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1.
Br J Radiol ; 93(1111): 20200311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32374629

RESUMO

Boron neutron capture therapy (BNCT) has great potential to selectively destroy cancer cells while sparing surrounding normal cells. The basic concept of BNCT was developed in the 1930s, but it has not yet been commonly used in clinical practice, even though there is now a large number of experimental and translational studies demonstrating its marked therapeutic potential. With the development of neutron accelerators that can be installed in medical institutions, accelerator-based BNCT is expected to become available at several medical institutes around the world in the near future. In this commentary, from the point of view of radiation microdosimetry, we discuss the biological effects of BNCT, especially the underlying mechanisms of compound biological effectiveness. Radiobiological perspectives provide insight into the effectiveness of BNCT in creating a synergy effect in the field of clinical oncology.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias/radioterapia , Boranos/uso terapêutico , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/instrumentação , Fluordesoxiglucose F18 , Humanos , Método de Monte Carlo , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Radiobiologia , Eficiência Biológica Relativa
2.
Anticancer Res ; 40(4): 1833-1841, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234871

RESUMO

BACKGROUND/AIM: Time-restricted feeding (TRF) during the dark phase of the day restores metabolic homeostasis in mice. MATERIALS AND METHODS: We performed untargeted metabolomic analysis on plasma from mice subjected to TRF that attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC). RESULTS: Twenty-four of 152 identified metabolites differed among the four dietary groups (non-LLC-bearing mice fed the AIN93G diet and LLC-bearing mice fed the AIN93G, the high-fat diet (HFD), or TRF of the HFD). Component 1 of sparse partial least squares-discriminant analysis showed a clear separation between non-LLC-bearing and LLC-bearing mice. Major metabolites responsible for the changes were elevations in α-tocopherol, docosahexaenoic acid, cholesterol, dihydrocholestrol, isoleucine, leucine, and phenylalanine and decreases in lactic acid and pyruvic acid in LLC-bearing mice particularly those fed the HFD. Time-restricted feeding shifted the metabolic profile of LLC-bearing mice towards that of non-LLC-bearing controls. CONCLUSION: Time-restricted feeding improves metabolic profile of LLC-bearing mice.


Assuntos
Carcinoma Pulmonar de Lewis/sangue , Jejum/sangue , Metabolômica , Animais , Carcinoma Pulmonar de Lewis/dietoterapia , Colestanol/sangue , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/sangue , Jejum/fisiologia , Humanos , Insulina/sangue , Isoleucina/sangue , Ácido Láctico/sangue , Leucina/sangue , Camundongos , Metástase Neoplásica , Fenilalanina/sangue , Ácido Pirúvico/sangue , alfa-Tocoferol/sangue
3.
Acta Crystallogr C Struct Chem ; 76(Pt 4): 328-345, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32229714

RESUMO

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc-tyrosine or Fmoc-phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan-2-yl)oxy]phenyl}propanoic acid or N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047-8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H...H, C...H/H...C and O...H/H...O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen-bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C-H...O, C-H...π, (fluorenyl)C-H...Cl(I), C-Br...π(fluorenyl) and C-I...π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further supported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supramolecular hydrogen-bonding patterns in biocomplexes are emphasized, for the first time.


Assuntos
Aminoácidos/química , Fluorenos/síntese química , Metiltirosinas/química , Fenilalanina/química , Aminoácidos/síntese química , Simulação por Computador , Cristalografia por Raios X , Fluorenos/química , Ligação de Hidrogênio , Conformação Molecular , Inquéritos e Questionários
4.
Plant Mol Biol ; 103(4-5): 489-505, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32306368

RESUMO

KEY MESSAGE: Cucumber plants adapt their transcriptome and metabolome as result of spider mite infestation with opposite consequences for direct and indirect defences in two genotypes. Plants respond to arthropod attack with the rearrangement of their transcriptome which lead to subsequent phenotypic changes in the plants' metabolome. Here, we analysed transcriptomic and metabolite responses of two cucumber (Cucumis sativus) genotypes to chelicerate spider mites (Tetranychus urticae) during the first 3 days of infestation. Genes associated with the metabolism of jasmonates, phenylpropanoids, terpenoids and L-phenylalanine were most strongly upregulated. Also, genes involved in the biosynthesis of precursors for indirect defence-related terpenoids were upregulated while those involved in the biosynthesis of direct defence-related cucurbitacin C were downregulated. Consistent with the observed transcriptional changes, terpenoid emission increased and cucurbitacin C content decreased during early spider-mite herbivory. To further study the regulatory network that underlies induced defence to spider mites, differentially expressed genes that encode transcription factors (TFs) were analysed. Correlation analysis of the expression of TF genes with metabolism-associated genes resulted in putative identification of regulators of herbivore-induced terpenoid, green-leaf volatiles and cucurbitacin biosynthesis. Our data provide a global image of the transcriptional changes in cucumber leaves in response to spider-mite herbivory and that of metabolites that are potentially involved in the regulation of induced direct and indirect defences against spider-mite herbivory.


Assuntos
Cucumis sativus/imunologia , Cucumis sativus/metabolismo , Metaboloma , Infestações por Ácaros/imunologia , Infestações por Ácaros/metabolismo , Tetranychidae , Transcriptoma , Animais , Vias Biossintéticas/genética , Cucumis sativus/genética , Cucumis sativus/parasitologia , Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Genoma de Planta , Genótipo , Herbivoria , Oxilipinas/metabolismo , Fenilalanina/metabolismo , Fenilpropionatos/metabolismo , Doenças das Plantas , Folhas de Planta/metabolismo , Metabolismo Secundário/genética , Terpenos/metabolismo , Fatores de Transcrição/genética , Triterpenos/metabolismo , Compostos Orgânicos Voláteis/metabolismo
5.
Lancet Haematol ; 7(5): e395-e407, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32213344

RESUMO

BACKGROUND: Multiple myeloma is an incurable haematological malignancy, representing over 10% of haematological cancers in the USA. We did a phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose of melflufen and to investigate its safety and efficacy. METHODS: We did a multicentre, international, dose-confirmation and dose-expansion, open-label, phase 1-2 study in seven centres in the USA and Europe. Eligible patients were aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. In phase 1, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 min on day 1 in 21-day cycles plus oral dexamethasone 40 mg weekly and did not receive melflufen as a single agent. Melflufen was also tested in a single-agent cohort late in phase 2 in a small number of patients at the maximum tolerated dose identified in phase 1. In phase 2, patients were enrolled at the maximum tolerated dose in the melflufen plus dexamethasone in the combination cohort.. The phase 1 primary objective was to determine the maximum tolerated dose. The phase 2 primary objective was to evaluate overall response rate and clinical benefit rate. This primary analysis was done per protocol, in the all-treated and efficacy-evaluable population (defined as patients who received at least two doses of melflufen and who had a response assessment after baseline). The single-agent melflufen cohort was closed on October 6, 2016, as per the recommendation by the data safety monitoring committee on the basis of interim data suggesting greater activity in the melflufen plus dexamethasone cohort. The study is completed but survival follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT01897714. FINDINGS: Patients were enrolled between July 4, 2013, and Dec 31, 2016: 23 patients in phase 1 and 58 in phase 2, including six patients from phase 1 treated at the maximum tolerated dose of melflufen 40 mg plus weekly dexamethasone. In phase 2, 45 patients were given a combination of melflufen plus dexamethasone and 13 patients were given single-agent melflufen. In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. No dose-limiting toxicities were observed in the first three dose cohorts (15 mg, 25 mg, and 40 mg). The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced grade 4 neutropenia with grade 4 thrombocytopenia also occurring in three of these patients; therefore, the planned highest dose of 70 mg was not tested. In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 0·2-36·0) and the clinical benefit rate was 23% (three of 13; 5-54). Among the 45 patients given melflufen plus dexamethasone during phase 2, the most common grade 3-4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-haematological toxicity was infrequent. 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (five [11%]). The most common grade 3-4 adverse events that occurred in the phase 2 single-agent cohort of 13 patients were neutropenia (nine [69%]) and thrombocytopenia (eight [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (two [15%]). There were three deaths from adverse events within 30 days of treatment that were possibly related to treatment: one in the 25 mg cohort in phase 1 (due to bacteraemia) and two in the phase 2 combination cohort (one due to neutropenic sepsis and one due to Escherichia coli sepsis), each in the setting of progressive disease. INTERPRETATION: These data show that melflufen is active in patients with relapsed and refractory multiple myeloma and tolerable in most patients. These results show the feasibility of this regimen and support the initiation of additional clinical studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens with additional classes of drugs. FUNDING: Oncopeptides AB.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Melfalan/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Fenilalanina/análogos & derivados , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Fenilalanina/administração & dosagem , Fenilalanina/efeitos adversos , Fenilalanina/uso terapêutico
6.
Science ; 367(6478): 643-652, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029621

RESUMO

Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.


Assuntos
Carcinogênese/genética , Membrana Celular/química , Janus Quinase 2/química , Janus Quinase 2/genética , Multimerização Proteica , Receptores da Eritropoetina/química , Receptores da Somatotropina/química , Receptores de Trombopoetina/química , Substituição de Aminoácidos/genética , Células HeLa , Humanos , Janus Quinase 2/antagonistas & inibidores , Ligantes , Microscopia de Fluorescência , Modelos Moleculares , Mutação , Fenilalanina/genética , Pirazóis/farmacologia , Transdução de Sinais , Imagem Individual de Molécula , Valina/genética
8.
Science ; 367(6478): 694-699, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029630

RESUMO

Prion-like domains (PLDs) can drive liquid-liquid phase separation (LLPS) in cells. Using an integrative biophysical approach that includes nuclear magnetic resonance spectroscopy, small-angle x-ray scattering, and multiscale simulations, we have uncovered sequence features that determine the overall phase behavior of PLDs. We show that the numbers (valence) of aromatic residues in PLDs determine the extent of temperature-dependent compaction of individual molecules in dilute solutions. The valence of aromatic residues also determines full binodals that quantify concentrations of PLDs within coexisting dilute and dense phases as a function of temperature. We also show that uniform patterning of aromatic residues is a sequence feature that promotes LLPS while inhibiting aggregation. Our findings lead to the development of a numerical stickers-and-spacers model that enables predictions of full binodals of PLDs from their sequences.


Assuntos
Ribonucleoproteína Nuclear Heterogênea A1/química , Transição de Fase , Fenilalanina/química , Príons/química , Tirosina/química , Sequência de Aminoácidos , Espectroscopia de Ressonância Magnética , Domínios Proteicos , Espalhamento a Baixo Ângulo , Difração de Raios X
9.
PLoS One ; 15(1): e0225289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31961910

RESUMO

TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Inflamação/genética , TYK2 Quinase/genética , Alelos , Substituição de Aminoácidos/genética , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Citocinas/química , Citocinas/genética , Regulação da Expressão Gênica/genética , Estudos de Associação Genética , Genótipo , Humanos , Inflamação/sangue , Inflamação/patologia , Fenilalanina/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , TYK2 Quinase/sangue
10.
J Agric Food Chem ; 68(5): 1397-1404, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31917559

RESUMO

Volatiles affect tea (Camellia sinensis) aroma quality and have roles in tea plant defense against stresses. Some volatiles defend against stresses through their toxicity, which might affect tea safety. Benzyl nitrile is a defense-related toxic volatile compound that accumulates in tea under stresses, but its formation mechanism in tea remains unknown. In this study, l-[2H8]phenylalanine feeding experiments and enzyme reactions showed that benzyl nitrile was generated from l-phenylalanine via phenylacetaldoxime in tea. CsCYP79D73 showed activity for converting l-phenylalanine into phenylacetaldoxime, while CsCYP71AT96s showed activity for converting phenylacetaldoxime into benzyl nitrile. Continuous wounding in the oolong tea process significantly enhanced the CsCYP79D73 expression level and phenylacetaldoxime and benzyl nitrile contents. Benzyl nitrile accumulation under continuous wounding stress was attributed to an increase in jasmonic acid, which activated CsCYP79D73 expression. This represents the first elucidation of the formation mechanism of benzyl nitrile in tea.


Assuntos
Camellia sinensis/metabolismo , Nitrilos/metabolismo , Fenilalanina/metabolismo , Camellia sinensis/química , Camellia sinensis/genética , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Ciclopentanos/metabolismo , Nitrilos/química , Oxilipinas/metabolismo , Fenilalanina/química , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico
11.
J Phys Chem Lett ; 11(3): 891-899, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31944766

RESUMO

Extreme-ultraviolet-induced charge migration in biorelevant molecules is a fundamental step in the complex path leading to photodamage. In this work we propose a simple interpretation of the charge migration recently observed in an attosecond pump-probe experiment on the amino acid tryptophan. We find that the decay of the prominent low-frequency spectral structure with increasing pump-probe delay is due to a quantum beating between two geometrically distinct, almost degenerate charge oscillations. Quantum beating is ubiquitous in these systems, and at least on the few-to-tens of femtosecond time scales, it may dominate over decoherence the line intensities of time-resolved spectra. We also address the experimentally observed phase shift in the charge oscillations of two different amino acids, tryptophan and phenylalanine. Our results indicate that a beyond mean-field treatment of the electron dynamics is necessary to reproduce the correct behavior.


Assuntos
Teoria da Densidade Funcional , Triptofano/química , Fenilalanina/química
12.
Nursing ; 50(2): 31-38, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31895198
14.
J Ind Microbiol Biotechnol ; 47(2): 233-242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31989326

RESUMO

Escherichia coli, a model microorganism for which convenient metabolic engineering tools are available and that grows quickly in cheap media, has been widely used in the production of valuable chemicals, including aromatic amino acids. As the three aromatic amino acids, L-tryptophan, L-tyrosine, and L-phenylalanine, share the same precursors, to increase the titer of a specific aromatic amino acid, the branch pathways to the others are usually permanently inactivated, which leads to the generation of auxotrophic strains. In this study, a tunable switch that can toggle between different states was constructed. Then, a switchable and non-auxotrophic E. coli strain for synthesis of aromatic amino acids was constructed using this tunable switch. By adding different inducers to cultures, three different production patterns of aromatic amino acids by the engineered strain could be observed. This tunable switch can also be applied in regulating other branch pathways and in other bacteria.


Assuntos
Escherichia coli/metabolismo , Fenilalanina/biossíntese , Triptofano/biossíntese , Tirosina/biossíntese , Escherichia coli/genética , Engenharia Metabólica
15.
BMC Genomics ; 21(1): 21, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906847

RESUMO

BACKGROUND: Disease resistance is an important factor that impacts rice production. However, the mechanisms underlying rice disease resistance remain to be elucidated. RESULTS: Here, we show that a robust set of genes has been defined in rice response to the infections of Xanthomonas oryzae pv. oryzae (Xoo) and Magnaporthe oryzae (Mor). We conducted a comprehensive analysis of the available microarray data from a variety of rice samples with inoculation of Xoo and Mor. A set of 12,932 genes was identified to be regulated by Xoo and another set of 2709 Mor-regulated genes was determined. GO enrichment analysis of the regulated genes by Xoo or Mor suggested mitochondrion may be an arena for the up-regulated genes and chloroplast be another for the down-regulated genes by Xoo or Mor. Cytokinin-related processes were most frequently repressed by Xoo, while processes relevant to jasmonic acid and abscisic acid were most frequently activated by Xoo and Mor. Among genes responsive to Xoo and Mor, defense responses and diverse signaling pathways were the most frequently enriched resistance mechanisms. InterPro annotation showed the zinc finger domain family, WRKY proteins, and Myb domain proteins were the most significant transcription factors regulated by Xoo and Mor. KEGG analysis demonstrated pathways including 'phenylpropanoid biosynthesis', 'biosynthesis of antibiotics', 'phenylalanine metabolism', and 'biosynthesis of secondary metabolites' were most frequently triggered by Xoo and Mor, whereas 'circadian rhythm-plant' was the most frequent pathway repressed by Xoo and Mor. CONCLUSIONS: The genes identified here represent a robust set of genes responsive to the infections of Xoo and Mor, which provides an overview of transcriptional reprogramming during rice defense against Xoo and Mor infections. Our study would be helpful in understanding the mechanisms of rice disease resistance.


Assuntos
Resistência à Doença/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas , Oryza/genética , Doenças das Plantas/genética , Ácido Abscísico/metabolismo , Antibacterianos/biossíntese , Ciclopentanos/metabolismo , Interações Hospedeiro-Patógeno , Magnaporthe/fisiologia , Oryza/metabolismo , Oryza/microbiologia , Oxilipinas/metabolismo , Fenilalanina/metabolismo , Doenças das Plantas/microbiologia , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Xanthomonas/fisiologia
16.
Trends Plant Sci ; 25(1): 66-79, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31679994

RESUMO

Aromatic amino acid deaminases are key enzymes mediating carbon flux from primary to secondary metabolism in plants. Recent studies have uncovered a tyrosine ammonia-lyase that contributes to the typical characteristics of grass cell walls and contributes to about 50% of the total lignin synthesized by the plant. Grasses are currently preferred bioenergy feedstocks and lignin is the most important limiting factor in the conversion of plant biomass to liquid biofuels, as well as being an abundant renewable carbon source that can be industrially exploited. Further research on the structure, evolution, regulation, and biological function of functionally distinct ammonia-lyases has multiple implications for improving the economics of the agri-food and biofuel industries.


Assuntos
Lignina , Fenilalanina Amônia-Liase , Amônia-Liases , Biocombustíveis , Biomassa , Fenilalanina
17.
Xenobiotica ; 50(1): 51-63, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31233370

RESUMO

1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age.2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown.3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.


Assuntos
Fenilalanina Hidroxilase/metabolismo , Carbocisteína/análogos & derivados , Carbocisteína/metabolismo , Humanos , Fenilalanina/metabolismo , Fenilalanina Hidroxilase/genética , Polimorfismo Genético
18.
Nat Chem Biol ; 16(1): 50-59, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819276

RESUMO

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Leucemia Mieloide Aguda/metabolismo , Precursores de RNA/metabolismo , Sarcoma de Ewing/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Hidrolases de Éster Carboxílico/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Fator de Especificidade de Clivagem e Poliadenilação/genética , Células HEK293 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Fenótipo , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Piperazinas/farmacologia , Ligação Proteica , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Sarcoma de Ewing/tratamento farmacológico
19.
Chemistry ; 26(2): 379-383, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609031

RESUMO

Peptide alcohols are clinically important compounds that are underexplored in structure-activity relationship (SAR) studies in drug discovery. One reason for this underutilization is that current syntheses are laborious and time consuming. Herein, we describe the preparation and utility of Rink, Ramage, and Sieber-chloride resins, which enables the use of a general, easy and practical method for the attachment of fluorenylmethoxycarbonyl (Fmoc)-amino alcohols to a solid support, in the synthesis of peptide alcohols. This method is the first straightforward Fmoc/tBu synthesis of peptide alcohols starting from a pre-loaded resin. The synthesized peptide alcohols can be detached from the linkers through conventional methods. Treatment with trifluoroacetic acid (TFA) (95 %) and scavengers such as triisopropylsilane and water for 2 h is sufficient to obtain a fully deprotected peptide alcohol, while treatment with 20 % hexafluoroisopropanol in dichloromethane renders a fully protected peptide alcohol that can be further modified at the C-terminus. As examples, the new resins were used in straightforward, relatively rapid syntheses of the peptide alcohols octreotide, alamethicin, and a segment of trichogin GA IV, as well as the first synthesis of stapled peptide alcohols.


Assuntos
Amino Álcoois/química , Peptídeos/química , Peptídeos/síntese química , Fenilalanina/análogos & derivados , Fenilalanina/química , Poliestirenos/química , Ácido Trifluoracético/química
20.
Am J Clin Nutr ; 111(2): 351-359, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31758682

RESUMO

BACKGROUND: Phenylalanine is an indispensable amino acid and, via tyrosine, is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine. Currently, dietary requirements for phenylalanine during pregnancy are unknown. OBJECTIVES: This study's aim was to determine phenylalanine requirements (in the presence of excess tyrosine) during early and late gestation using direct amino acid oxidation (DAAO; with l-[1-13C]phenylalanine) and indicator amino acid oxidation (IAAO; with l-[1-13C]leucine). METHODS: Twenty-three healthy women (age: 30.4 ± 3.1 y, mean ± SD) were studied at a range of phenylalanine intakes (5.5-30.5 mg · kg-1 · d-1 in early and late pregnancy using DAAO, and 2.5-30.5 mg · kg-1 · d-1 in late pregnancy using IAAO) for a total of 76 study days. Test intakes were provided as 8 isocaloric and isonitrogenous meals with 1.5 g · kg-1 · d-1 protein and energy at 1.7 times the measured resting energy expenditure. Breath samples were analyzed on an isotope ratio mass spectrometer for 13C enrichment. Phenylalanine requirement was determined using a 2-phase linear regression crossover model to identify a breakpoint in 13CO2 production (representing the mean requirement) in response to phenylalanine intakes. RESULTS: Phenylalanine requirement during early pregnancy was determined to be 15 mg · kg-1 · d-1 (95% CI: 10.4, 19.9 mg · kg-1 · d-1); during late pregnancy, it was determined to be 21 mg · kg-1 · d-1 by DAAO (95% CI: 17.4, 24.7 mg · kg-1 · d-1) and IAAO (95% CI: 10.5, 32.2 mg · kg-1 · d-1). CONCLUSIONS: Our results suggest a higher requirement (40%) for phenylalanine during late pregnancy than during early pregnancy. Moreover, the early pregnancy requirements are higher than the previous adult male requirement (9.1 mg · kg-1 · d-1; 95% CI: 4.6, 13.6 mg · kg-1 · d-1), although the 95% CIs overlap. Both DAAO and IAAO methods provided similar breakpoints in late pregnancy, showing that the DAAO method was appropriate even though low phenylalanine intakes could not be tested. These results have potential implications for gestation stage-specific dietary phenylalanine recommendations in future.This trial was registered at clinicaltrials.gov as NCT02669381.


Assuntos
Necessidades Nutricionais , Fenilalanina/administração & dosagem , Adulto , Aminoácidos/sangue , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Lineares , Refeições , Oxirredução , Fenilalanina/sangue , Fenilalanina/metabolismo , Gravidez
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