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The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections).

In the current work, sulfur and nitrogen co-doped carbon dots (S,N-CDs) as simple, sensitive, and selective turn-off fluorescent nanosensors were utilized for analysis of three phenothiazine derivatives, including acetophenazine (APZ), chlorpromazine (CPH), and promethazine (PZH). S,N-CDs were synthesized through a green one-pot microwave-assisted technique using widely available precursors (thiourea and ascorbic acid). HRTEM, EDX, FTIR spectroscopy, UV-Vis absorption spectroscopy, and fluorescence spectroscopy were used to characterize the as-synthesized CDs. When excited at 330 nm, the carbon dots produced a maximum emission peak at 410 nm. The cited drugs statically quenched the S,N-CDs fluorescence as revealed by the Stern-Volmer equation. The current method represents the first spectrofluorimetric approach for the determination of the studied drugs without the need for chemical derivatization or harsh reaction conditions. The importance of the proposed work is magnified as the cited drugs do not have any fluorescent properties. The fluorescence of the developed sensor exhibited a linear response to APZ, CPH, and PZH in the concentration ranges of 5.0-100.0, 10.0-100.0, and 10.0-200.0 μM with detection limits of 1.53, 1.66, and 2.47 μM, respectively. The developed fluorescent probes have the advantages of rapidity and selectivity for APZ, CPH, and PZH analysis in tablets with acceptable % recoveries of (98.06-101.66 %). Evaluation of the method's greenness was performed using the Complementary Green Analytical Procedure Index (ComplexGAPI) and Analytical GREEnness metric (AGREE) metrics, indicating that the method is environmentally friendly. Validation of the proposed method was performed according to ICHQ2 (R1) guidelines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As an important chemical raw material, hydrazine brings convenience to people's lives and provides opportunities for human development. However, the misuse or leakage of hydrazine has brought pollution to the environment, including water, soil and living organisms. At the same time, hydrazine poses a potential threat to human health as a carcinogen. Despite the enormous challenges, it is crucial to develop an effective method to detect hydrazine in environmental samples. In this work, we have synthesized a series of probes based on phenothiazine fluorophore by the introduction of different substituents and developed a novel probe for the detection of hydrazine. The probe is capable of detecting hydrazine in aqueous solutions with high sensitivity and selectivity, and can be easily fabricated into paper test strips for use in in situ samples. In addition, the probe is effective in detecting hydrazine in water, soil, cells, and zebrafish, providing an excellent tool for detecting hydrazine in the environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A fluorescent probe has been designed using cyanine phenothiazine and 7-nitro-1,2,3-benzoxadiazole (NBD) for selective detection of Cys-SO 2 components. The probe utilizes the NBD structure to achieve specificity towards Cys and employs a reaction mechanism between the double bond of cyanine and phenothiazine with SO 3 2- to achieve selectivity towards SO 2 . Importantly, the NBPI phenothiazine structure incorporates a large C-O bond energy attached to NBD, effectively eliminating interference from Hcy and ensuring highly selective response to Cys. The optimized design of the probe enables excellent linearity and extremely low detection limits for Cys-SO 2 components in vitro experiments. The probe NBPI allows separate detection of Cys-SO 2 in the presence of both components. Furthermore, the probe NBPI demonstrated successful imaging of endogenous and exogenous Cys and SO 2 in cell studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this study, a simple, rapid, and ultrasensitive technique was developed to identify five pairs of phenothiazine drugs by using ultrasound-enhanced and surfactant-assisted dispersive liquid-liquid microextraction (UESA-DLLME), field-amplified sample injection with capillary electrophoresis (FASI-CE), and capacitively coupled capacitively coupled contactless conductivity detection (C 4 D). During the CE separation process, UESA-DLLME was used for sample clean-up and offline concentration, and FASI-CE was used for the online concentration of phenothiazine enantiomers. At baseline, the five pairs of phenothiazine enantiomer drugs required 18 min for separation. UESA-DLLME was then used to extract 0.01 mM Tween 80 at pH 10 from a sample solution (extraction solvent, 100 mL of dichloromethane). Subsequently, FASI was used to stack the sample solution (buffer, 30 mM 2-(N-morpholino)ethanesulfonic acid/aspartic acid, additive 4 mM hydroxypropyl-γ-cyclodextrin, pH 2.5), and C 4 D was used for signal detection (amplitude, 2 Vpp; frequency, 400 kHz). The results indicated that the linear range for quantifying all analyte enantiomers was 1.0-150 nM, with a coefficient of determination exceeding 0.99. In addition, the relative standard deviations in the migration time and peak areas for the 10 analytes were less than 3.2% and 7.2%, respectively. The proposed system has a limit of detection (LOD) for the 10 analytes at a signal-to-noise ratio of 3, ranging from 0.24 to 0.28 nM. The sensitivity enhancement, which compares the LOD 0 (limit of detection in the normal method) to LOD 1 (limit of detection achieved using the proposed UESA-DLLME-FASI-CE-C 4 D method), varies between approximately 1200 and 2000 for the 10 analytes. Analysis of the 10 separated analytes spiked in urine and serum samples revealed recovery rates of 88%-106% and 89%-105%, respectively. Therefore, this highly sensitive advanced technique was successfully used to analyze phenothiazine enantiomers in urine and serum samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hypochlorite (ClO - ) plays a key role in life systems and it is necessary to develop an effective detection method. In view of the significant advantages of the fluorescent probe, we have synthesized a naked-eye recognition fluorescent probe NNCF for the detection of ClO - based on phenothiazine and naphthalimide. The probe NNCF is sensitive (LOD = 9.5 nM) and fast for ClO - (within 30 s), and its Stokes shift is as large as 161 nm. In addition, the probe NNCF has been successfully used for imaging detection of exogenous ClO - in MCF-7 cells with low toxicity., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) is a process in which a photosensitizer (PS) is exposed to specific wavelengths and generates reactive oxygen species (ROS) which act within nanometers. The low invasive nature and directed cytotoxicity of this approach render it attractive to the treatment of different conditions, including the ones that affect the central nervous system (CNS). The effect of PDT on healthy neurons is one main concern over its use in the CNS, since neuronal-like cells were shown to be particularly sensitive to certain PSs. Among available PSs, 1,9-dimethyl-methylene blue (DMMB) stands out as being resistant to reduction to its inactive leuco form and by being able to produce high levels of singlet‑oxygen. In this study, we aimed to investigate DMMB photodamage mechanisms in the hippocampal cell line HT22. Our results demonstrate that DMMB-PDT decrease in cell viability was linked with an increase in cell death and overall ROS production. Besides, it resulted in a significant increase in mitochondrial ROS production and decreased mitochondria membrane potential. Furthermore, DMMB-PDT significantly increased the presence of acidic autolysosomes, which was accompanied by an increase in ATG1 and ATG8 homologue GaBarap1 expression, and decreased DRAM1 expression. Taken together our results indicated that mitochondrial and autophagic dysfunction underlie DMMB-PDT cytotoxicity in neuronal cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Organic materials with Mechanofluorochromism (MFC) properties have potential application value. Phenothiazine derivatives are a class of substances with MFC properties that have been synthesized and reported in experiments (Dyes and Pigments 172 (2020) 107835). Dual fluorescence of a series of phenothiazine derivatives is observed in the experiment, which proved that the ESIPT process is carried out. In this work, we choose phenothiazine derivatives (C2PAHN, C4PAHN, C8PAHN) as models to theoretically analyze the influence of different alkyl chain lengths on the excited state intramolecular proton transfer (ESIPT). In addition, the shift value of fluorescence spectrum is related to the length of alkyl chain. The fluorescence shift of C2PAHN is the largest (6.31 nm), and that of C8PAHN is the smallest (2.40 nm). The theory of density functional theory (DFT) and time-dependent density functional theory (TD-DFT) are adopted to simulate the molecular dynamics in the ground state and excited state. The analysis of the optimized molecular geometry parameters and infrared vibrational spectroscopy (IR) illustrate the stronger hydrogen bonding of the excited state molecules, which is favorable for the progress of ESIPT. Fluorescence spectroscopy reveals that the appropriate increase or decrease of alkyl chains would change the photophysical properties of the molecules. Frontier molecular orbitals (FMOs) indicate that the rearrangement of electron density from electronic level to is the driving force of the ESIPT process. Reduction density gradient (RDG) surfaces and Natural Population Analysis (NPA) tentatively lead to the conclusion that alkyl chain length is inversely proportional to hydrogen bond strength. Finally, the data are qualitatively analyzed by scanning the potential energy curves, and it is concluded that the longer the alkyl chain, the weaker the hydrogen bonding effect and the more unfavorable the ESIPT process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In this work, a multiplexed electrochemical aptasensor based on mixed valence Ce-MOF was constructed for the simultaneous determination of malathion and chlorpyrifos. Firstly, Ce(III, IV)-MOF materials with many catalytic sites were synthesized and characterized by SEM, TEM, XPS, FT-IR, XRD, and UV-Vis. Then, the chlorpyrifos and malathion signal markers based on Ce(III, IV)-MOF were prepared using thionine (Thi) and ferrocene (Fc) used as the electrochemical probe. The electrochemical signal was amplified by the reduction of thionine catalyzed by the spontaneous cycle of Ce(III, IV) in Ce(III, IV)-MOF skeleton and the reduction of ferrocene catalyzed by ascorbic acid (AA) in solution. The detection of the two targets did not interfere with each other, and the quantitative detection was realized with high sensitivity. The detection range of chlorpyrifos and malathion were 1.0 μM ∼ 0.1 pM, and the detection limits of chlorpyrifos and malathion were 0.038 and 0.045 pM (S/N = 3), respectively. The sensor provided a new idea for the simultaneous determination of multi-component and had a high application prospect in the field of food safety in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Cardiac troponin-I (CTnI) is one of the most popular biomarkers which can be utilized for the diagnosis and control of acute myocardial infarction in clinical practice. Here, a sandwich-type electrochemical immunosensor has been established using the zinc-based metal-organic framework/Fe 3 O 4 -COOH/thionine labeled anti-CTnI monoclonal antibody (Ab 1 -Zn-MOF/Fe 3 O 4 -COOH/Thi) nanocomposite as signaling molecule and a polymer film of cetyltrimethylammonium bromide (pCTAB) in the presence of choline chloride-urea deep eutectic solvent (DES) and anti-CTnI polyclonal antibody (Ab 2 ) as immobilization substance of detecting surface. The porous ultrathin layers of Zn-MOF nanosheets successfully prepare a well-defined structure for Fe 3 O 4 -COOH electrocatalyst and Thi within a certain two dimensional (2D) regions, which enhances electrochemical reduction of Thi. The Ab 1 -Zn-MOF/Fe 3 O 4 -COOH/Thi nanocomposites were introduced to CTnI in the specimen and on the surface of pCTAB/DES-Au-SPE quantitative determination of CTnI was achieved using differential pulse voltammetry after sandwiching the CTnI target between Ab 1 -nanocomposite and Ab 2 which was encapsulated into the pCTAB/DES-Au-SPE. This immunosensor indicated the appropriate assay performance for CTnI with the detection range of 0.04 ng mL -1 to 50 ng mL -1 and the limit of detection of 0.0009 ng mL -1 . This study provides convenient plan for sensitive detection of bioanalytes and opens a path for the establishment of user-friendly and cost-effective device., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Azaphenothiazines (AZA), modified phenothiazine derivatives, have been reported to exhibit a wide spectrum of biological activities, including anticancer activities, but the mechanisms of their interactions with biomolecules are not fully recognized. In this work, the mode of interaction of selected AZA with calf thymus DNA was investigated using UV-Vis absorption, fluorescence spectroscopy (competition experiment with ethidium bromide, quenching of fluorescence) and molecular docking. The investigated AZA represent dipyrido[3,4-b;3'4'-e][1,4]thiazine, quino[3,2-b]benzo[1,4]thiazine and diquino[3,2-b;2',3'-e][1,4]thiazine possessing tricyclic, tetracyclic and pentacyclic ring system with the additional N,N-dimethylaminopropyl group at the nitrogen atom in the 1,4 thiazine ring. The results obtained from spectroscopic studies showed that AZA bind to DNA by insertion of a fragment of the fused rings system between the base pair stack in the double helix of DNA. In addition, the number of rings in the AZA structures seemed to be related to the strength of the interaction, because pentacyclic AZA (binding constant K b  = 6.31 × 10 6 L/mol) demonstrated 10-fold higher affinity towards DNA than the tetracyclic AZA and about 100-fold higher affinity than that of tricyclic AZA. The molecular docking results showed that the binding mode of AZA to DNA helix was an intercalation mode with the partial insertion of one planar part of the AZA structure (the pyridine or quinoline ring) into the neighboring bases of one of the DNA chains with additional hydrogen bonding with the minor groove through the positively charged N,N-dimethylaminopropyl group. Chemical potential (μ), chemical hardness (ƞ), electronegativity (χ) and the value of electrons transferred from one system to another (ΔN) calculated from the HOMO and LUMO energies by the density functional theory method indicated that AZA acted as the electron acceptors to the DNA bases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypochlorite (ClO - ), a type of reactive oxygen species (ROS), plays an essential role in complex biological systems. Real-time detection of the content and distribution of ClO - in cells or subcellular organelle is critically essential. In this paper, a lysosomal-targeted fluorescent probe, Cou-Lyso, was constructed for real-time detection of ClO - in a ratiometric manner, achieving high sensitivity with a low detection limit (0.58 μM). Upon reaction with ClO - , this probe was subjected to a significant fluorescence change from red emission (λ max em = 610 nm) to green emission (λ max em = 535 nm) with the ratio of I 535 nm /I 610 nm displaying a 76-fold enhancement from 0.04 to 3.03. The confocal imaging experiments for Cou-Lyso showed that this probe could detect ClO - in living cell and zebra fish. This probe has been successfully applied to stain lysosome and image lysosomal ClO - based on co-localization imaging experiments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bifunctional fluorescent probes with dual-emission response attract extensive attention. A novel fluorescent probe FP, a hybrid of fluoran and phenothiazine, has been designed and synthesized for selective sensing of Fe 3+ and ClO - with dual-emission changes, which involes mechanisms of Fe 3+ -promoted spirolactone ring opening and ClO - -induced oxidation of phenothiazine moiety, respectively. In addition, the detection limits for Fe 3+ and ClO - were estimated to be 49.1 and 35.9 nM, respectively. Significantly, FP can be employed as an tracer for the detection of Fe 3+ ions within living HeLa cells by fluorescence imaging., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

How to sensitively detect early biomarkers of Alzheimer's disease (AD) is nowadays, one of the major challenges. In this work, Aβ oligomers (AβO), one of the AD biomarkers, was analyzed using an electrochemical aptasensor, which was prepared based on thionine (Th) - functionalized three - dimensional carbon nanomaterials (reduced graphene oxide (rGO) and multi-wall carbon nanotubes (MWCNTs)) immobilized DNA-aptamer. Th, a positively charged planar aromatic molecule, form many π - π conjugated structures with rGO and MWCNTs, then improving the structural stability, electron transfer and the capacitive properties of Th-rGO-MWCNTs nanocomposites. Under the optimal conditions, differential pulse voltammetry (DPV) current responses decreased with the increase of AβO concentration. The obtained AβO aptasensor presented a wide linear range of 0.0443 pM-443.00 pM and limit of detection (LOD) was 10 fM. Meanwhile, AβO aptasensor displayed remarkable stability and selectivity. It has a great potential for early diagnosis of AD in human real serum samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The single tumor antigen does not have enough specificity and sensitivity to meet the accurate diagnostic criteria, and single antigen measurement is often prone to false negative and false positive perceptions. Therefore, simultaneous monitoring of multiple tumor antigens related to precise tumors in serum samples has become an interesting and encouraging analytical method. In this work, we demonstrated an electrochemical biosensor based on multiple signal amplification methods, and simultaneously detect two lung cancer markers, cytokeratin 19 fragment 21-1 (CYFRA21-1) and carcinoembryonic antigen (CEA). Large number of gold nanoparticles distributed on the surface of three-dimensional graphene (3D-G), poly-thionine (pThi) and poly-m-Cresol purple (pMCP) not only provide large number of binding sites for antigen and antibody, but also enhance the electrochemical signal of biosensor and greatly improves the sensitivity of the biosensor. The detection linear range extends from 0.5 to 200 ng/mL, with low detection limits (LOD) of 0.18 ng/mL and 0.31 ng/mL for CYFRA21-1 and CEA, respectively. Overall, this kind of immune-biosensor provides great potential for the simultaneous detection of multiple targets in early clinical diagnosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: The coronavirus disease 2019 (COVID-19) pandemic has swept the globe and no specific effective drug has been identified. Drug repurposing is a well-known method to address the crisis in a time-critical fashion. Antipsychotic drugs (APDs) have been reported to inhibit DNA replication of hepatitis B virus, measles virus germination, and HIV infection, along with replication of SARS-CoV and MERS-CoV, both of which interact with host cells as SARS-CoV-2., Methods: Nineteen APDs were screened using ACE2-HEK293T cell membrane chromatography (ACE2-HEK293T/CMC). Cytotoxicity assay, coronavirus spike pseudotype virus entry assay, surface plasmon resonance, and virtual molecular docking were applied to detect affinity between ACE2 protein and drugs and a potential antiviral property of the screened compounds., Key Findings: After the CMC screening, 8 of the 19 APDs were well-retained on ACE2-HEK293T/CMC column and showed significant antiviral activities in vitro. Three quarters of them belong to phenothiazine and could significantly inhibit the entrance of coronavirus into ACE2-HEK293T cells. Aother two drugs, aripiprazole and tiapride, exhibited weaker inhibition. We selected five of the drugs for subsequent evaluation. All five showed similar affinity to ACE2 and virtual molecular docking demonstrated they bound with different amino acids respectively on ACE2 which SARS-CoV-2 binds to., Significance: Eight APDs were screened for binding with ACE2, five of which demonstrated potential protective effects against SARS-CoV-2 through acting on ACE2. Although the five drugs have a weak ability to block SARS-CoV-2 with a single binding site, they may provide a synergistic effect in adjuvant therapy of COVID-19 infection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Interleukin-6 (IL-6) is of high importance for disease diagnosis and prognosis in human health since it's a crucial component in immune homeostasis, hematopoiesis, and metabolism. Herein, an immunosensor has been developed for monitoring IL-6, which is fabricated by Au nanoparticles (Au NPs)-thionine (THI)-carboxylated multi walled carbon nanotubes (CMWCNTs) as the substrate with high conductivity. Staphylococcal protein A (SPA) could directionally capture antibody to reduce steric hindrance caused by random immobilization. Built upon the high efficiency of IL-6 antibody immobilization by the SPA on the sensing surface, the immunosensor exhibited a favorable activity for IL-6 detection. Under optimal conditions, the biosensor presented a LOD of 2.87 pg mL -1 and a wide linear range from 0.01 ng mL -1 to 800 ng mL -1 in serum samples. Furthermore, the assembled sensor successfully quantified the IL-6 concentration in serum and different tissue lapping liquids (lung, heart, liver) from rats with myocardial infarction. The satisfactory performance of the proposed sensor not only broadens its application in clinical monitoring of IL-6 but also provides a novel approach to study inflammation in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Near-infrared (NIR) light-activated phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has gained considerable attention due to the advantages of high efficiency and minimally invasiveness. However, the development of a single component therapeutic agent with clear structure and molecular weight that achieve photodynamic/photothermal synergistic therapy is still challenging. Herein, we design and synthesize a new smart photosensitizer (PRX) by conjugation of perylene diimide (PDI) and methylene violet (RAX). The typical donor-acceptor (D-A) structure of RAX facilitates the red-shift of absorption to the near-infrared (NIR) region. The amphiphilic PRX could self-assemble into monodispersed nanoparticles (PRX NPs) with enhanced and broadened absorption. Under a single 808 nm laser irradiation, PRX NPs could generate efficient reactive oxygen species (ROS) and heat simultaneously with the photothermal conversion efficiency as high as 59%. PRX NPs displays strong interaction with DNA and can damage plasmid DNA upon light irradiation. The biocompatibility and high phototoxicity of PRX NPs against A549 cells are further confirmed through MTT assay. Therefore, the as-prepared PRX NPs could be served as a promising antitumor nanoagent through photothermal/photodynamic combination manner., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This work reports the proof-of-concept of novel and powerful enzyme-free voltammetric aptasensor of colorectal cancer-related carcinoembryonic antigen (CEA) without the participation of any antibodies. The aptasensor was prepared by means of immobilizing thiolated CEA aptasensor on gold nanoparticle-deposited glassy carbon electrode. Thionine-doped silica nanoparticles were synthesized via reverse micelle method and functionalized with p-aminophenylboronic acid by the epoxy-amino reaction for specific conjugation of subsequent CEA glycoprotein. In the presence of target CEA, the analyte initially reacted with immobilized aptamer on the electrode to generate an aptamer-CEA complex. Then, phenylboronic acid immobilized on silica nanoparticle specifically recognized with CEA glycoprotein based on sugar-boronic acid interaction to form a sandwich-type complex on the electrode. Within the applied potentials, the doped thionine molecules into the silica nanoparticles were used as the electron mediators to produce well-defined voltammetric signals (vs. Ag/AgCl). Under optimum conditions, the voltammetric peak current increased linearly within the CEA concentration in the range from 1.0 pg mL -1 to 10 ng mL -1 , and the limit of detection was 0.49 pg mL -1 at 3δ. A repeatability and intermediate precision of ≤8.7% was accomplished at CEA levels in the batch-to-batch mode. The method was highly specific for CEA over other disease-related biomarkers. The accuracy and inter-laboratory validation of this system were evaluated for target CEA detection in human serum specimens, and the results were in accordance with those obtained by a commercial ELISA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of 2,2'-dichloro-3,3'-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic diquinothiazine ring systems were identified as diquino[3,2-b;3',4'-e][1,4]thiazine, diquino[3,2-b;5',6'-e][1,4]thiazine, diquino[3,2-b;6',5'-e][1,4]thiazine and diquino[3,2-b;8',7'-e][1,4]thiazine with advanced two-dimensional 1 H and 13 C NMR techniques (COSY, ROESY, HSQC and HMBC) of N-methyl derivatives. The identification of pentacyclic ring system was confirmed by X-ray diffraction analysis of selected N-alkyl derivatives. The X-ray analysis revealed different spatial structures of the ring system (planar and folded). NH-diquinothiazines were further transformed into N-alkyl and N-dialkylaminoalkyl derivatives. Most of diquinothiazines exhibited significant cancer cell growth inhibition against the human glioblastoma SNB-19, colorectal carcinoma Caco-2, breast cancer MDA-MB-231 and lung cancer A549 cell lines with the IC 50 values < 3 µM. This anti-proliferative activity was found to be more than for cisplatin. The most promising compound, 7-dimethylaminopropyldiquino[3,2-b;6',5'-e]thiazine, was used for gene expression analysis by reverse transcription-quantitative real-time PCR (RT-QPCR) method. The expression of H3, TP53, CDKN1A, BCL-2 and BAX genes revealed that this compound inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2) in two cancer cell lines (SNB-19 and Caco-2)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this study, a molecularly imprinted polymer based chemiluminescence array capable of simultaneous determining phenothiazines and benzodiazepines was first reported. Two polymers were coated in different wells of the conventional 96-well microtiter plate as the recognition reagents, and the added analytes competed with a horseradish peroxidase-labeled bi-hapten conjugate to bind the recognition reagents. The light signal was induced by using a highly effective luminol-H 2 O 2 -IMP system. The assay procedure consisted of only one sample-loading step prior to data acquisition. Then, the array was used to determine 4 phenothiazines and 5 benzodiazepines in pork simultaneously. The limits of detection for the 9 drugs were in a range of 0.001-0.01 ng/mL, and the recoveries from the fortified blank pork were in a range of 63.5%-94.1%. Furthermore, the array could be reused for 8 times. The detection results for some real pork samples were consistent with an ultra performance liquid chromatography method., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A. Additional insight into the structural, molecular, and biological framework driving the efficacy of these therapeutic strategies will provide a foundation for the refinement and development of novel and clinically tractable PP2A targeted therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Absorption and emission spectral characteristics of the two structurally similar phenothiazine dyes, azure B and toluidine blue, in aqueous solutions of the two sets of molecular additives (ureas and monosaccharides) were studied as a function of the dye and additive concentrations. The absorption spectra of the dyes were also studied in pure tetramethylurea with an aprotic nature. The spectral data were analyzed using DECOM Program. The dimer structure of the interacting molecules in these dyes was discussed using the exciton model. The urea class of additives was found to act as water structure-breakers over the range of studied concentration. The carbohydrate additives were found to act as water structure-breakers at low concentrations. However, the water structure breaking process may be disfavored by the additive-additive interactions at higher concentrations. It can be concluded that at low additive concentrations, the main driving force for breaking the dye association is water-additive interaction, which disrupts the water hydrogen bonds induced by the additives. However, at the high additive concentrations, the different phenomena including additive-additive and additive-dye interactions can change the structure, strength, and aggregative properties of the dyes. Finally, the urea in water induces noticeably fluorescence quenching in emission spectra of both the dyes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The development of specific tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). However, chemoresistance of tumor cells to TKIs has already been described, and several mechanisms account for the multidrug resistance (MDR) phenotypes, including the overexpression of P-glycoprotein (P-gp). This decreases the rate of healing and complete tumor remission. Nanotechnological tools have been studied to allow advances in this field. Poloxamers (Pluronics(®)) have been proposed as drug carriers to improve therapeutic efficacy and decrease side effects, even in cancer therapy, due to their ability to inhibit P-gp. Antipsychotic phenothiazines have been described as potent cytotoxic drugs against several types of tumor cells in vitro. Here, we show that nanostructured micellar systems containing the phenothiazine derivative chlorpromazine (CPZ) potentiated the cytotoxicity of free CPZ and increased the selectivity against CML tumor cells, demonstrating the pharmacological potential of these poloxamer-based nanostructured systems containing CPZ in cancer therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this study, the inhibitory effects of three phenothiazines [toluidine blue O (TBO), thionine (TH) and methylene violet (MV)] were tested on human plasma butyrylcholinesterase (BChE) and their inhibitory mechanisms were studied in detail. MV acted as a linear mixed type inhibitor of human BChE with Ki = 0.66 ± 0.06 μM and α = 13.6 ± 3.5. TBO and TH caused nonlinear inhibition of human BChE, compatible to double occupancy. Ki values estimated by nonlinear regression analysis for TBO and TH were 0.008 ± 0.003 μM and 2.1 ± 0.42 μM, respectively. The inhibitory potential of TBO was also tested on human erythrocyte AChE. TBO acted as a linear mixed type inhibitor of human AChE with Ki = 0.041 ± 0.005 μM and α = 1.6 ± 0.007. Using four site-directed BChE mutants, the role of peripheral anionic site residues of human BChE was also investigated in the binding of TBO to BChE. The peripheral anionic site mutants of BChE caused 16-69-fold increase in Ki value of TBO, compared to recombinant wild-type, suggesting that peripheral anionic site residues are involved in the binding of TBO to human BChE. In conclusion, TBO which is a potent inhibitor of human cholinesterases, may be a potential drug candidate for the treatment of Alzheimer's disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Synthesis of magnetic iron oxide nanoparticles and its surface modification with methacrylic acid (MAA) was performed simultaneously by adding Fe(2+)/Fe(3+) to an alkaline MAA solution under nitrogen atmosphere. MAA coated magnetite (Fe3O4@MAA) has abundant reactive double bonds on the surface that can initiate polymerization. Magnetic molecularly imprinted polymers (MMIPs) were synthesized through distillation-precipitation polymerization of MAA as monomer, perphenazine (PPZ) as template, and ethylene glycol di-methacrylate (EGDMA) as cross linker on Fe3O4@MAA, with concise control of experimental conditions in about 90min. The produced super paramagnetic MMIPs can be separated from the solution in the presence of external magnetic field in less than 1min. Characterizations of the synthesized particles were performed by electron microscopes, thermo-gravimetric analysis (TGA), vibrating sample magnetometer (VSM), Fourier transform infrared (FT-IR) spectroscopy, and BET. The data showed that Fe3O4@MAA was well encapsulated in the polymer shell. The MMIPs showed high porosity. Moreover, MMIPs were used for rapid pre-concentration and separation of PPZ in human plasma and urine without any dilution and pretreatments using high performance liquid chromatography equipped with a photo diode array detector (HPLC-PDA). The calibration curve in urine and plasma has shown the same slope as the external calibration curve. Linear range of 20-5000ngmL(-1), and a detection limit of 5.3ngmL(-1) was obtained. The results showed 97.92% recovery along with the relative standard deviation of 6.07% (n=6) for 1μgmL(-1) PPZ. Pre-concentration factor was 13. The MMIPs adsorbed PPZ in 1min and then desorbed it by MeOH:HOAc in 2min., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Phenothiazine derivatives are non-antibiotics with antimicrobial, fungistatic and fungicidal effects. We exposed to a high energy UV laser beam phenothiazines solutions in water at 20mg/mL concentration to increase antibacterial activity of resulting mixtures. Compared to previous results obtained on bacteria, more research is needed about UV laser irradiated phenothiazines applications on cancer cell cultures to evidence possible anticancerous properties. Evaluation of the safety of the newly obtained photoproducts in view of use on humans is also needed. Due to expensive animal testing in toxicology and pressure from general public and governments to develop alternatives to in vivo testing, in vitro cell-based models are attractive for preliminary testing of new materials. Cytotoxicity screening reported here shows that laser irradiated (4h exposure time length) chlorpromazine and promazine are more efficient against some cell cultures. Interaction of laser irradiated phenothiazines with fabrics show that promethazine and chlorpromazine have improved wetting properties. Correlation of these two groups of properties shows that chlorpromazine appears to be more recommended for applications on tissues using fabrics as transport vectors. The reported results concern stability study of phenothiazines water solutions to know the time limits within which they are stable and may be used., (Copyright © 2015 Elsevier B.V. All rights reserved.)

High-speed capillary electrophoresis (CE) enables the simple, rapid, and inexpensive analysis of large sets of chiral samples in the pharmaceutical industry. Hence, we developed a novel method for separating enantiomers of d,L-phenothiazines simply and rapidly, based on using poly(diallyldimethylammonium chloride) (PDDAC) as an additive and hydroxypropyl-γ-cyclodextrin (Hp-γ-CD) as a chiral selector in capillary electrophoresis. Adding 0.9% PDDAC to the background electrolyte generated a stable, high, and reversed electroosmotic flow (EOF). Hp-γ-CD not only worked as a complexing agent to increase the chiral resolution between d,L-phenothiazines but also decreased the effective electrophoretic mobility of these drugs. Combining PDDAC and Hp-γ-CD as buffer additives enabled CE to achieve a high-speed enantioseparation of five pairs of d,L-phenothiazines. A decrease in capillary length and an increase in the intensity of the electric field further shortened the separation time. When the background electrolyte contained 0.9% PDDAC, 5mM Hp-γ-CD, and 75 mM formic acid (pH 3.0), enantioseparation of the d,L-phenothiazines was attained within 230 s by applying a capillary length of 32.5 cm and an electric field of 292 V cm(-1). The limit of detection (LOD) of the d,L-phenothiazines at a signal-to-noise ratio of 3 ranged from 2 to 8 μM. We demonstrated the feasibility of this method by detecting the five pairs of d,L-phenothiazines in urine samples., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This chapter reviews the spectrum and mechanisms of neurologic adverse effects of commonly used gastrointestinal drugs including antiemetics, promotility drugs, laxatives, antimotility drugs, and drugs for acid-related disorders. The commonly used gastrointestinal drugs as a group are considered safe and are widely used. A range of neurologic complications are reported following use of various gastrointestinal drugs. Acute neurotoxicities, including transient akathisias, oculogyric crisis, delirium, seizures, and strokes, can develop after use of certain gastrointestinal medications, while disabling and pervasive tardive syndromes are described following long-term and often unsupervised use of phenothiazines, metoclopramide, and other drugs. In rare instances, some of the antiemetics can precipitate life-threatening extrapyramidal reactions, neuroleptic malignant syndrome, or serotonin syndrome. In contrast, concerns about the cardiovascular toxicity of drugs such as cisapride and tegaserod have been grave enough to lead to their withdrawal from many world markets. Awareness and recognition of the neurotoxicity of gastrointestinal drugs is essential to help weigh the benefit of their use against possible adverse effects, even if uncommon. Furthermore, as far as possible, drugs such as metoclopramide and others that can lead to tardive dyskinesias should be used for as short time as possible, with close clinical monitoring and patient education., (© 2014 Elsevier B.V. All rights reserved.)

Herein, a novel label-free electrochemical aptasensor based on direct immobilization of the redox probes on an electrode surface was reported. Gold electrode coated Nafion was firstly modified with redox probe-thionine (Thi) through ion exchange adsorption. Then, with the help of chemisorption and electrostatic adsorption, negatively charged nano-Au and positively charged Thi were layer-by-layer (LBL) self-assembled onto the modified electrode surface, which formed {nano-Au/Thi(+)}(n) multilayer films for improving the amount of redox probes and immobilizing thiolated thrombin aptamers (TBA). In the presence of target thrombin (TB), the TBA on the multilayer film could catch the TB onto the electrode surface, which resulted in a barrier for electro-transfer, leading to decrease of the current. The proposed method avoided the cubsome redox probe labeling process, increased the amount of redox probe and reduced the distance between the redox probe and electrode surface. Thus, the approach showed a high sensitivity and a wider linearity to TB in the range from 0.12 nM to 46 nM with a detection limit of 40 pM., (Copyright 2010 Elsevier B.V. All rights reserved.)

A novel immunosensor for rapid separation-free determination of carcinoembryonic antigen (CEA) in human serum is proposed. The immunosensor is prepared by co-immobilizing thionine and horseradish peroxidase (HRP)-labeled CEA antibody on a glassy carbon electrode (GCE) through covalently binding them to GCE with a glutaraldehyde (GA) linkage. The electrochemical behavior of the immobilized thionine displays a surface-controlled electrode process with an average electron transfer rate constant of 4.74+/-2.99 s(-1). It can be used as an electron transfer mediator for enzymatic activity detection of the HRP-labeled antibody to CEA. After the immunosensor is incubated with CEA solution at 23 degrees C for 40 min, the access of activity center of the HRP to thionine is partly inhibited, which leads to a linear decrease in the catalytic efficiency of the HRP to the oxidation of immobilized thionine by H(2)O(2) at -300 mV over two CEA concentration ranges from 0.5 to 3.0 and 3.0 to 167 ng/ml. Under optimal conditions, the detection limit for the CEA immunoassay is 0.1 ng/ml at three times background noise. The immunosensor shows good accuracy and acceptable storage stability, precision and reproducibility with intra-assay CVs of 6.1% and 5.8% at 2.5 and 50 ng/ml CEA, respectively, and an inter-assay CV of 6.3% at 50 ng/ml. This method is economical and shortens the analytical time, making it potentially attractive for clinical immunoassays.

Previous studies have demonstrated that syngeneic transplants of striatal tissue can ameliorate locomotor deficits in rodent models of Huntington's disease (HD). In the present study, we have examined whether human to rat xenografts of fetal striatal tissue can exert a similar recovery of function. Rodents with unilateral striatal lesions were transplanted with human striatal cells from a donor 14 weeks post-conception, and subsequently displayed a progressive decrease in rotational asymmetry in comparison to sham (saline) transplanted animals. Histological analysis revealed acetylcholinesterase (AChE)-positive fibers and NADPH-diaphorase (NADPH-d)-positive neurons within transplanted tissue. These results suggest that human fetal striatum at a gestational age of 14 weeks may potentially be useful as a source of donor tissue for transplantation in the treatment of HD.

Studies of speed, resolution, and sensitivity indicate packed column supercritical fluid chromatography is a viable technique for the analysis of antipsychotic drugs. Fourteen such drugs (mostly phenothiazines) were studied from a cyanopropyl liquid chromatography packed column with a tertiary mobile phase of carbon dioxide, methanol, and isopropylamine. An arbitrary mix of 10 components was baseline resolved in approximately 11 min. Detection limits were as low as 125 ppb, with a feasible 10-fold decrease. Without the isopropylamine in the mobile phase, none of the solutes eluted. With the additive, all produced symmetrical peaks and high efficiency (i.e., > 80% of theoretical). Changing modifier concentration was the most effective physical parameter for changing retention but had little effect on selectivity. Temperature changes had a modest effect on retention but provided surprisingly large changes in selectivity, with numerous peak reversals occurring over only a 30 degrees C temperature range. In addition, temperature programming was the most effective means to optimize resolution of the 10-component mix. No noticeable loss in efficiency accompanied the temperature programs.

A sensitive high-performance liquid chromatography (HPLC) method has been developed for the determination of bound sulfur in mammalian serum. In this work, bound sulfur is defined as divalent sulfur that is easily liberated as sulfide by reduction with dithiothreitol. Released sulfide was treated by flow gas dialysis and converted into a fluorescent derivative, thionine, through the reaction with p-phenylenediamine and ferric ion. Thionine was then determined by HPLC using fluorometric detection. The calibration curve for bound sulfur is linear in the range from 0.1 to 10 microM, and the sensitivity of this method allows detection of less than 10 nM bound sulfur (0.5-ml sample). Recoveries of low-molecular-weight and high-molecular-weight bound sulfur added to human serum at 1.0-5.0 microM levels averaged between 94 and 101%. The proposed method was applied to the determination of bound sulfur in human and various animal sera. The mean concentration in normal human serum was 1.16 +/- 0.09 microM for males (n = 5) and 1.07 +/- 0.18 microM for females (n = 5). The mean concentrations ranged from 1.55 to 6.18 microM in animal sera. The form of the sulfur bound in serum was also discussed.

Chlorpromazine N-oxide, fluphenazine N4'-oxide, prochlorperazine N4'-oxide, sulforidazine N-oxide, and trifluoperazine N4'-oxide were synthesized by oxidation of the designated nitrogen atom in the N-10 side chain of the respective parent drug with 3-chloroperoxybenzoic acid. In the case of trifluoperazine, a stepwise increase in the amount of oxidant yielded the N1',N4'-dioxide and N1',N4',S-trioxide. The N',S-dioxides of chlorpromazine and sulforidazine were obtained by hydrogen peroxide oxidation of the appropriate parent drug.

A silica gel thin-layer chromatographic procedure is described for the study of the myelin lipid patterns in a small phylogenetic series of nerve tissue specimens. It involves the selective staining by the thiazine dye thionine and the interpretations were facilitated by a preceding primary alkylamine O-deacylation step. Glycolipids, including sulfatides, and ethanolamine plasmalogens were the principal characterizing lipids.

A sensitive method has been developed for the visualization of nonradiolabeled glycosaminoglycan oligosaccharides resolved by polyacrylamide gel electrophoresis using fixation with azure A followed by staining with ammoniacal silver. This method, which can detect as little as 1-2 ng of a single oligosaccharide species, can be used to stain a few micrograms of a complex oligosaccharide mixture. The combination of gradient polyacrylamide gel electrophoresis and sequential azure A/silver staining can be applied to the analysis of all the complex glycosaminoglycans (i.e., heparin, heparan sulfate, chondroitin/dermatan sulfate, keratan sulfate) and hyaluronate, as well as to comparisons of specificities of the glycosaminoglycan-degrading enzymes. This procedure may be particularly valuable in situations where the availability of glycosaminoglycan is very limited and/or where radiolabeling is impractical or undesirable.