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1.
Psychophysiology ; : e14670, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39169561

RESUMO

According to the arousal model of vigilance, the locus coeruleus-norepinephrine (LC-NE) system modulates sustained attention over long periods by regulating physiological arousal. Recent research has proposed that transcutaneous auricular vagus nerve stimulation (taVNS) modulates indirect physiological markers of LC-NE activity, although its effects on vigilance have not yet been examined. Aiming to develop a safe and noninvasive procedure to prevent vigilance failures in prolonged tasks, the present study examined whether taVNS can mitigate vigilance loss while modulating indirect markers of LC-NE activity. Following a preregistered protocol (https://osf.io/tu2xy/), 50 participants completed three repeated sessions in a randomized order, in which either active taVNS at individualized intensity set by participant, active taVNS set at 0.5 mA for all participants, or sham taVNS, was delivered while performing an attentional and vigilance task (i.e., ANTI-Vea). Changes in salivary alpha-amylase and cortisol concentrations were measured as markers of LC-NE activity. Self-reports of feelings associated with stimulation and guessing rate of active/sham conditions supported the efficacy of the single-blind procedure. Contrary to our predictions, the observed vigilance decrement was not modulated by active taVNS. Pairwise comparisons showed a mitigation by active taVNS on cortisol reduction across time. Interestingly, Spearman's correlational analyses showed some interindividual effects of taVNS on indirect markers of LC-NE, evidenced by positive associations between changes in salivary alpha-amylase and cortisol in active but not sham taVNS. We highlight the relevance of replicating and extending the present outcomes, investigating further parameters of stimulation and its effects on other indirect markers of LC-NE activity.

2.
Int Orthop ; 48(8): 1971-1978, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38658421

RESUMO

PURPOSE: The Sanders Scoring System has revolutionized the way we assess the remaining growth potential of the skeleton. However, because it involves radiation exposure, it must be used with caution in children. The purpose of the study was to evaluate whether the Sanders skeletal maturity score (SMS) could be accurately determined using ultrasound (U). METHODS: We took radiographs (R) of the hand and performed U of the thumb and index finger in 115 patients between six and 19 years of age who were undergoing treatment for scoliosis or limb deformities. Paediatric orthopaedic surgeons, a paediatrician, and a paediatric radiologist were evaluated the blinded images. Those classified images are based on the SMS and the Thumb Ossification Composite Index (TOCI). RESULTS: Intrarater reliability was high for SMS and slightly weaker for TOCI, but still significant. Interrater reliability was clear for R and weaker for U in both staging systems. Ultimately, SMS 3 and 7 achieved the highest percentage of concordance (P) of 71.7% and 66.0%, respectively, when U was performed. Combining the clinically relevant groups of SMS 3&4 and SMS 7&8 also significantly increased peak scores (SMS 3 and 4 P = 76.7%; SMS 7 and 8 P = 79.7%). The probabilities of peak scores were significantly weaker when the TOCI score was examined. CONCLUSION: Our study shows that U can be used effectively especially to measure stages 3 and 4 and stages 7 and 8 of SMS. The U method is easy to use and therefore may offer advantages in clinical practice without the need for radiation exposure.


Assuntos
Determinação da Idade pelo Esqueleto , Tomada de Decisão Clínica , Ultrassonografia , Humanos , Criança , Adolescente , Masculino , Feminino , Ultrassonografia/métodos , Determinação da Idade pelo Esqueleto/métodos , Tomada de Decisão Clínica/métodos , Reprodutibilidade dos Testes , Adulto Jovem , Radiografia/métodos , Mãos/diagnóstico por imagem , Escoliose/diagnóstico por imagem , Variações Dependentes do Observador
3.
Angew Chem Int Ed Engl ; 63(38): e202404492, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-38948941

RESUMO

While plastics like polyethylene terephthalate can already be degraded efficiently by the activity of hydrolases, other synthetic polymers like polyurethanes (PUs) and polyamides (PAs) largely resist biodegradation. In this study, we solved the first crystal structure of the metagenomic urethanase UMG-SP-1, identified highly flexible loop regions to comprise active site residues, and targeted a total of 20 potential hot spots by site-saturation mutagenesis. Engineering campaigns yielded variants with single mutations, exhibiting almost 3- and 8-fold improved activity against highly stable N-aryl urethane and amide bonds, respectively. Furthermore, we demonstrated the release of the corresponding monomers from a thermoplastic polyester-PU and a PA (nylon 6) by the activity of a single, metagenome-derived urethanase after short incubation times. Thereby, we expanded the hydrolysis profile of UMG-SP-1 beyond the reported low-molecular weight carbamates. Together, these findings promise advanced strategies for the bio-based degradation and recycling of plastic materials and waste, aiding efforts to establish a circular economy for synthetic polymers.


Assuntos
Metagenoma , Hidrólise , Metagenômica , Glicosídeo Hidrolases/metabolismo , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/genética , Modelos Moleculares , Engenharia de Proteínas
4.
Plant Cell Physiol ; 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37927069

RESUMO

Wounding caused by insects or abiotic factors such as wind and hail can cause severe stress for plants. Intrigued by the observation that wounding induces expression of genes involved in surface wax synthesis in a jasmonoyl-isoleucine (JA-Ile)-independent manner, the role of wax biosynthesis and respective genes upon wounding was investigated. Wax, a lipid-based barrier, protects plants both from environmental threats as well as from an uncontrolled loss of water. Its biosynthesis is described to be regulated by abscisic acid (ABA), whereas the main wound-signal is the hormone JA-Ile. We show in this study, that genes coding for enzymes of surface wax synthesis are induced upon wounding in Arabidopsis thaliana leaves in a JA-Ile-independent but ABA-dependent manner. Furthermore, the ABA-dependent transcription factor MYB96 is a key regulator of wax biosynthesis upon wounding. On the metabolite level, wound-induced wax accumulation is strongly reduced in JA-Ile-deficient plants, but this induction is only slightly decreased in ABA-reduced plants. To further analyze the ABA-dependent wound response, we conducted wounding experiments in high humidity. They show that high humidity prevents the wound-induced wax accumulation in A. thaliana leaves. Together the data presented in this study show that wound-induced wax accumulation is JA-Ile-dependent on the metabolite level, but the expression of genes coding for enzymes of wax synthesis is regulated by ABA.

5.
Bioorg Chem ; 139: 106685, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37418786

RESUMO

Inflammatory responses are orchestrated by a plethora of lipid mediators, and perturbations of their biosynthesis or degradation hinder resolution and lead to uncontrolled inflammation, which contributes to diverse pathologies. Small molecules that induce a switch from pro-inflammatory to anti-inflammatory lipid mediators are considered valuable for the treatment of chronic inflammatory diseases. Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) are afflicted with side effects caused by the inhibition of beneficial prostanoid formation and redirection of arachidonic acid (AA) into alternative pathways. Multi-target inhibitors like diflapolin, the first dual inhibitor of soluble epoxide hydrolase (sEH) and 5-lipoxygenase-activating protein (FLAP), promise improved efficacy and safety but are confronted by poor solubility and bioavailability. Four series of derivatives bearing isomeric thiazolopyridines as bioisosteric replacement of the benzothiazole core and two series additionally containing mono- or diaza-isosteres of the phenylene spacer were designed and synthesized to improve solubility. The combination of thiazolo[5,4-b]pyridine, a pyridinylen spacer and a 3,5-Cl2-substituted terminal phenyl ring (46a) enhances solubility and FLAP antagonism, while preserving sEH inhibition. Moreover, the thiazolo[4,5-c]pyridine derivative 41b, although being a less potent sEH/FLAP inhibitor, additionally decreases thromboxane production in activated human peripheral blood mononuclear cells. We conclude that the introduction of nitrogen, depending on the position, not only enhances solubility and FLAP antagonism (46a), but also represents a valid strategy to expand the scope of application towards inhibition of thromboxane biosynthesis.


Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase , Inibidores de Lipoxigenase , Humanos , Inibidores de Lipoxigenase/farmacologia , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Solubilidade , Leucócitos Mononucleares/metabolismo , Epóxido Hidrolases/metabolismo , Inibidores Enzimáticos/farmacologia , Anti-Inflamatórios/farmacologia , Piridinas/farmacologia , Tromboxanos , Lipídeos
6.
Int J Mol Sci ; 24(8)2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37108702

RESUMO

The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A4 epoxide which is converted to a chemotactic leukotriene B4 (LTB4) by leukotriene A4 hydrolase (LTA4H). In addition, LTA4H possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTA4H, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTA4H at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTA4H with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB4 and can potentially be used as modulators of inflammatory response by the 5-LOX pathway.


Assuntos
Calcogênios , Epóxido Hidrolases , Leucotrieno A4 , Epóxido Hidrolases/metabolismo , Araquidonato 5-Lipoxigenase , Aminopeptidases/metabolismo
7.
Plant Cell Physiol ; 63(3): 317-325, 2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-34910213

RESUMO

Ceramides (Cers) and long-chain bases (LCBs) are plant sphingolipids involved in the induction of plant programmed cell death (PCD). The fatty acid hydroxylase mutant fah1 fah2 exhibits high Cer levels and moderately elevated LCB levels. Salicylic acid glucoside level is increased in this mutant, but no cell death can be detected by trypan blue staining. To determine the effect of Cers with different chain lengths, fah1 fah2 was crossed with ceramide synthase mutants longevity assurance gene one homologue1-3 (loh1, loh2 and loh3). Surprisingly, only triple mutants with loh2 show cell death detected by trypan blue staining under the selected conditions. Sphingolipid profiling revealed that the greatest differences between the triple mutant plants are in the LCB and LCB-phosphate (LCB-P) fraction. fah1 fah2 loh2 plants accumulate LCB d18:0, LCB t18:0 and LCB-P d18:0. Crossing fah1 fah2 loh2 with the salicylic acid (SA) synthesis mutant sid2-2 and with the SA signaling mutants enhanced disease susceptibility 1-2 (eds1-2) and phytoalexin deficient 4-1 (pad4-1) revealed that lesions are SA- and EDS1-dependent. These quadruple mutants also confirm that there may be a feedback loop between SA and sphingolipid metabolism as they accumulated less Cers and LCBs. In conclusion, PCD in fah1 fah2 loh2 is a SA- and EDS1-dependent phenotype, which is likely due to accumulation of LCBs.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Apoptose , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ácidos Graxos/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Oxirredutases , Fenótipo , Ácido Salicílico/metabolismo , Esfingolipídeos/metabolismo
8.
Scand J Public Health ; 50(4): 440-447, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33739184

RESUMO

AIM: We aimed to understand the interplay between retirement pathways and healthcare use in the postponed and structurally changing context of retirement. METHODS: Based on Swedish register data on income and healthcare use, we applied combined sequence and cluster analysis to identify typical pathways into retirement and analysed their relation to healthcare use developments. RESULTS: We detected five distinct pathways into retirement. Level of healthcare use was significantly higher for the pathway via disability pensions. We saw an overall increase in healthcare use across the retirement process that was related to age rather than to the different pathways. CONCLUSIONS: Level of healthcare use at the beginning of the retirement process may be related to selection into different pathways of retirement. We did not find clear evidence across several healthcare measures that different pathways lead to different developments in healthcare use.


Assuntos
Pensões , Aposentadoria , Estudos de Coortes , Atenção à Saúde , Humanos , Renda
9.
New Phytol ; 226(1): 170-188, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31758808

RESUMO

Sphingolipids act as regulators of programmed cell death (PCD) and the plant defence response. The homeostasis between long-chain base (LCB) and ceramide (Cer) seems to play an important role in executions of PCD. Therefore, deciphering the role of neutral ceramidases (NCER) is crucial to identify the sphingolipid compounds that trigger and execute PCD. We performed comprehensive sphingolipid and phytohormone analyses of Arabidopsis ncer mutants, combined with gene expression profiling and microscopic analyses. While ncer1 exhibited early leaf senescence (developmentally controlled PCD - dPCD) and an increase in hydroxyceramides, ncer2 showed spontaneous cell death (pathogen-triggered PCD-like - pPCD) accompanied by an increase in LCB t18:0 at 35 d, respectively. Loss of NCER1 function resulted in accumulation of jasmonoyl-isoleucine (JA-Ile) in the leaves, whereas disruption of NCER2 was accompanied by higher levels of salicylic acid (SA) and increased sensitivity to Fumonisin B1 (FB1 ). All mutants were also found to activate plant defence pathways. These data strongly suggest that NCER1 hydrolyses ceramides whereas NCER2 functions as a ceramide synthase. Our results reveal an important role of NCER in the regulation of both dPCD and pPCD via a tight connection between the phytohormone and sphingolipid levels in these two processes.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Regulação da Expressão Gênica de Plantas , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Morte Celular , Ceramidase Neutra/genética , Reguladores de Crescimento de Plantas , Esfingolipídeos
10.
Org Biomol Chem ; 17(19): 4906-4916, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042251

RESUMO

Melleolides from the honey mushroom Armillaria mellea represent a structurally diverse group of polyketide-sesquiterpene hybrids. Among various bioactivites, melleolides show antifungal effects against Aspergillus and other fungi. This bioactivity depends on a Δ2,4-double bond present in dihydroarmillylorsellinate (DAO) or arnamial, for example. Yet, the mode of action of Δ2,4-unsaturated, antifungal melleolides has been unknown. Here, we report on the molecular target of DAO in the fungus Aspergillus nidulans. Using a combination of synthetic chemistry to create a DAO-labelled probe, protein pulldown assays, MALDI-TOF-based peptide analysis and western blotting, we identify the eukaryotic translation elongation factor 2 (eEF2) as a binding partner of DAO. We confirm the inhibition of protein biosynthesis in vivo with an engineered A. nidulans strain producing the red fluorescent protein mCherry. Our work suggests a binding site dissimilar from that of the protein biosynthesis inhibitor sordarin, and highlights translational elongation as a valid antifungal drug target.


Assuntos
Antifúngicos/farmacologia , Armillaria/efeitos dos fármacos , Armillaria/metabolismo , Fator 2 de Elongação de Peptídeos/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Sesquiterpenos/metabolismo , Antifúngicos/química , Armillaria/genética , Proteínas Luminescentes/biossíntese , Conformação Molecular , Simulação de Acoplamento Molecular , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Proteína Vermelha Fluorescente
11.
Z Gerontol Geriatr ; 52(Suppl 1): 40-51, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30456473

RESUMO

BACKGROUND: In the last two decades labor market participation for older employees has undergone a gradual political paradigm shift in many European countries from a policy of early retirement to one of extending working lives and active aging. OBJECTIVE: This study investigated if this political paradigm shift is causing new social inequalities in retirement transition due to restricted financial possibilities for early retirement. MATERIAL AND METHODS: Data were derived from the European Union Labor Force Survey from the years 2006 and 2012 and selected European countries (Germany, Austria, Sweden and Estonia) were analyzed. RESULTS: Associations between the specific implementation of the policy of active aging, the freedom of choice in retirement timing and retirement transition were found. It seems that voluntary retirement transitions are highest in those countries where the labor market and social policies are most coherent and aimed at supporting older workers' employability. CONCLUSION: The reduction of early retirement incentives should be supported by active labor market policies and a policy of extensive age-independent further training measures in order to minimize social inequalities.


Assuntos
Envelhecimento , Emprego/tendências , Política Pública , Aposentadoria/economia , Aposentadoria/tendências , Mudança Social , Idoso , Áustria , Emprego/estatística & dados numéricos , Estônia , Europa (Continente) , Alemanha , Humanos , Pessoa de Meia-Idade , Fatores Socioeconômicos , Suécia
12.
Chemistry ; 24(44): 11319-11324, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-29846024

RESUMO

We characterized two key biosynthetic intermediates of the intriguing rubterolone family (tropolone alkaloids) that contain a highly reactive pyran moiety (in equilibrium with the hydrolyzed 1,5-dione form) and undergo spontaneous pyridine formation in the presence of primary amines. We exploited the intrinsic reactivity of the pyran moiety and isolated several new rubterolone derivatives, two of which contain a unique thiazolidine moiety. Three rubterolone derivatives were chemically modified with fluorescence and biotin tags using peptide coupling and click reaction. Overall, eight derivatives were fully characterized by HRMS/MS and 1D and 2D NMR spectroscopy and their antimicrobial, cytotoxic, anti-inflammatory and antiparasitic activities evaluated.

13.
Molecules ; 23(2)2018 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-29495286

RESUMO

Age-related diseases, such as osteoarthritis, Alzheimer's disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging.


Assuntos
Catepsina G/antagonistas & inibidores , Franquincenso/química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Triterpenos/síntese química , Triterpenos/isolamento & purificação
14.
Bioinformatics ; 32(22): 3388-3395, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27466621

RESUMO

MOTIVATION: As the tree of life is populated with sequenced genomes ever more densely, the new challenge is the accurate and consistent annotation of entire clades of genomes. We address this problem with a new approach to comparative gene finding that takes a multiple genome alignment of closely related species and simultaneously predicts the location and structure of protein-coding genes in all input genomes, thereby exploiting negative selection and sequence conservation. The model prefers potential gene structures in the different genomes that are in agreement with each other, or-if not-where the exon gains and losses are plausible given the species tree. We formulate the multi-species gene finding problem as a binary labeling problem on a graph. The resulting optimization problem is NP hard, but can be efficiently approximated using a subgradient-based dual decomposition approach. RESULTS: The proposed method was tested on whole-genome alignments of 12 vertebrate and 12 Drosophila species. The accuracy was evaluated for human, mouse and Drosophila melanogaster and compared to competing methods. Results suggest that our method is well-suited for annotation of (a large number of) genomes of closely related species within a clade, in particular, when RNA-Seq data are available for many of the genomes. The transfer of existing annotations from one genome to another via the genome alignment is more accurate than previous approaches that are based on protein-spliced alignments, when the genomes are at close to medium distances. AVAILABILITY AND IMPLEMENTATION: The method is implemented in C ++ as part of Augustus and available open source at http://bioinf.uni-greifswald.de/augustus/ CONTACT: stefaniekoenig@ymail.com or mario.stanke@uni-greifswald.deSupplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Genoma , Alinhamento de Sequência , Animais , Drosophila melanogaster , Éxons , Humanos , Camundongos
15.
Chembiochem ; 16(17): 2445-50, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26416255

RESUMO

The siderophore myxochelin A is a potent inhibitor of human 5-lipoxygenase (5-LO). To clarify whether the iron-chelating properties of myxochelin A are responsible for this activity, several analogues of this compound were generated in the native producer Pyxidicoccus fallax by precursor-directed biosynthesis. Testing in a cell-free assay unveiled three derivatives with bioactivity comparable with that of myxochelin A. Furthermore, it became evident that inhibition of 5-LO by myxochelins does not correlate with their iron affinities.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/metabolismo , Lisina/análogos & derivados , Araquidonato 5-Lipoxigenase/química , Humanos , Concentração Inibidora 50 , Inibidores de Lipoxigenase/química , Lisina/biossíntese , Lisina/química , Myxococcales/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
16.
J Nat Prod ; 78(2): 335-8, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25686392

RESUMO

Extracts of the predatory myxobacterium Pyxidicoccus fallax HKI 727 showed antiproliferative effects on leukemic K-562 cells. Bioactivity-guided fractionation led to the isolation of the bis-catechol myxochelin A and two new congeners. The biosynthetic origin of myxochelins C and D was confirmed by feeding studies with isotopically labeled precursors. Pharmacological testing revealed human 5-lipoxygenase (5-LO) as a molecular target of the myxochelins. In particular, myxochelin A efficiently inhibited 5-LO activity with an IC50 of 1.9 µM and reduced the proliferation of K-562 cells at similar concentrations.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Lisina/análogos & derivados , Myxococcales/química , Sideróforos/isolamento & purificação , Curcumina/química , Células HeLa , Humanos , Células K562 , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/isolamento & purificação , Lisina/química , Lisina/isolamento & purificação , Lisina/farmacologia , Estrutura Molecular , Sideróforos/química , Estereoisomerismo
17.
New Phytol ; 202(3): 823-837, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24483326

RESUMO

Verticillium longisporum is a soil-borne vascular pathogen causing economic loss in rape. Using the model plant Arabidopsis this study analyzed metabolic changes upon fungal infection in order to identify possible defense strategies of Brassicaceae against this fungus. Metabolite fingerprinting identified infection-induced metabolites derived from the phenylpropanoid pathway. Targeted analysis confirmed the accumulation of sinapoyl glucosides, coniferin, syringin and lignans in leaves from early stages of infection on. At later stages, the amounts of amino acids increased. To test the contribution of the phenylpropanoid pathway, mutants in the pathway were analyzed. The sinapate-deficient mutant fah1-2 showed stronger infection symptoms than wild-type plants, which is most likely due to the lack of sinapoyl esters. Moreover, the coniferin accumulating transgenic plant UGT72E2-OE was less susceptible. Consistently, sinapoyl glucose, coniferyl alcohol and coniferin inhibited fungal growth and melanization in vitro, whereas sinapyl alcohol and syringin did not. The amount of lignin was not significantly altered supporting the notion that soluble derivatives of the phenylpropanoid pathway contribute to defense. These data show that soluble phenylpropanoids are important for the defense response of Arabidopsis against V. longisporum and that metabolite fingerprinting is a valuable tool to identify infection-relevant metabolic markers.


Assuntos
Arabidopsis/imunologia , Arabidopsis/microbiologia , Propanóis/metabolismo , Verticillium/fisiologia , Arabidopsis/genética , Biomarcadores/metabolismo , Vias Biossintéticas/efeitos dos fármacos , Cinamatos/farmacologia , Ácidos Cumáricos/metabolismo , Resistência à Doença/imunologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Genes de Plantas , Glucosídeos/farmacologia , Lignanas/metabolismo , Lignina/metabolismo , Metabolômica , Mutação/genética , Fenóis/química , Fenóis/farmacologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/imunologia , Folhas de Planta/microbiologia , Feixe Vascular de Plantas/citologia , Feixe Vascular de Plantas/metabolismo , Solubilidade , Verticillium/efeitos dos fármacos , Verticillium/crescimento & desenvolvimento
18.
Chemistry ; 20(48): 15933-40, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25287056

RESUMO

The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin-resistant Staphylococcus aureus, but no cytotoxic effects on human cells.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/química , Bacteriocinas/biossíntese , Bacteriocinas/química , Produtos Biológicos/química , Macrolídeos/química , Macrolídeos/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Policetídeos/química , Antibacterianos/farmacologia , Bacteriocinas/farmacologia , Humanos , Macrolídeos/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Estrutura Molecular , Família Multigênica
19.
Bioorg Med Chem ; 22(15): 3856-61, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25028062

RESUMO

The melleolides are structurally unique and bioactive natural products of the basidiomycete genus Armillaria. Here, we report on cytotoxic effects of melleolides from Armillaria mellea towards non-transformed human primary monocytes and human cancer cell lines, respectively. In contrast to staurosporine or pretubulysin that are less cytotoxic for monocytes, the cytotoxic potency of the active melleolides in primary monocytes is comparable to that in cancer cells. The onset of the cytotoxic effects of melleolides was rapid (within <1 h), as compared to the apoptosis inducer staurosporine, the protein biosynthesis inhibitor cycloheximide, and the DNA transcription inhibitor actinomycin D (>5 h, each). Side-by-side comparison with the detergent triton X-100 and staurosporine in microscopic and flow cytometric analysis studies as well as analysis of the viability of mitochondria exclude cell lysis and apoptosis as relevant or primary mechanisms. Our results rather point to necrotic features of cell death mediated by an as yet elusive but rapid mechanism.


Assuntos
Apoptose/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células HeLa , Humanos , Células K562 , Microscopia , Monócitos/citologia , Monócitos/metabolismo , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/toxicidade , Estaurosporina/química , Estaurosporina/isolamento & purificação , Estaurosporina/toxicidade , Relação Estrutura-Atividade
20.
Res Aging ; 45(3-4): 259-279, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35588492

RESUMO

Increasing numbers of older workers continue to work after being eligible to claim a state pension, yet little is known about the quality of these jobs. We examine how psychosocial and physical job quality as well as job satisfaction vary over the late career in three contrasting national settings: Sweden, Japan and the United States. Analyses using random effects modelling drew on data from the Swedish Longitudinal Occupational Survey of Health (n = 13,936-15,520), Japanese Study of Ageing and Retirement (n = 3704) and the Health and Retirement Study (n = 6239 and 8002). Age was modelled with spline functions in which two knots were placed at ages indicating eligibility for pensions claiming or mandatory retirement. In each country, post-pensionable-age jobs were generally less stressful, freer and more satisfying than jobs held by younger workers, results that held irrespective of gender or education level.


Assuntos
Pensões , Aposentadoria , Humanos , Estados Unidos , Suécia/epidemiologia , Japão , Aposentadoria/psicologia , Envelhecimento
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