sites
PubMed: 36206305
DOI: 10.1371/journal.pcbi.1010583 -
Methylene blue as adjunctive therapy in septic shock: correct drug diluent derives optimal efficacy.Critical Care (London, England) Aug 2023
Topics: Humans; Methylene Blue; Shock, Septic; Dental Care; Patients
PubMed: 37644588
DOI: 10.1186/s13054-023-04615-2 -
Biotechnic & Histochemistry : Official... Nov 2024Romanowsky staining was an important methodological breakthrough in diagnostic hematology and cytopathology during the late 19 and early 20 centuries; it has facilitated... (Review)
Review
Romanowsky staining was an important methodological breakthrough in diagnostic hematology and cytopathology during the late 19 and early 20 centuries; it has facilitated for decades the work of biologists, hematologists and pathologists working with blood cells. Despite more than a century of studying Romanowsky staining, no systematic review has been published that explains the chemical processes that produce the "Romanowsky effect" or "Romanowsky-Giemsa effect" (RGE), i.e., a purple coloration arising from the interaction of an azure dye with eosin and not due merely to their simultaneous presence. Our review is an attempt to build a bridge between chemists and biomedical scientists and to summarize the available data on methylene blue (MB) demethylation as well as the related reduction and decomposition of MB to simpler compounds by both light and enzyme systems and microorganisms. To do this, we analyze modern data on the mechanisms of MB demethylation both in the presence of acids and bases and by disproportionation due to the action of light. We also offer an explanation for why the RGE occurs only when azure B, or to a lesser extent, azure A is present by applying experimental and calculated physicochemical parameters including dye-DNA binding constants and electron density distributions in the molecules of these ligands. Finally, we discuss modern techniques for obtaining new varieties of Romanowsky dyes by modifying previously known ones. We hope that our critical literature study will help scientists understand better the chemical and physicochemical processes and mechanisms of cell staining with such dyes.
Topics: Azure Stains; Staining and Labeling; Coloring Agents; Methylene Blue; Eosine Yellowish-(YS)
PubMed: 37929609
DOI: 10.1080/10520295.2023.2273860 -
ACS Chemical Neuroscience May 2021Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called...
Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound as a potent and selective acetylcholinesterase inhibitor with IC = 8 nM and as a potent butyrylcholinesterase inhibitor with IC = 15 nM. Selected hybrids, namely, , , , , and , showed a significant inhibitory activity toward τ peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, and exerted a remarkable ability to inhibit self-induced Aβ aggregation. Notwithstanding, studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when was administered to mice at 14 mg/kg (i.p.). was also able to permeate to the CNS as shown by and models. The maximum brain concentration was close to the IC value for acetylcholinesterase inhibition with a relatively slow elimination half-time. showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Mice; Phenothiazines; Structure-Activity Relationship; Tacrine
PubMed: 33852284
DOI: 10.1021/acschemneuro.1c00184 -
Sensors (Basel, Switzerland) Nov 2023This paper describes the development of a simple voltammetric biosensor for the stereoselective discrimination of myo-inositol (myo-Ins) and D-chiro-inositol...
This paper describes the development of a simple voltammetric biosensor for the stereoselective discrimination of myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) by means of bovine serum albumin (BSA) adsorption onto a multi-walled carbon nanotube (MWCNT) graphite screen-printed electrode (MWCNT-GSPE), previously functionalized by the electropolymerization of methylene blue (MB). After a morphological characterization, the enantioselective biosensor platform was electrochemically characterized after each modification step by differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The results show that the binding affinity between myo-Ins and BSA was higher than that between D-chiro-Ins and BSA, confirming the different interactions exhibited by the novel BSA/MB/MWCNT/GSPE platform towards the two diastereoisomers. The biosensor showed a linear response towards both stereoisomers in the range of 2-100 μM, with LODs of 0.5 and 1 μM for myo-Ins and D-chiro-Ins, respectively. Moreover, a stereoselectivity coefficient α of 1.6 was found, with association constants of 0.90 and 0.79, for the two stereoisomers, respectively. Lastly, the proposed biosensor allowed for the determination of the stereoisomeric composition of myo-/D-chiro-Ins mixtures in commercial pharmaceutical preparations, and thus, it is expected to be successfully applied in the chiral analysis of pharmaceuticals and illicit drugs of forensic interest.
Topics: Inositol; Methylene Blue; Stereoisomerism
PubMed: 38005597
DOI: 10.3390/s23229211 -
Molecules (Basel, Switzerland) Feb 2023Antipsychotics have narrow therapeutic windows, and their monitoring in biological fluids is therefore important; consequently, stability in those fluids must be...
Antipsychotics have narrow therapeutic windows, and their monitoring in biological fluids is therefore important; consequently, stability in those fluids must be investigated during method development and validation. This work evaluates the stability of chlorpromazine, levomepromazine, cyamemazine, clozapine, haloperidol, and quetiapine in oral fluid (OF) samples, using the dried saliva spots (DSS) sampling approach and gas chromatography coupled to tandem mass spectrometry. Since many parameters can influence the stability of the target analytes, design of experiments was adopted to check the crucial factors that affect that stability in a multivariate fashion. The studied parameters were the presence of preservatives at different concentrations, temperature, light, and time. It was possible to observe that antipsychotic stability improved when OF samples in DSS were stored at 4 °C, with a low ascorbic acid concentration, and in the absence of light. With these conditions, chlorpromazine and quetiapine were stable for 14 days, clozapine and haloperidol were stable for 28 days, levomepromazine remained stable for 44 days, and cyamemazine was stable for the entire monitored period (146 days). This is the first study that evaluates the stability of these antipsychotics in OF samples after application to DSS cards.
Topics: Antipsychotic Agents; Clozapine; Quetiapine Fumarate; Haloperidol; Chlorpromazine; Methotrimeprazine; Gas Chromatography-Mass Spectrometry
PubMed: 36903275
DOI: 10.3390/molecules28052030 -
Revista Brasileira de Psiquiatria (Sao... 2021
Topics: Antipsychotic Agents; Antiviral Agents; COVID-19; Humans; Phenothiazines; SARS-CoV-2
PubMed: 33440401
DOI: 10.1590/1516-4446-2020-0024 -
ACS Applied Bio Materials Oct 2023A formate (HCOO) bioanode was developed by utilizing a phenothiazine-based electropolymerized layer deposited on sucrose-derived carbon. The electrode modified with...
A formate (HCOO) bioanode was developed by utilizing a phenothiazine-based electropolymerized layer deposited on sucrose-derived carbon. The electrode modified with NAD-dependent formate dehydrogenase and the electropolymerized layer synergistically catalyzed the oxidation of the coenzyme (NADH) and fuel (HCOO) to achieve efficient electron transfer. Further, the replacement of carbon nanotubes with water-dispersible sucrose-derived carbon used as the electrode base allowed the fabrication of a surfactant-free bioanode delivering a maximum current density of 1.96 mA cm in the fuel solution. Finally, a separator- and surfactant-free HCOO/O biofuel cell featuring the above bioanode and a gas-diffusion biocathode modified with bilirubin oxidase and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) was fabricated, delivering a maximum power density of 70 μW cm (at 0.24 V) and an open-circuit voltage of 0.59 V. Thus, this study demonstrates the potential of formic acid as a fuel and possibilities for the application of carbon materials in bioanodes.
Topics: Surface-Active Agents; Bioelectric Energy Sources; Nanotubes, Carbon; Formates; Phenothiazines; Sucrose
PubMed: 37750824
DOI: 10.1021/acsabm.3c00502