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Tau protein has been described for several decades as a promoter of tubulin assembly into microtubules. Dysregulation or alterations in Tau expression have been related to various brain cancers, including the highly aggressive and lethal brain tumor glioblastoma multiform (GBM). In this respect, Tau holds significant promise as a target for the development of novel therapies. Here, we examined the structure-activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau binding, Tau fibrillation, and cellular effects on Tau-expressing cancer cells. By spectrofluorometric approach, we found that two compounds, 2 and 9, demonstrated high affinity for Tau and exhibited a strong propensity to inhibit Tau fibrillation. Then, the biological activity of these compounds was evaluated on several Tau-expressing cells derived from glioblastoma. The two lead compounds displayed a high anti-metabolic activity on cells related to an increased fission of the mitochondria network. Moreover, we showed that both compounds induced microtubule bundling within newly formed neurite-like protrusions, as well as with defection of cell migration. Taken together, our results provide a strong experimental basis to develop new potent molecules targeting Tau-expressing cancer cells, such as GBM.
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Glioblastoma , Proteínas tau , Humanos , Proteínas tau/metabolismo , Glioblastoma/metabolismo , Microtúbulos/metabolismo , Tiazóis/farmacologia , Tubulina (Proteína)/metabolismo , Ligação ProteicaRESUMO
The aims of the present study were to characterize the mechanical output of final road sprints of an elite sprinter during international competitions in relation to his power-velocity-endurance characteristics and to investigate the relationship between this sprint performance and the power produced during preceding phases of the race. The sprinter performed a set of short and long sprints (5 to 15-s) on a cycle ergometer to determine his maximal power-velocity-endurance profile. Based on eleven races, the distribution of power throughout each race, peak and mean power (Ppeak and Pmean ) and associated pedaling rates (vPpeak and vPmean ) during the final sprint were analyzed. The power-velocity-endurance profile of the sprinter indicated that his theoeretical mean maximal power and corresponding optimal pedaling rate ranged from 20.0 W.kg-1 (124 rpm) for a 1-s sprint to 15.0 W.kg-1 (109 rpm) for 20 s. Race data showed that final road sprints were mainly performed on the ascending limb of the power-velocity relationship (vPpeak , 104 ± 8 and vPmean , 101 ± 8 rpm). Additionally, Ppeak and Pmean were lower than the theoretical maximal power determined from the power-velocity-endurance profile (9.9 ± 7.0% and 10.6 ± 9.8%, respectively), which highlighted a significant state of fatigue induced by the race. Finally, sprint power exhibited a high variability between races and was strongly related to the level of power produced during the last minute before the sprint. These findings show the importance of considering both the power-velocity-endurance qualities and the power demand of the last lead-up phase before the sprint in order to optimize final sprint performance.
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Ciclismo , Ergometria , Humanos , Estudos LongitudinaisRESUMO
Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and active ingredients issued from realistic bioprocesses, this work re-evaluates the HGA pigment and makes an updated inventory of its syntheses, microbial pathways, and properties, with tracks and recent advances for its large-scale production. The mechanism of the HGA polymerization is also well documented. In alkaptonuria, pyomelanin formation leads to connective tissue damage and arthritis, most probably due to the ROS issued from HGA oxidation. While UV radiation on human melanin may generate degradation products, pyomelanin is not photodegradable, is hyperthermostable, and has other properties better than L-Dopa melanin. This review aims to raise awareness about the potential of this pigment for various applications, not only for skin coloring and protection but also for other cells, materials, and as a promising (semi)conductor for bioelectronics and energy.
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Ácido Homogentísico , Melaninas , Ácido Homogentísico/metabolismo , Humanos , Melaninas/metabolismo , Pigmentação , TirosinaRESUMO
The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.
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The absence of Klotho (KL) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, KL protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the KL promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate KL transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express KL endogenously. All compounds elevated KL protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed FGF23 (fibroblast growth factor 23) signalling. Compounds G-I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with KL siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of KL regulation. Further optimization will provide pharmacological tools for in vivo studies of KL.
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Regulação da Expressão Gênica/efeitos dos fármacos , Glucuronidase/metabolismo , Envelhecimento/fisiologia , Animais , Linhagem Celular , Clonagem Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/fisiologia , Glucuronidase/genética , Rim/citologia , Proteínas Klotho , Camundongos , Gambás , RatosRESUMO
Hemiindigoids comprise a range of natural and synthetic scaffolds that share the same aromatic hydrocarbon backbone as well as promising biological and optical properties. The encouraging therapeutic potential of these scaffolds has been unraveled by many studies over the past years and uncovered representants with inspiring pharmacophoric features such as the acetylcholinesterase inhibitor donezepil and the tubulin polymerization inhibitor indanocine. In this review, we summarize the last advances in the medicinal potential of hemiindigoids, with a special attention to molecular design, structure-activity relationship, ligand-target interactions, and mechanistic explanations covering their effects. As their strong fluorogenic potential and photoswitch behavior recently started to be highlighted and explored in biology, giving rise to the development of novel fluorescent probes and photopharmacological agents, we also discuss these properties in a medicinal chemistry perspective.
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Química Farmacêutica , Inibidores da Colinesterase , Acetilcolinesterase , Benzofuranos , Inibidores da Colinesterase/farmacologia , Corantes Fluorescentes , Indanos , Ligantes , Moduladores de TubulinaRESUMO
Despite being extensively studied for several decades, the microtubule-associated protein Tau has not finished revealing its secrets. For long, Tau has been known for its ability to promote microtubule assembly. A less known feature of Tau is its capability to bind to cancer-related protein kinases, suggesting a possible role of Tau in modulating microtubule-independent cellular pathways that are associated with oncogenesis. With the intention of finding new therapeutic targets for cancer, it appears essential to examine the interaction of Tau with these kinases and their consequences. This review aims at collecting the literature data supporting the relationship between Tau and cancer with a particular focus on glioblastoma tumors in which the pathological significance of Tau remains largely unexplored. We will first treat this subject from a mechanistic point of view showing the pivotal role of Tau in oncogenic processes. Then, we will discuss the involvement of Tau in dysregulating critical pathways in glioblastoma. Finally, we will outline promising strategies to target Tau protein for the therapy of glioblastoma.
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In chlordecone (CLD)-contaminated soils of the French West Indies, if microbial remediation or a physicochemical remediation process, e.g., in situ chemical reduction, is implemented, concentrations of degradation byproducts, such as hydrochlordecones, are expected to increase in the ecosystems. To study their impact in mixtures with CLD, bioassays were carried out. They consisted in evaluating the regenerative capacity of hydra polyps, from a clone whose phylogenetic analysis confirmed that it belonged to the species Hydra vulgaris Pallas, 1766. Hydra gastric sections were exposed to CLD alone or CLD plus dechlorinated byproducts (CLD-BP) for 96 h to assess regeneration. Based on chromatographic analysis, the CLD-BP mix was composed of the 5-monohydrochlordecone isomer (CAS nomenclature), four dihydrochlordecone isomers, and one trihydrochlordecone isomer representing 50%, 47%, and 3% of the total chromatographic area, respectively. A total of 18 mixtures of CLD and CLD-BP were tested. Six environmental concentrations of CLD (2.10-4 µM to 4.10-2 µM) and a similar range of CLD-BP were used. Results from exposures to CLD alone showed the following: (i) a significant decrease in the regenerative capacity of hydra, except at the lowest concentration (2.10-4 µM); (ii) a concentration-independent deleterious effect. The regeneration scores obtained after the exposure to the addition of CLD-BP were not significantly different from those obtained after exposure to CLD alone. Using an experimental design, a modeling of the regeneration scores of hydra exposed to mixtures is proposed. Interpreted carefully, since they are limited to only one type of bioassay, the present results suggest that the situation in the aquatic environments should not become worse in terms of toxicity, if soil remediation programs resulting in the formation of hydrochlordecones are put in place.
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Clordecona , Hydra , Animais , Projetos de Pesquisa , Ecossistema , Filogenia , Misturas ComplexasRESUMO
Pyomelanin is a polymer of homogentisic acid synthesized by microorganisms. This work aimed to develop a production process and evaluate the quality of the pigment. Three procedures have been elaborated and optimized, (1) an HGA-Mn2+ chemical autoxidation (PyoCHEM yield 0.317 g/g substrate), (2) an induced bacterial culture of Halomonas titanicae through the 4-hydroxyphenylacetic acid-1-hydroxylase route (PyoBACT, 0.55 g/L), and (3) a process using a recombinant laccase extract with the highest level produced (PyoENZ, 1.25 g/g substrate) and all the criteria for a large-scale prototype. The chemical structures had been investigated by 13C solid-state NMR (CP-MAS) and FTIR. Car-Car bindings predominated in the three polymers, Car-O-Car (ether) linkages being absent, proposing mainly C3-C6 (α-bindings) and C4-C6 (ß-bindings) configurations. This work highlighted a biological decarboxylation by the laccase or bacterial oxidase(s), leading to the partly formation of gentisyl alcohol and gentisaldehyde that are integral parts of the polymer. By comparison, PyoENZ exhibited an Mw of 5,400 Da, was hyperthermostable, non-cytotoxic even after irradiation, scavenged ROS induced by keratinocytes, and had a highly DPPH-antioxidant and Fe3+-reducing activity. As a representative pigment of living cells and an available standard, PyoENZ might also be useful for applications in extreme conditions and skin protection.
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INTRODUCTION: Mini-invasive bronchoscopic techniques (such as radial endobronchial ultrasonography (rEBUS) and electromagnetic navigation (EMN)) have been developed to reach the peripheral lung but result in small samples. The feasibility of an adequate molecular testing from these specimens has been very little studied. METHODS: We retrospectively reviewed EMN and rEBUS procedures performed in patients diagnosed with lung cancer in our institution in 2017 and 2018. We analysed the sensitivity for rEBUS and EMN and each sampling method, and the feasibility of a comprehensive molecular testing. RESULTS: In total, 317 rEBUS and 14 EMN were performed. Median sizes of tumours were 16 and 32â mm for EMN and rEBUS, respectively. Overall sensitivity for rEBUS and EMN was 84.3%. Cytology was found to be complementary with biopsies, with 13.3% of cancer diagnosed on cytology while biopsies were negative. Complication rate was 2.4% (pneumothorax 1.5%, mild haemoptysis 0.9%). Genotyping (immunohistochemistry for ROS1 and ALK followed by fluorescence in situ hybridisation if positive and hybrid capture next-generation sequencing covering 48 genes), when ordered (n=188), was feasible in 69.1% (EGFR 17.7%, KRAS 31.7%, BRAF 4.8%, ALK 1.2%, MET 3.1%, HER2 0.8%). PD-L1 (programmed death-ligand 1) expression, when ordered (n=232), could be analysed in 94% of cases. Overall, 56.9% (33 out of 58) of patients for whom genotyping was not feasible underwent a second sampling (12 pretreatment, 21 at progression), allowing for the detection of six actionable genotypes (five EGFR, one MET). CONCLUSION: rEBUS and EMN are sensitive and safe procedures that result in limited samples, often not suitable for genotyping, highlighting the importance of integrating liquid biopsy in routine testing.
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Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified.
Assuntos
Acridinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Acridinas/síntese química , Humanos , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases DyrkRESUMO
In our search for potent anti-HIV and antiplasmodial agents, novel series of flavonoid derivatives and their chalcone intermediates were synthesized and evaluated for inhibition of HIV multiplication and antiproliferative activity on Plasmodium falciparum parasites. Chalcones exhibited a more selective antiplasmodial activity than flavonoids. Methoxyflavone 7e was the only one compound active in both P. falciparum and HIV-1 whereas aminomethoxyflavones showed activity against HIV-2. Para substitution on the B ring seemed to increase HIV-2 potency.
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Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Fármacos Anti-HIV/síntese química , Antimaláricos/síntese química , Linhagem Celular , Sobrevivência Celular , Flavonoides/síntese química , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacosRESUMO
The complete (1)H and (13)C NMR assignment of 9 acetamidochalcones, 18 acetamidoflavones, 18 aminoflavones, 9 acetamidoflavonols and 9 aminoflavonols has been performed using one- and two-dimensional NMR techniques including COSY, HMQC and HMBC experiments.
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Acetamidas/química , Acetamidas/síntese química , Flavonoides/química , Flavonoides/síntese química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética/normas , Estrutura Molecular , Prótons , Padrões de Referência , EstereoisomerismoRESUMO
Chlordecone (CLD) is an organochlorine pesticide widely used in the past to control pest insects in banana plantations in the French West Indies. Due to its persistence in the environment, CLD has contaminated the soils where it has been spread, as well as the waters, and is still present in them. The objective of our study was to evaluate the effects of chronic exposure to environmentally relevant CLD concentrations in an animal model, the freshwater hydra (Hydra circumcincta). In a multi-marker approach, we have studied the expression of some target stress genes, the morphology, and the asexual reproduction rates. Our data showed that exposure to low concentrations of chlordecone leads to (i) a modulation of the expression of target genes involved in oxidative stress, detoxification, and neurobiological processes, and (ii) morphological damages and asexual reproduction impairment. We have observed non-monotonic dose-response curves, which agree with endocrine-disrupting chemical effects. Thus, "U-shaped" dose-response curves were observed for SOD, GRed, Hym355, and potentially GST gene expressions; inverted "U-shaped" curves for GPx and CYP1A gene expressions and reproductive rates; and a biphasic dose-response curve for morphological damages. Therefore, in the range of environmental concentrations tested, very low concentrations of CLD can produce equally or more important deleterious effects than higher ones. Finally, to our knowledge, this study is the first one to fill the lack of knowledge concerning the effects of CLD in Hydra circumcincta and confirms that this diploblastic organism is a pertinent freshwater model in the risk assessment.
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Clordecona , Cnidários , Hydra , Inseticidas , Poluentes do Solo , Animais , Clordecona/análise , Exposição Ambiental , Água Doce , Inseticidas/análise , Poluentes do Solo/análise , Índias OcidentaisRESUMO
The biological activities of berberine, a natural plant molecule, are known to be affected by structural modifications, mostly at position 9 and/or 13. A series of new 13-substituted berberine derivatives were synthesized and evaluated in term of antimicrobial activity using various microorganisms associated to human diseases. Contrarily to the original molecule berberine, several derivatives were found strongly active in microbial sensitivity tests against Mycobacterium, Candida albicans and Gram-positive bacteria, including naïve or resistant Bacillus cereus, Staphylococcus aureus and Streptococcus pyogenes with minimal inhibitory concentration (MIC) of 3.12 to 6.25 µM. Among the various Gram-negative strains tested, berberine's derivatives were only found active on Helicobacter pylori and Vibrio alginolyticus (MIC values of 1.5-3.12 µM). Cytotoxicity assays performed on human cells showed that the antimicrobial berberine derivatives caused low toxicity resulting in good therapeutic index values. In addition, a mechanistic approach demonstrated that, contrarily to already known berberine derivatives causing either membrane permeabilization, DNA fragmentation or interacting with FtsZ protein, active derivatives described in this study act through inhibition of the synthesis of peptidoglycan or RNA. Overall, this study shows that these new berberine derivatives can be considered as potent and safe anti-bacterial agents active on human pathogenic microorganisms, including ones resistant to conventional antibiotics.
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We have synthesized quinolinones with potential antiparasitic and anti-HIV activities by an original two-step method involving microwave irradiation and have evaluated their activities against Plasmodium falciparum, Leishmania donovani, Trichomonas vaginalis, and HIV. None of the tested compounds had been previously described using this method of synthesis. One of the compounds had interesting antiparasitic and anti-HIV activity, which could be improved by substitution with different radicals.
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Fármacos Anti-HIV/síntese química , Antiparasitários/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Quinolonas/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/toxicidade , Antiparasitários/química , Antiparasitários/toxicidade , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/toxicidade , Humanos , Leishmania donovani/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Quinolonas/toxicidade , Trichomonas vaginalis/efeitos dos fármacosRESUMO
Small non-coding microRNAs (miRNAs) have been found to play critical roles in many biological processes by controlling gene expression at the post-transcriptional level. They appear to fine-tune the immune response by targeting key regulatory molecules, and their abnormal expression is associated with immune-mediated inflammatory disorders. Monocytes actively contribute to tissue homeostasis by triggering acute inflammatory reactions as well as the resolution of inflammation and tissue regeneration, in case of injury or pathogen invasion. Their contribution to tissue homeostasis can have many aspects because they are able to differentiate into different cell types including macrophages, dendritic cells, and osteoclasts, which fulfill functions as different as bone remodeling and immune response. Monocytes consist of different subsets with subset-specific expression of miRNAs linked to distinct biological processes dedicated to specific roles. Therefore, understanding the role of miRNAs in the context of monocyte heterogeneity may provide clues as to which subset gives rise to which cell type in tissues. In addition, because monocytes are involved in the pathogenesis of chronic inflammation, associated with loss of tissue homeostasis and function, identifying subset-specific miRNAs might help in developing therapeutic strategies that target one subset while sparing the others. Here, we give an overview of the state-of-the-art research regarding miRNAs that are differentially expressed between monocyte subsets and how they influence monocyte functional heterogeneity in health and disease, with descriptions of specific miRNAs. We also revisit the existing miRNome data to propose a canonical signature for each subset.
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MicroRNAs/imunologia , Monócitos/imunologia , Animais , HumanosRESUMO
The discovery of the potent anticancer properties of natural alkaloids in the pyrido-thiazolo-acridine series has suggested that thiazolo-acridine derivatives could be of great interest. In a continuous attempt to develop DNA-binding molecules and DNA photo-cleavers, 16 new thiazolo[5,4-a]acridines were synthesized and studied for their photo-inducible DNA-intercalative, cytotoxic and mutagenic activities, by use of the DNA methyl-green bioassay, the Alamar Blue viability assay and the Salmonella mutagenicity test using strains TA97a and TA98 with and without metabolic activation and photo-activation. Without photo-activation, one compound showed a DNA-intercalative activity in the DNA major groove while three compounds displayed intercalating properties after photo-activation. In the dark, four molecules possessed cytotoxic activities against a THP1 acute monocytic leukemia cell line while 15 derivatives displayed photo-inducible cytotoxic activity against this cell line. All compounds were mutagenic in strain TA97a with metabolic activation (+S9mix) and 15 molecules were mutagenic in strain TA98 without activation (-S9mix). Study of the quantitative structure-activity relationships (QSAR) from the Salmonella mutagenicity data revealed that several descriptors could describe cytotoxic and mutagenic activities after photo-activation. From the results of the mutagenicity test, four compounds with elevated mutagenic activities were selected for additional experiments. Their capacities to induce single-strand breaks (SSB) and chromosome-damaging effects were monitored by the comet and the micronucleus assays in normal human keratinocytes. Comparison of the minimal genotoxic concentrations showed that two compounds possessed higher capacities to induce SSB after photo-activation. In the micronucleus assay, three molecules were able to induce high numbers of micronuclei following photo-activation. Overall, the results of this study confirm that acridines are predominantly genotoxic via a DNA-intercalating mechanism in the dark, while DNA-adducts were probably induced following photo-activation.
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Acridinas/toxicidade , Dano ao DNA , Luz , Mutagênicos/toxicidade , Tiazóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Substâncias Intercalantes/toxicidade , Testes de Mutagenicidade , Relação Quantitativa Estrutura-AtividadeRESUMO
Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6Chigh and non-classical Ly6Clow monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a-/- mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6Chigh monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a-/- mice. Results: We showed that the expression of miR-146a is reduced in the Ly6Chigh subset of CIA mice and in the analogous monocyte subset (CD14+CD16-) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo. In vivo delivery of miR-146a to Ly6Chigh monocytes, and not to Ly6Clow monocytes, rescues bone erosion in miR-146a-/- arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a+/+ mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a-/- Ly6Chigh monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6Chigh, and not Ly6Clow, monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6Chigh monocytes to prevent joint destruction while sparing inflammation in arthritis.
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Antígenos Ly/análise , Artrite/patologia , Osso e Ossos/patologia , Diferenciação Celular , MicroRNAs/análise , Monócitos/fisiologia , Osteoclastos/fisiologia , Animais , Artrite/induzido quimicamente , Artrite/terapia , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , MicroRNAs/administração & dosagem , Monócitos/químicaRESUMO
Europe has a growing aging population, leading to the need for adapted healthcare services. Our work aims at proposing a solution for falls detection of elderly people using sound recognition based on a hierarchical i-vectors system. The system presented in this paper improves significantly the accuracy of sound recognition compared to the state of the art methods. The latter provides a good recognition rate of 81.98% on noiseless sounds. This system needs to be tested in a noisy environment and this can be improved by using new sound descriptors.