67 research outputs found
Cancer chemopreventive diterpenes from Salvia corrugata
No full textNMR and NP-HPLC-UV profiling of the exudate of Salvia corrugata revealed that its secondary metabolite
composition was largely dominated by a-hydroxy-b-isopropyl-benzoquinone diterpenoids. Among them,
four diterpenes not described previously were isolated and identified as fruticulin C (3), 7a-methoxy-19-
acetoxy-royleanone (4), 7a,19-diacetoxy-royleanone (5), and 7-dehydroxy-conacytone (7). In addition,
the known diterpenes fruticulin A (1), demethyl-fruticulin A (2) and 7a-O-methyl-conacytone (6) were
also obtained. The isolated compounds were evaluated for their cancer chemopreventive activity by measuring
quinone reductase induction activity and histone deacetylase inhibition. Three compounds (1, 2
and 5) showed promising activity
Structural features for HDAC6 inhibitory specificity of Salvia corrugata Vahl. diterpene α-hydroxyquinones
No full textHistone deacetylases (HDACs) are enzymes that
deacetylate lysine residues from histones as well as from several
other nuclear, cytoplasmic and mitochondrial non-histone proteins.
In mammals, 11 zinc-dependent HDACs have been classified into
three classes: Class I (HDACs 1 to 3 and HDAC8), class II which is
subdivided into classes IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6and 10), and class IV (HDAC11) [1]. Because of its central role in
memory, protein aggregate elimination, neuronal oxidative stress
and mitochondrial functions, HDAC6 appears as a promising target
for Alzheimer's disease [1, 2]. However, developing new selective
HDAC6 inhibitors is a challenge and their design is usually based
on structural modifications on the cap portion, which is separated
from a zinc-binding group by a linker portion [2].
Aims: To search for potential structural features within natural scaffolds
which are able to provide isoform inhibitory specificity for
HDAC6 compared to class I HDACs
Novel HDAC inhibitors with a phenylcinnamic scaffold: synthesis and evaluation of antitumor activity
No full textInappropriate epigenetic modifications of gene expression are associated with malignant phenotype and tumor progression. Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Inhibitors of histone deacetylase (HDAC) enzymes have gained prominence as an emerging class of anticancer agents.
We synthesized a series of hydroxamic acid-based HDAC inhibitors, characterized by a biphenyl-4-yl-acrylohydroxamic acid skeleton. The compounds were designed based on the hypothesis that the phenyl ring, extended from the hydroxamic acid via a double bond, could be suitable to occupy the narrow tube-like pocket of the HDAC active site. On the contrary, the cap structure appeared to accommodate in a large cavity, without a significant steric clash. Thus, a modification of the cap group appeared the most promising strategy to optimize drug-target interaction. Molecular docking was used to predict the optimal conformation of different molecules in the active site of a representative isoform from class I (HDAC2, sharing 85% sequence identity and 93% of sequence homology with HDAC1) and class II (HDAC6). From the results of docking studies three potential candidates with increased drug-target interactions were selected. All of them showed an activity towards HDAC1, 2 and 6 in the low μM range, estimated through a fluorimetric activity assay [2]. One of the compounds was further tested in vitro and in vivo in a colon carcinoma model and showed significant proapoptotic and antitumor activities
Exploring the CAP and the ZBG functionalities of HDAC inhibitors with a phenyl-4-yl-acrylohydroxamic acids scaffold
No full textRegulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. The latter mechanism includes dynamic acetylation and deacetylation of lysine residues present in the tail of core histones. Acetylation is executed by histone acetyltransferases (HATs) and is reversed by histone deacetylases (HDACs).
Inhibition of HDACs causes histone hyperacetylation with transcriptional activation of genes associated with cell cycle arrest or apoptosis in tumor cells.
Well characterized HDAC inhibitors typically contain three structural features that are thought to be required for optimal activity: an aromatic cap group (CAP), a linker chain and a zinc binding group (ZBG).
Based on molecular modeling studies, we have developed a series of hydroxamic acid-based compounds, characterized by a cinnamic spacer capped with a substituted phenyl group.1
Here we report our recent efforts to optimize drug-target interaction by modification of the cap group and the ZBG-functionality.
Molecular docking was used to predict the optimal conformation of different molecules in the active site of a representative isoform from class I (HDAC2, sharing 85% sequence identity and 93% of sequence homology with HDAC1) and class II (HDAC6).
Whereas most of the candidates with alternative Zn-binding groups were less effective than the parent hydroxamic acid, selected compounds modified in the cap region showed an activity towards HDAC1, 2 and 6 in the low μM range, assessed through a fluorimetric assay. One of the compounds was further tested in vitro and in vivo in a colon carcinoma model and showed significant proapoptotic and antitumor activity
Os efeitos do SARS CoV-2 no processo jornalístico: o caso do Telejornal, da RTP1 e do JT das 20 horas, da France2
No full textDissertação para obtenção de grau de Mestre em Ciências da Comunicação, Vertente em JornalismoEste estudo propõe-se identificar as principais mudanças nas rotinas jornalísticas, no processo e no conteúdo informativo no Telejornal da RTP1 e no JT das 20H da France2, nos períodos de isolamento social de Portugal e França e no pós-confinamento de 1 a 15 de janeiro de 2022. Para o efeito caracterizaram-se as motivações da decisão editorial inerente ao gatekeeping, dos dois jornais televisivos; verificou-se como se processou a relação entre os jornalistas e as fontes; compreendeu-se a perceção dos repórteres do TJ da RTP e do JT das 20H, sobre os efeitos do SARS CoV-2 no processo jornalístico ocorridos durante o confinamento e avaliando a perceção que estes jornalistas têm da prática profissional pós isolamento social. A abordagem metodológica é mista, através das técnicas de análise de conteúdo, do inquérito por questionário e da entrevista semiestruturada. A pesquisa foi suportada nas teorias do newsmaking e do gatekeeping, da agenda- setting e framing. Os resultados sugerem: os jornalistas dos dois jornais televisivos colocaram-se no epicentro da doença para dar as informações necessárias à proteção das populações; os profissionais afastaram-se da redação, das organizações e das fontes. Os especialistas foram as vozes mais confiáveis. A tecnologia foi o elemento facilitador do jornalismo. As fontes confinadas também foram produtoras de conteúdos.
Na crise da Covid-19 nem sempre os profissionais separaram a experiência pessoal da de informar. Os jornalistas, tanto no JT das 20H como no TJ da RTP1 sentiram medo e tiveram em consideração os apelos políticos em prol da coesão social que viram necessários durante a crise da Covid-19, afetando os conteúdos noticiosos. Dois anos após o confinamento os dados sugerem que muitas destas mudanças têm efeito duradouro. As plataformas de conversação, o arquivo e o grafismo passaram a ser elementos de um jornalismo televisivo mais sentado e afastado.This study aims to identify a) the main changes in the newsrooms routines, in the process and news content on RTP1's Telejornal and France2's JT 20H, during the lockdowns in Portugal and France and after between January 1st and 15th, 2022; b) detail the motivations for the editorial decision inherent to gatekeeping of both televisions news; c) verify how the relationship between journalists and sources was processed; d) understand the perception of reporters from RTP’s TJ and 20H JT on the effects of SARS CoV-2 in the journalistic process that occurred during lockdown and assess the perception that these journalists have of professional practice after lockdown. The methodology followed is mixed, using content analysis techniques, questionnaire surveys and semi-structured interviews. The research was supported by the theories of newsmaking and gatekeeping, agenda-setting and framing. The results suggest: journalists from the two television news placed themselves at the epicenter of the disease to provide the information necessary to protect populations; the virus pushed journalists out of newsrooms, organizations and away from sources. The experts were the most trusted voices. Technology was the enabler element for journalism. The confined sources were also content producers. The Covid-19 crisis was difficult to cover by journalists, they did not always separate personal experience from reporting. Journalists, both on JT at 8pm and on TJ on RTP1, felt fear and took into consideration the political appeals in favor of
social cohesion that they saw necessary during the Covid-19 crisis, affecting news content. Two years after lockdown, data suggests that many of these changes have a lasting effect. Chat forums, archives and graphics became elements of television journalism that is less dynamic and further away from the news field.N/
Os efeitos do SARS CoV-2 no processo jornalístico: o caso do Telejornal, da RTP1 e do JT das 20 horas, da France2
No full textDissertação para obtenção de grau de Mestre em Ciências da Comunicação, Vertente em JornalismoEste estudo propõe-se identificar as principais mudanças nas rotinas jornalísticas, no processo e no conteúdo informativo no Telejornal da RTP1 e no JT das 20H da France2, nos períodos de isolamento social de Portugal e França e no pós-confinamento de 1 a 15 de janeiro de 2022. Para o efeito caracterizaram-se as motivações da decisão editorial inerente ao gatekeeping, dos dois jornais televisivos; verificou-se como se processou a relação entre os jornalistas e as fontes; compreendeu-se a perceção dos repórteres do TJ da RTP e do JT das 20H, sobre os efeitos do SARS CoV-2 no processo jornalístico ocorridos durante o confinamento e avaliando a perceção que estes jornalistas têm da prática profissional pós isolamento social. A abordagem metodológica é mista, através das técnicas de análise de conteúdo, do inquérito por questionário e da entrevista semiestruturada. A pesquisa foi suportada nas teorias do newsmaking e do gatekeeping, da agenda- setting e framing. Os resultados sugerem: os jornalistas dos dois jornais televisivos colocaram-se no epicentro da doença para dar as informações necessárias à proteção das populações; os profissionais afastaram-se da redação, das organizações e das fontes. Os especialistas foram as vozes mais confiáveis. A tecnologia foi o elemento facilitador do jornalismo. As fontes confinadas também foram produtoras de conteúdos.
Na crise da Covid-19 nem sempre os profissionais separaram a experiência pessoal da de informar. Os jornalistas, tanto no JT das 20H como no TJ da RTP1 sentiram medo e tiveram em consideração os apelos políticos em prol da coesão social que viram necessários durante a crise da Covid-19, afetando os conteúdos noticiosos. Dois anos após o confinamento os dados sugerem que muitas destas mudanças têm efeito duradouro. As plataformas de conversação, o arquivo e o grafismo passaram a ser elementos de um jornalismo televisivo mais sentado e afastado.This study aims to identify a) the main changes in the newsrooms routines, in the process and news content on RTP1's Telejornal and France2's JT 20H, during the lockdowns in Portugal and France and after between January 1st and 15th, 2022; b) detail the motivations for the editorial decision inherent to gatekeeping of both televisions news; c) verify how the relationship between journalists and sources was processed; d) understand the perception of reporters from RTP’s TJ and 20H JT on the effects of SARS CoV-2 in the journalistic process that occurred during lockdown and assess the perception that these journalists have of professional practice after lockdown. The methodology followed is mixed, using content analysis techniques, questionnaire surveys and semi-structured interviews. The research was supported by the theories of newsmaking and gatekeeping, agenda-setting and framing. The results suggest: journalists from the two television news placed themselves at the epicenter of the disease to provide the information necessary to protect populations; the virus pushed journalists out of newsrooms, organizations and away from sources. The experts were the most trusted voices. Technology was the enabler element for journalism. The confined sources were also content producers. The Covid-19 crisis was difficult to cover by journalists, they did not always separate personal experience from reporting. Journalists, both on JT at 8pm and on TJ on RTP1, felt fear and took into consideration the political appeals in favor of
social cohesion that they saw necessary during the Covid-19 crisis, affecting news content. Two years after lockdown, data suggests that many of these changes have a lasting effect. Chat forums, archives and graphics became elements of television journalism that is less dynamic and further away from the news field.N/
Anti-inflammatory, antimicrobial and antioxidant activities of Diospyros bipindensis (Gürke) extracts and its main constituents
No full textEthnopharmacological relevance: Diospyros bipindensis (Gürke) stem bark is used in Cameroon by Baka Pygmies for the treatment of respiratory disorders.
Aim of the study: To assess the anti-inflammatory, antibacterial and antioxidant properties of constituents from the bark extracts through bioassay-guided fractionation.
Materials and methods: The anti-inflammatory activity of extracts, fractions and pure compounds was assessed through the inhibition of the pro-inflammatory mediator nuclear factor-kappa B (NF-κB) transcriptional activity and nitric oxide (NO) production. DPPH, ABTS and ORAC assays were used for determining the antioxidant properties. The activity against Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Klebsiella pneumoniae, was evaluated on the basis of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) by the macrodilution method.
Results: The water extract showed antimicrobial activity against S. pneumoniae (MIC: 300 μg/ml) and S. pyogenes (MIC: 300 μg/ml). The dichloromethane extract efficiently inhibited NF-κB transcriptional activity and NO production and exhibited significant antioxidant activity in the ORAC assay. An interesting activity was also found against S. pneumoniae (MIC: 200 μg/ml), S. aureus (MIC: 400 μg/ml) and S. pyogenes (MIC: 200 μg/ml). The phytochemical investigation of the dichloromethane extract afforded plumbagin, canaliculatin, ismailin, betulinic acid and 4-hydroxy-5-methyl-coumarin as the main constituents. Plumbagin and ismailin were found to be responsible for the main biological activities observed..
Conclusions: These results may provide a rational support for the traditional use of Diospyros bipindensis stem bark in the treatment of respiratory disorders, since the anti-inflammatory, antimicrobial and antioxidant compounds isolated from the dichloromethane extract were also present in the traditional water extract
Molecular analysis of the interaction between cardosin A and phospholipase Dalpha
No full textCardosin A is an RGD-containing aspartic proteinase from the stigmatic papillae of Cynara cardunculus L. A putative cardosin A-binding protein has previously been isolated from pollen suggesting its potential involvement in pollen-pistil interaction [Faro C, Ramalho-Santos M, Vieira M, Mendes A, Simoees I, Andrade R, Verissimo P, Lin X, Tang J & Pires E (1999) J Biol Chem 274, 28724-28729]. Here we report the identification of phospholipase Dα as a cardosin A-binding protein. The interaction was confirmed by coimmunoprecipitation studies and pull-down assays. To investigate the structural and molecular determinants involved in the interaction, pull-down assays with cardosin A and various glutathione S-transferase-fused phospholipase D{alpha} constructs were performed. Results revealed that the C2 domain of phospholipase D{alpha} contains the cardosin A-binding activity. Further assays with mutated recombinant forms of cardosin A showed that the RGD motif as well as the unprecedented KGE motif, which is structurally and charge-wise very similar to RGD, are indispensable for the interaction. Taken together our results indicate that the C2 domain of plant phospholipase Dα can act as a cardosin A-binding domain and suggest that plant C2 domains may have an additional role as RGD/KGE-recognition domains
Biphenyl-4-yl-acrylohydroxamic acids: identification of a novel indolyl-substituted HDAC inhibitor with antitumor activity
No full textModification of the cap group of biphenylacrylohydroxamic acid-based HDAC inhibitors led to the identification of a new derivative (3) characterized by an indolyl-substituted 4-phenylcinnamic skeleton. Molecular docking was used to predict the optimal conformation in the class I HDACs active site. Compound 3 showed HDAC inhibitory activity and antiproliferative activity against a panel of tumor cell lines, in the low μM range. The compound was further tested in vitro for acetylation of histone H4 and other non-histone proteins, and in vivo in a colon carcinoma model, showing significant proapoptotic and antitumor activities
RADUAN NASSAR'S ARCHAEAL CLEARANCE: A POSSIBILITY FOR READING THE CONTEMPORARY WORLD
No full textThe objective of this text is to analyze the work of Archaic Lavoura, (1989) by Raduan Nassar as a possibility for a new reading of the contemporary world. The world reading comes from the way the author interprets and lives the social reality in which it is inserted. The work Lavoura Arcaica is a literary text of postmodern production of Brazilian literature, at which time it was reflected on the end of dominant ideologies and loss of references, denouncing the existential crisis of the subject. In this way, the present work refers to a documentary research, that approaches the analysis of the literary work exposing its structure and its social context. The theoretical assumptions are based on historical and dialectical materialism. The analysis of the literary work made it possible to understand that the author has the possibility of recreating reality through aesthetic reflection, leading the reader to appropriate knowledge of different times and spaces.Univ Estadual Londrina, Londrina, PR, BrazilUniv Estadual Londrina, Programa Posgrad Educ, Educ, Londrina, BrazilUniv Estadual Paulista UNESP, Marilia, SP, BrazilUniv Estadual Paulista, Programa Posgrad Educ, Educ, Sao Paulo, BrazilUniv Estadual Paulista UNESP, Marilia, SP, BrazilUniv Estadual Paulista, Programa Posgrad Educ, Educ, Sao Paulo, Brazi
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