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2.
Psychiatr Pol ; : 1-14, 2024 Feb 05.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-38587972

RESUMO

OBJECTIVES: One of the dangerous phenomena that reinforces a negative attitude towards one's own body is the so-called family fat talk1, i.e. conversations initiated by carers/siblings selfdevaluing body shapes and sizes. The aim of our own research was to adapt the self-report two-factor tool Family Fat Talk Questionnaire (FFTQ) by MacDonald et al., which may be used in the prophylaxis of maladaptive behaviours towards eating and the body, especially in the adolescent population. METHODS: The study covered 391 people at the turn of late adolescence and early adulthood. The following were used: (1) personal questionnaire - to control secondary variables (e.g. gender, BMI, difference between the actual and desired body weight), (2) Family Fat Talk Questionnaire in the Polish language version (FFTQ-PL) and (3) Kwestionariusz wizerunku ciala (KWCO) by A. Glebocka to check external accuracy. RESULTS: The research results indicate that the FFTQ-PL has satisfactory reliability and measurement accuracy, and its two-factor structure (factor 1 - "I"; factor 2 - "Family") has been confirmed. CONCLUSIONS: This measure is worth using in screening studies to identify people - especially adolescents - engaging in self-devaluing conversations within the family. It turns out that fat talk, especially in the case of people with a negative body image, can become a risk factor for risky eating practices.

3.
Sci Rep ; 14(1): 3594, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351313

RESUMO

Fungal pathogens are considered as serious factors for deadly diseases and are a case of medical concern. Invasive fungal infections also complicate the clinical course of COVID-19, leading to a significant increase in mortality. Furthermore, fungal strains' multidrug resistance has increased the demand for antifungals with a different mechanism of action. The present study aimed to identify antifungal compounds targeting yeast topoisomerase II (yTOPOII) derived from well-known human topoisomerase II (hTOPOII) poisons C-1305 and C-1311. Two sets of derivatives: triazoloacridinones (IKE1-8) and imidazoacridinones (IKE9-14) were synthetized and evaluated with a specific emphasis on the molecular mechanism of action. Our results indicated that their effectiveness as enzyme inhibitors was not solely due to intercalation ability but also as a result of influence on catalytic activity by the formation of covalent complexes between plasmid DNA and yTOPOII. Lysine conjunction increased the strength of the compound's interaction with DNA and improved penetration into the fungal cells. Triazoloacridinone derivatives in contrast to starting compound C-1305 exhibited moderate antifungal activity and at least twice lower cytotoxicity. Importantly, compounds (IKE5-8) were not substrates for multidrug ABC transporters whereas a derivative conjugated with lysine (IKE7), showed the ability to overcome C. glabrata fluconazole-resistance (MIC 32-64 µg mL-1).


Assuntos
Antifúngicos , Lisina , Humanos , Antifúngicos/farmacologia , Fluconazol/farmacologia , Transportadores de Cassetes de Ligação de ATP , Candida glabrata , DNA , Testes de Sensibilidade Microbiana
4.
J Enzyme Inhib Med Chem ; 39(1): 2302920, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38221785

RESUMO

Human DNA topoisomerases are essential for crucial cellular processes, including DNA replication, transcription, chromatin condensation, and maintenance of its structure. One of the significant strategies employed in cancer treatment involves the inhibition of a specific type of topoisomerase, known as topoisomerase II (Topo II). Carbazole derivatives, recognised for their varied biological activities, have recently become a significant focus in oncological research. This study assesses the efficacy of three symmetrically substituted carbazole derivatives: 2,7-Di(2-furyl)-9H-carbazole (27a), 3,6-Di(2-furyl)-9H-carbazole (36a), and 3,6-Di(2-thienyl)-9H-carbazole (36b) - as anticancer agents. Among investigated carbazole derivatives, compound 3,6-di(2-furyl)-9H-carbazole bearing two furan moieties emerged as a novel catalytic inhibitor of Topo II. Notably, 3,6-di(2-furyl)-9H-carbazole effectively selectively inhibited the relaxation and decatenation activities of Topo IIα, with minimal effects on the IIß isoform. These findings underscore the potential of compound 3,6-Di(2-furyl)-9H-carbazole as a promising lead candidate warranting further investigation in the realm of anticancer drug development.


Assuntos
Antineoplásicos , Inibidores da Topoisomerase II , Humanos , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Carbazóis/farmacologia , Carbazóis/química , DNA Topoisomerases Tipo II , Apoptose
5.
Inorg Chem ; 63(2): 1296-1316, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38174357

RESUMO

Organometallic half-sandwich complexes [(η5-Cp)IrCl(L)]PF6 (1) and [(η5-Cp)RhCl(L)]PF6 (2) were prepared using pentamethylcyclopentadienyl chloride dimers of iridium(III) or rhodium(III) with the 4-amino-N-(2,2'-bipyridin-5-yl)benzenesulfonamide ligand (L) and ammonium hexafluorophosphate. The crystal structures of L, 1, and 2 were analyzed in detail. The coordination reactions of the ligand with the central ions were confirmed using various spectroscopic techniques. Additionally, the interactions between sulfaligand, Ir(III), and Rh(III) complexes with carbonic anhydrase (CA), human serum albumin (HSA), and CT-DNA were investigated. The iridium(III) complex (1) did not show any antiproliferative properties against four different cancer cell lines, i.e., nonsmall cell lung cancer A549, colon cancer HCT-116, breast cancer MCF7, lymphoblastic leukemia Nalm-6, and a nonmalignant human embryonic kidney cell line HEK293, due to high binding affinity to GSH. The sulfonamide ligand (L) and rhodium(III) complex (2) were further studied. L showed competitive inhibition toward CA, while complexes 1 and 2, uncompetitive. All compounds interacted with HSA, causing a conformational change in the protein's α-helical structure, suggesting the induction of a more open conformation in HSA, reducing its biological activity. Both L and 2 were found to induce cell death through a caspase-dependent pathway. These findings position L and 2 as potential starting compounds for pharmaceutical, therapeutic, or medicinal research.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Complexos de Coordenação , Neoplasias Pulmonares , Ródio , Humanos , Complexos de Coordenação/química , Ligantes , Irídio/farmacologia , Irídio/química , Ródio/farmacologia , Ródio/química , Células HEK293 , Antineoplásicos/química , Linhagem Celular Tumoral
6.
Nanotechnology ; 35(17)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38150722

RESUMO

Strain built-in electronic and optoelectronic devices can influence their properties and lifetime. This effect is particularly significant at the interface between two-dimensional materials and substrates. One such material is epitaxial hexagonal boron nitride (h-BN), which is grown at temperatures often exceeding 1000 °C. Due to the high growth temperature, h-BN based devices operating at room temperature can be strongly affected by strain generated during cooling due to the differences in lattice thermal expansion of h-BN and the substrate. Here, we present results of temperature-dependent Raman studies of the in-plane E2ghighphonon mode in the temperature range of 300-1100 K measured for h-BN grown by metalorganic vapor phase epitaxy. We observe a change, by an order of magnitude, in the rate of the temperature-induced frequency shift for temperatures below 900 K, indicating a strong reduction of the effective h-BN/substrate interaction. We attribute this behavior to the creation of h-BN wrinkles which results in strain relaxation. This interpretation is supported by the observation that no change of layer/substrate interaction and no wrinkles are observed for delaminated h-BN films transferred onto silicon. Our findings demonstrate that wrinkle formation is an inherent process for two-dimensional materials on foreign substrates that has to be understood to allow for the successful engineering of devices based on epitaxially grown van der Waals heterostructures.

7.
Int J Mol Sci ; 24(10)2023 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-37240092

RESUMO

The measurement of oxygen consumption is an important element in the understanding of an organism's metabolic state. Oxygen is also a phosphorescence quencher, which allows the evaluation of phosphorescence emitted by oxygen sensors. Two Ru(II)-based oxygen-sensitive sensors were used to study the effect of chemical compounds [(1) = [CoCl2(dap)2]Cl, and (2) = [CoCl2(en)2]Cl (AmB = amphotericin B) against reference and clinical strains of Candida albicans. The tris-[(4,7-diphenyl-1,10-phenanthroline)ruthenium(II)] chloride ([Ru(DPP)3]Cl2) (Box) adsorbed onto the DavisilTM silica gel was embedded in the silicone rubber Lactite NuvaSil® 5091 and the coating on the bottom of 96-well plates. The water-soluble oxygen sensor (BsOx = tris-[(4,7-diphenyl-1,10-phenanthrolinedisulphonic acid disodium)ruthenium(II)] chloride 'x' hydrate = {Ru[DPP(SO3Na)2]3}Cl2 = water molecules were omitted in the BsOx formula) was synthesized and characterized by RP-UHPLC, LCMS, MALDI, elemental analysis, ATR, UV-Vis, 1H NMR, and TG/IR techniques. The microbiological studies were performed in the environment of RPMI broth and blood serum. Both Ru(II)-based sensors turned out to be useful in the study of the activity of Co(III) complexes and the commercial antifungal drug amphotericin B. In addition, a new activity of the oxygen sensor, the soluble Ru(II) complex BsOx, was demonstrated, which is a mixture with amphotericin B that caused a significant increase in its antifungal activity. Thus, it is also possible to demonstrate the synergistic effect of compounds active against the microorganisms under study.


Assuntos
Antifúngicos , Rutênio , Antifúngicos/farmacologia , Anfotericina B/farmacologia , Rutênio/farmacologia , Rutênio/química , Cloretos , Água/química , Oxigênio/química
8.
Cells ; 12(4)2023 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-36831186

RESUMO

Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology.


Assuntos
Proteínas Quinases Ativadas por AMP , Schizosaccharomyces , Proteínas Quinases Ativadas por AMP/metabolismo , Saccharomyces cerevisiae/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Schizosaccharomyces/metabolismo , Autofagia/fisiologia
9.
Nano Lett ; 23(4): 1267-1272, 2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36689737

RESUMO

Hydrogen is an important building block in global strategies toward a future green energy system. To make this transition possible, intense scientific efforts are needed, also in the field of materials science. Two-dimensional crystals, such as hexagonal boron nitride (hBN), are very promising in this regard, as it has been demonstrated that micrometer-sized flakes are excellent barriers to molecular hydrogen. However, it remains an open question whether large-area layers fabricated by industrially relevant methods preserve such promising properties. In this work, we show that electron-beam-induced splitting of water creates hBN bubbles that effectively store molecular hydrogen for weeks and under extreme mechanical deformation. We demonstrate that epitaxial hBN allows direct visualization and monitoring of the process of hydrogen generation by radiolysis of interfacial water. Our findings show that hBN is not only a potential candidate for hydrogen storage but also holds promise for the development of unconventional hydrogen production schemes.

10.
J Cell Mol Med ; 26(14): 3950-3964, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35701366

RESUMO

The acridanone derivative 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) has been described as a potent inhibitor of cancer cell growth. Its mechanism of action in in vitro conditions was attributed, among others, to its ability to bind and stabilize the microtubule network and subsequently exhibit its tumour-suppressive effects in synergy with paclitaxel (PTX). Therefore, the objective of the present study was to analyse the effects of the combined treatment of C-1305 and PTX in vivo. In addition, considering the results of previous genomic analyses, particular attention was given to the effects of this treatment on tumour angiogenesis. Treatment with C-1305 revealed antitumor effect in A549 lung cancer cells, and combined treatment with PTX showed tendency to anticancer activity in HCT116 colon cancer xenografts. It also improved tumour blood perfusion in both tumour models. The plasma level of CCL2 was increased and that of PDGF was decreased after combined treatment with C-1305 and PTX. The experimental results showed that the levels of FGF1, TGF-ß and Ang-4 decreased, whereas the levels of ERK1/2 and Akt phosphorylation increased in HCT116 tumour tissue following combined treatment with both drugs. The results of in vitro capillary-like structure formation assay demonstrated the inhibiting effect of C-1305 on this process. Although previous in vitro and in vivo studies suggested a positive effect of C-1305 on cancer cells, combined treatment of HCT116 human colon and A549 lung cancer cells with both PTX and C-1305 in vivo showed that the antitumor activity was restricted and associated with the modulation of tumour angiogenesis.


Assuntos
Neoplasias do Colo , Neoplasias Pulmonares , Acridinas , Apoptose , Neoplasias do Colo/tratamento farmacológico , Xenoenxertos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Triazóis
11.
Cells ; 11(9)2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35563873

RESUMO

Cellular, small invertebrate and vertebrate models are a driving force in biogerontology studies. Using various models, such as yeasts, appropriate tissue culture cells, Drosophila, the nematode Caenorhabditis elegans and the mouse, has tremendously increased our knowledge around the relationship between diet, nutrient-response signaling pathways and lifespan regulation. In recent years, combinatorial drug treatments combined with mutagenesis, high-throughput screens, as well as multi-omics approaches, have provided unprecedented insights in cellular metabolism, development, differentiation, and aging. Scientists are, therefore, moving towards characterizing the fine architecture and cross-talks of growth and stress pathways towards identifying possible interventions that could lead to healthy aging and the amelioration of age-related diseases in humans. In this short review, we briefly examine recently uncovered knowledge around nutrient-response pathways, such as the Insulin Growth Factor (IGF) and the mechanistic Target of Rapamycin signaling pathways, as well as specific GWAS and some EWAS studies on lifespan and age-related disease that have enhanced our current understanding within the aging and biogerontology fields. We discuss what is learned from the rich and diverse generated data, as well as challenges and next frontiers in these scientific disciplines.


Assuntos
Proteínas de Caenorhabditis elegans , Longevidade , Envelhecimento/genética , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Drosophila/metabolismo , Longevidade/fisiologia , Camundongos , Nutrientes
12.
Artigo em Inglês | MEDLINE | ID: mdl-35564396

RESUMO

The occurrence of pediatric cancer is an example of a non-normative situation that reorganizes family life. The aim of the study was to evaluate the functioning of a family with a child affected by cancer. The study was conducted on 339 families. The study group consisted of 153 families with children with cancer (mean age 36.4 ± 6.8 years). The control group was composed of 186 families with healthy children (mean age 39.0 ± 6.3 years). All of them completed the author's survey questionnaire on family functioning and the Resilience Measurement Scale (RMS). A statistically significant association was found between the place of residence (p < 0.001), education (p < 0.001), assessment of the material status (p < 0.001) and employment structure (p < 0.001) of parents and the membership in the study group or the control group. Statistical significance was achieved for the main effects as measured on the RMS (5 factors and 2 groups). The study group showed consistently lower levels of the factors of the scale. Statistically significant observations were reported for Factor 1 (perseverance, proactive approach) and Factor 4 (tolerance to failure, life as a challenge) (12.0 vs. 14.5, p < 0.001, 13.4 vs. 14.2, p = 0.04, respectively). Parents of children with cancer were characterized by lower persistence, determination and tolerance to failure, which could affect the quality of life of the whole family. In addition, different socio-economic conditions of family functioning were found in families with children with cancer as compared to families with healthy children.


Assuntos
Neoplasias , Qualidade de Vida , Adulto , Criança , Família , Relações Familiares , Humanos , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Inquéritos e Questionários
13.
Int J Mol Sci ; 22(24)2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34948278

RESUMO

Antibiotic resistance is a global problem, and one promising solution to overcome this issue is using metallodrugs, which are drugs containing metal ions and ligands. These complexes are superior to free ligands in various characteristics including anticancer properties and mechanism of action. The pharmacological potential of metallodrugs can be modulated by the appropriate selection of ligands and metal ions. A good example of proper coordination is the combination of sulfonamides (sulfamerazine, sulfathiazole) with a ruthenium(III) ion. This work aimed to confirm that the activity of sulfonamides antibacterial drugs is initiated and/or stimulated by their coordination to an Ru(III) ion. The study determined the structure, electrochemical profile, CT-DNA affinity, and antimicrobial as well as anticancer properties of the synthesized complexes. The results proved that Ru(III) complexes exhibited better biological properties than the free ligands.


Assuntos
Rutênio/química , Rutênio/farmacologia , Sulfonamidas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Complexos de Coordenação/química , DNA/química , Eletroquímica , Ligantes , Estrutura Molecular , Rutênio/metabolismo , Espectrometria de Fluorescência/métodos , Sulfonamidas/química , Sulfonamidas/metabolismo
14.
Ann Surg ; 274(1): e1-e9, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373926

RESUMO

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Neoplasias Intestinais/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Intestinais/sangue , Neoplasias Intestinais/genética , Neoplasias Intestinais/cirurgia , Intestino Delgado , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/cirurgia , Projetos Piloto , Estudos Prospectivos , Curva ROC , Resultado do Tratamento , Regulação para Cima
15.
Cancer Res ; 81(3): 580-593, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33172932

RESUMO

In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. SIGNIFICANCE: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.See related commentary by Pardini and Dragomir, p. 535.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Neoplasias da Mama/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/genética
16.
Biomolecules ; 10(8)2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32764519

RESUMO

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3-5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid-spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3',3'-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 µM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.


Assuntos
Fármacos Anti-HIV/síntese química , Simulação de Acoplamento Molecular , Triterpenos/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Fosfatos/química , Ligação Proteica , Succinatos/química , Succinatos/farmacologia , Triterpenos/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química
17.
Sci Rep ; 10(1): 11767, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678219

RESUMO

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically active compounds. Pyrazine-functionalized carbazole derivative was constructed by coupling 2-amino-5-bromo-3-methylaminepyrazine (ABMAP) into 3 and 6 positions of the carbazole ring. Multi-experimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder,1H and13C NMR), electrochemical (cyclic voltammetry), and optical techniques, to receive the complete structural analysis, physicochemical (pKa, logP) and biological profile of a new carbazole derivative with acronym 3,6-PIRAMICAR. The interaction ability of the compound studied with potential cellular targets like Calf Thymus DNA (CT-DNA), or Bovine Serum Albumin (BSA) were also taken into account. Experiments showed the existence of strong binding, but no DNA or BSA cleavage was observed. The comparative analyzes of compounds anti-Candida action clearly show pH-dependent antifungal activity of 3,6-PIRAMICAR, which was strongly stimulated in the acidic media. Surprisingly, the titled compound turn out to be much more effective (14 times by MIC50; 8 times by MIC; c.a. 4 times by MFC) against Candida krusei than fluconazole at pH 4.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Carbazóis/química , Concentração de Íons de Hidrogênio , Luz , Pirazinas/química , Pirazinas/farmacologia , Citometria de Fluxo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
18.
Redox Biol ; 32: 101522, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32305006

RESUMO

2-methoxyestradiol (2-ME) is a physiological anticancer compound, metabolite of 17ß-estradiol. Previously, our group evidenced that from mechanistic point of view one of anticancer mechanisms of action of 2-ME is specific induction and nuclear hijacking of neuronal nitric oxide synthase (nNOS), resulting in local generation of nitro-oxidative stress and finally, cancer cell death. The current study aims to establish the substantial mechanism of generation of reactive nitrogen species by 2-ME. We further achieved to identify the specific reactive nitrogen species involved in DNA-damaging mechanism of 2-ME. The study was performed using metastatic osteosarcoma 143B cells. We detected the release of biologically active (free) nitric oxide (•NO) with concurrent measurements of peroxynitrite (ONOO-) in real time in a single cell of 143B cell line by using •NO/ONOO- sensitive microsensors after stimulation with calcium ionophore. Detection of nitrogen dioxide (•NO2) and determination of chemical rate constants were carried out by a stopped-flow technique. The affinity of reactive nitrogen species toward the guanine base of DNA was evaluated by density functional theory calculations. Expression and localization of nuclear factor NF-kB was determined using imaging cytometry, while cell viability assay was evaluated by MTT assay. Herein, we presented that 2-ME triggers pro-apoptotic signalling cascade by increasing cellular reactive nitrogen species overproduction - a result of enzymatic uncoupling of increased nNOS protein levels. In particular, we proved that ONOO- and •NO2 directly formed from peroxynitrous acid (ONOOH) and/or by auto-oxidation of •NO, are inducers of DNA damage in anticancer mechanism of 2-ME. Specifically, the affinity of reactive nitrogen species toward the guanine base of DNA, evaluated by density functional theory calculations, decreased in the order: ONOOH > ONOO- > â€¢NO2 > â€¢NO. Therefore, we propose to consider the specific inducers of nNOS as an effective tool in the field of chemotherapy.


Assuntos
Neoplasias Ósseas , Osteossarcoma , 2-Metoxiestradiol , DNA , Humanos , Óxido Nítrico , Óxido Nítrico Sintase Tipo I , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Ácido Peroxinitroso , Espécies Reativas de Nitrogênio
19.
Cent Eur J Immunol ; 45(4): 414-424, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33658890

RESUMO

The aim of the study was to analyse the relationship between nutritional disorders and the expression of innate antibacterial response genes in patients admitted to the intensive care unit (ICU). In 46 patients with severe malnutrition and life-threatening surgical complications, nutritional status tests were performed on the basis of the NRS 2002 (Nutritional Risk Screening) scale, cytokine, albumin, C-reactive protein concentrations, anthropometric tests, and body composition analysis. Concurrently, the expression of Toll-like receptor 2, NOD1, TRAF6, and HMGB1 genes was determined in peripheral blood leukocytes at the mRNA level using real-time polymerase chain reaction. It was found that both the nutritional status and the gene expression changed depending on the group of patients studied (including the group of survivors vs. non-survivors). Significant correlations were found between the results of routine tests used in the diagnostics of malnutrition (including NRS 2002, resistance, reactance, phase angle, excess of extracellular water) and the expression of the studied genes. Moreover, the expression of TRAF6 and HMGB1 genes correlated with the Acute Physiology and Chronic Health Evaluation II scale and the age of the patients. The results of the research suggest that the expression of innate antibacterial response genes may be a new diagnostic tool complementing the assessment of nutritional disorders in surgical patients admitted to the ICU. These tests may be helpful in providing more accurate diagnostics of the genetic effects of malnutrition and in the monitoring of patients for whom nutritional treatment is planned to support the functions of the immune system, thereby increasing the effectiveness of this type of treatment in the ICU.

20.
Bioorg Chem ; 94: 103454, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31787344

RESUMO

A series of new sulforaphane analogs bearing various (poly)fluoroaryl substituents bonded to the sulfinyl sulfur atom in place of the original methyl group and having different number of methylene groups in the central alkyl chain were synthesized and fully characterized. The new compounds were tested in vitro for their anticancer, antibacterial, antifungal and antiviral properties. Some of them demonstrated a much higher anticancer activity against selected lines of cancer: skin (MALME-3M), colon (HT-29) and breast (MCF7 and MDA-MB-231) cells than that exhibited by native sulforaphane (SFN). Related lines of untransformed (normal) cells, taken from the same organs as the cancer ones, i.e. MALME3, CRL-1790 and MCF10, respectively, were checked, which allowed for the determination of the selectivity indexes (SI). In certain cases, the latter exceeded 3.2. Concerning the antibacterial activity, gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) were susceptible to some newly synthesized SFN analogs, while the selected probiotic strains were from 10 to 100 fold more resistant to them, which gives a possibility of protection of symbiont strains during a potential therapy with such compounds. The antifungal activity of the new compounds possessing the fluorophenyl substituent was found to be higher than the activity of the parent SFN. In turn, most of the new compounds showed generally no anti-HIV activity. The influence of the particular structural differences in the new molecules, analogs of SFN, on their biological activity is discussed.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Isotiocianatos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Isotiocianatos/síntese química , Isotiocianatos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfóxidos
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