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Cancer Medicine Nov 2019Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key...
BACKGROUND
Lung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment.
METHODS
We used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case-control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning.
RESULTS
The regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival.
CONCLUSION
Using an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.
Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Case-Control Studies; Drug Repositioning; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; Phenotype; Prognosis; Survival Analysis; Transcription Factors
PubMed: 31503425
DOI: 10.1002/cam4.2493 -
Journal of Analytical Toxicology Aug 2022Promazine is one of the oldest phenothiazine derivatives that have been proposed for the treatment of various psychiatric disorders. The drug is available as tablets, as...
Promazine is one of the oldest phenothiazine derivatives that have been proposed for the treatment of various psychiatric disorders. The drug is available as tablets, as syrups and in injectable forms. Despite its prescription to millions of subjects, its detection in human hair has seldom been reported. The aim of the present work is to develop a specific method to identify promazine in human hair by liquid chromatography-tandem mass spectrometry and to apply it to a patient who was self-medicating. The method involves overnight incubation of 20 mg of cut hair in 1 mL of pH 9.5 borate buffer in the presence of amitriptyline-d3 at 40°C. The chromatographic separation was performed using a reverse phase column HSS C18 with a gradient elution for 15 min. Linearity was verified from 0.5 to 500 pg/mg (r2 = 0.9996), after spiking blank hair with the corresponding amounts of promazine. The limit of detection was estimated at 0.1 pg/mg. The precision was lower than 20%. Promazine was detected in the hair of a psychotic subject at 228-270 pg/mg in a 3 × 1 cm segment. Given this was a patient who was self-medicating, her physician requested an immediate drug discontinuation. In a fresh hair specimen collected 3 months later, the proximal segment (0-1 cm) tested positive at 0.9 pg/mg, clearly indicating that the time to obtain a negative result after promazine discontinuation is about 3-4 months.
Topics: Chromatography, Liquid; Female; Hair; Humans; Promazine; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 34518883
DOI: 10.1093/jat/bkab101 -
Chemistry, An Asian Journal Feb 2020Designed transition metal complexes predominantly catalyze Michael addition reactions. Inorganic and organic base-catalyzed Michael addition reactions have been...
Designed transition metal complexes predominantly catalyze Michael addition reactions. Inorganic and organic base-catalyzed Michael addition reactions have been reported. However, known base-catalyzed reactions suffer from the requirement of solvents, additives, high pressure and also side-reactions. Herein, we demonstrate a mild and environmentally friendly strategy of readily available KO Bu-catalyzed Michael addition reactions. This simple inorganic base efficiently catalyzes the Michael addition of underexplored acrylonitriles, esters and amides with (oxa-, aza-, and thia-) heteroatom nucleophiles. This catalytic process proceeds under solvent-free conditions and at room temperature. Notably, this protocol offers an easy operational procedure, broad substrate scope with excellent selectivity, reaction scalability and excellent TON (>9900). Preliminary mechanistic studies revealed that the reaction follows an ionic mechanism. Formal synthesis of promazine is demonstrated using this catalytic protocol.
PubMed: 31957937
DOI: 10.1002/asia.201901647 -
Frontiers in Microbiology 2020The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment...
The emergence of multidrug-resistant bacteria constitutes a significant public health issue worldwide. Consequently, there is an urgent clinical need for novel treatment solutions. It has been shown that phenothiazines can act as adjuvants to antibiotics whereby the minimum inhibitory concentration (MIC) of the antibiotic is decreased. However, phenothiazines do not perform well , most likely because they can permeate the blood-brain (BBB) barrier and cause severe side-effects to the central nervous system. Therefore, the aim of this study was to synthesize a promazine derivate that would not cross the BBB but retain its properties as antimicrobial helper compound. Surprisingly, studies showed that the novel compound, JBC 1847 exhibited highly increased antimicrobial activity against eight Gram-positive pathogens (MIC, 0.5-2 mg/L), whereas a disc diffusion assay indicated that the properties as an adjuvant were lost. JBC 1847 showed significant ( < 0.0001) activity against a strain compared with the vehicle, in an wound infection model. However, both and analyses showed that JBC 1847 possesses strong affinity for human plasma proteins and an Ames test showed that generally, it is a non-mutagenic compound. Finally, predictions suggested that the compound was not prone to pass the BBB and had a suitable permeability to the skin. In conclusion, JBC 1847 is therefore suggested to hold potential as a novel topical agent for the clinical treatment of skin and soft tissue infections, but pharmacokinetics and pharmacodynamics need to be further investigated.
PubMed: 33101232
DOI: 10.3389/fmicb.2020.560798 -
Journal of Alzheimer's Disease : JAD 2020We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old...
We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.
Topics: Aged; Biperiden; Cerebral Cortex; Fluorodeoxyglucose F18; Frontotemporal Dementia; Humans; Male; Mental Status and Dementia Tests; Muscarinic Antagonists; Neuroimaging; Positron-Emission Tomography
PubMed: 32144991
DOI: 10.3233/JAD-191290 -
Antimicrobial Agents and Chemotherapy Mar 2020Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some...
Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on , reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against but also against some spp., in particular against In parallel, we identified drugs that had antifungal activity against and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.
Topics: Amphotericin B; Animals; Antifungal Agents; Auranofin; Candida albicans; Candidiasis; Cell Line; Ciclopirox; Cryptococcosis; Cryptococcus neoformans; Drug Evaluation, Preclinical; Drug Repositioning; Drug Synergism; Erythromycin; Flucytosine; Humans; Mice; Microbial Sensitivity Tests; Opportunistic Infections; RAW 264.7 Cells; Zebrafish
PubMed: 31988099
DOI: 10.1128/AAC.01921-19 -
Spectrochimica Acta. Part A, Molecular... Feb 2020Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular...
Phenothiazines are very effective antipsychotic drugs, which also have anticancer and antimicrobial activities. Despite being used in human treatment, the molecular mechanism of the biological actions of these molecules is not yet understood in detail. The role of the interactions between phenothiazines and proteins or lipid membranes has been much discussed. Herein, fourier-transform infrared (FTIR) spectroscopic studies were used to investigate the effect of three phenothiazines: fluphenazine (FPh); chlorpromazine (ChP); and propionylpromazine (PP) on the structures of a positively charged poly-l-lysine (PLL) peptide, a negatively charged dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DPPC/DPPG) membrane, and on the mutual interactions between electrostatically associated PLL molecules and DPPC/DPPG membranes. Phenothiazine-induced alterations in the secondary structure of PLL, the conformational state (trans/gauche) of the hydrocarbon lipid chains, and the hydration of the DPPC/DPPG membrane interface were studied on the basis of amide I' vibrations, antisymmetric and symmetric stretching vibrations of the CH groups of the lipid hydrocarbon chains (νCH), and stretching vibrations of the lipid C=O groups (νC = O), respectively. It was shown that in the presence of negatively charged DPPC/DPPG membranes, the phenothiazines were able to modify the secondary structure of charged PLL molecules. Additionally, the effect of PLL on the structure of DPPC/DPPG membranes was also altered by the presence of the phenothiazine molecules.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Antipsychotic Agents; Cell Membrane; Chlorpromazine; Fluphenazine; Humans; Phosphatidylglycerols; Polylysine; Promazine; Spectroscopy, Fourier Transform Infrared
PubMed: 31689607
DOI: 10.1016/j.saa.2019.117563