RESUMEN
The ability of parasitic wasps to manipulate a host's metabolism is under active investigation. Components of venom play a major role in this process. In the present work, we studied the effect of the venom of the ectoparasitic wasp Habrobracon hebetor on the metabolism of the greater wax moth host (Galleria mellonella). We identified and quantified 45 metabolites in the lymph (cell-free hemolymph) of wax moth larvae on the second day after H. hebetor venom injection, using NMR spectroscopy and liquid chromatography coupled with mass spectrometry. These metabolites included 22 amino acids, nine products of lipid metabolism (sugars, amines and alcohols) and four metabolic intermediates related to nitrogenous bases, nucleotides and nucleosides. An analysis of the larvae metabolome suggested that the venom causes suppression of the tricarboxylic acid cycle, an increase in the number of free amino acids in the lymph, an increase in the concentration of trehalose in the lymph simultaneously with a decrease in the amount of glucose, and destructive processes in the fat body tissue. Thus, this parasitoid venom not only immobilizes the prey but also modulates its metabolism, thereby providing optimal conditions for the development of larvae.
Asunto(s)
Hemolinfa , Larva , Mariposas Nocturnas , Venenos de Avispas , Avispas , Animales , Avispas/fisiología , Venenos de Avispas/metabolismo , Venenos de Avispas/química , Mariposas Nocturnas/parasitología , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/metabolismo , Larva/crecimiento & desarrollo , Larva/metabolismo , Hemolinfa/metabolismo , Hemolinfa/química , Metaboloma/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Interacciones Huésped-Parásitos/efectos de los fármacosRESUMEN
INTRODUCTION: In soccer, most studies evaluate metabolic profile changes in male athletes, often using data from a single match. Given the current landscape of women's soccer and the effects of biological sex on the physiological response and adaptation to exercise, more studies targeting female athletes and analyzing pre- and post-game moments throughout the season are necessary. OBJECTIVES: To describe the metabolomics profile of female soccer athletes from an elite team in Brazil. The study observed the separation of groups in three pre- and post-game moments and identified the discriminating metabolites. METHODS: The study included 14 female soccer athletes. Urine samples were collected and analyzed using Nuclear Magnetic Resonance in pre-game and immediate post-game moments over three national championship games. The metabolomics data were then used to generate OPLS-DA and VIP plots. RESULTS: Forty-three metabolites were identified in the samples. OPLS-DA analyses demonstrated a progressive separation between pre-post conditions, as supported by an increasing Q2 value (0.534, 0.625, and 0.899 for games 1, 2 and 3, respectively) and the first component value (20.2% and 19.1% in games 1 and 2 vs. 29.9% in game 3). Eight out of the fifteen most discriminating metabolites appeared consistently across the three games: glycine, formate, citrate, 3-hydroxyvalerate, glycolic acid, trimethylamine, urea, and dimethylglycine. CONCLUSION: The main difference between the three games was the increasing separation between groups throughout the championship. Since the higher VIP-scores metabolites are linked to energy and protein metabolism, this separation may be attributed several factors, one being the accumulation of fatigue.
Asunto(s)
Atletas , Biomarcadores , Metabolómica , Fútbol , Fútbol/fisiología , Humanos , Metabolómica/métodos , Biomarcadores/orina , Femenino , Adulto Joven , Metaboloma , Adulto , Brasil , Espectroscopía de Resonancia Magnética/métodosRESUMEN
Paired-pulse transcranial magnetic stimulation is a valuable tool for investigating inhibitory mechanisms in motor cortex. We recently demonstrated its use in measuring cortical inhibition in visual cortex, using an approach in which participants trace the size of phosphenes elicited by stimulation to occipital cortex. Here, we investigate age-related differences in primary visual cortical inhibition and the relationship between primary visual cortical inhibition and local GABA+ in the same region, estimated using magnetic resonance spectroscopy. GABA+ was estimated in 28 young (18 to 28 years) and 47 older adults (65 to 84 years); a subset (19 young, 18 older) also completed a paired-pulse transcranial magnetic stimulation session, which assessed visual cortical inhibition. The paired-pulse transcranial magnetic stimulation measure of inhibition was significantly lower in older adults. Uncorrected GABA+ in primary visual cortex was also significantly lower in older adults, while measures of GABA+ that were corrected for the tissue composition of the magnetic resonance spectroscopy voxel were unchanged with age. Furthermore, paired-pulse transcranial magnetic stimulation-measured inhibition and magnetic resonance spectroscopy-measured tissue-corrected GABA+ were significantly positively correlated. These findings are consistent with an age-related decline in cortical inhibition in visual cortex and suggest paired-pulse transcranial magnetic stimulation effects in visual cortex are driven by GABAergic mechanisms, as has been demonstrated in motor cortex.
Asunto(s)
Envejecimiento , Espectroscopía de Resonancia Magnética , Inhibición Neural , Estimulación Magnética Transcraneal , Corteza Visual , Ácido gamma-Aminobutírico , Humanos , Estimulación Magnética Transcraneal/métodos , Adulto , Anciano , Masculino , Femenino , Adulto Joven , Espectroscopía de Resonancia Magnética/métodos , Inhibición Neural/fisiología , Ácido gamma-Aminobutírico/metabolismo , Anciano de 80 o más Años , Adolescente , Envejecimiento/fisiología , Corteza Visual/fisiología , Corteza Visual/diagnóstico por imagenRESUMEN
The metabolomic profile of aging is complex. Here, we analyse 325 nuclear magnetic resonance (NMR) biomarkers from 250,341 UK Biobank participants, identifying 54 representative aging-related biomarkers associated with all-cause mortality. We conduct genome-wide association studies (GWAS) for these 325 biomarkers using whole-genome sequencing (WGS) data from 95,372 individuals and perform multivariable Mendelian randomization (MVMR) analyses, discovering 439 candidate "biomarker - disease" causal pairs at the nominal significance level. We develop a metabolomic aging score that outperforms other aging metrics in predicting short-term mortality risk and exhibits strong potential for discriminating aging-accelerated populations and improving disease risk prediction. A longitudinal analysis of 13,263 individuals enables us to calculate a metabolomic aging rate which provides more refined aging assessments and to identify candidate anti-aging and pro-aging NMR biomarkers. Taken together, our study has presented a comprehensive aging-related metabolomic profile and highlighted its potential for personalized aging monitoring and early disease intervention.
Asunto(s)
Envejecimiento , Bancos de Muestras Biológicas , Biomarcadores , Estudio de Asociación del Genoma Completo , Metabolómica , Humanos , Envejecimiento/genética , Envejecimiento/metabolismo , Reino Unido/epidemiología , Masculino , Femenino , Metabolómica/métodos , Anciano , Persona de Mediana Edad , Biomarcadores/metabolismo , Análisis de la Aleatorización Mendeliana , Espectroscopía de Resonancia Magnética , Metaboloma , Estudios Longitudinales , Secuenciación Completa del Genoma , Adulto , Anciano de 80 o más Años , Biobanco del Reino UnidoRESUMEN
Hyperpolarized pyruvate is a widely used marker to track metabolism in vivo and a benchmark molecule for hyperpolarization methods. Here, we show how a combination of improved bullet-DNP instrumentation, an optimized sample preparation and a further sensitivity increase via a 13C-1H polarization transfer after dissolution enable the observation of pyruvate at a concentration of 250 nM immediately after dissolution. At this concentration, the experiment employs a total mass of pyruvate of only 20 ng or 180 pmol. If the concentration is increased to 45 µM, pyruvate may be detected 1 min after dissolution with a signal-to-noise ratio exceeding 50. The procedure can be extended to observe a mixture of amino acids at low micromolar concentrations.
Asunto(s)
Aminoácidos , Ácido Pirúvico , Aminoácidos/análisis , Aminoácidos/química , Ácido Pirúvico/química , Ácido Pirúvico/análisis , Espectroscopía de Resonancia Magnética/métodosRESUMEN
In vivo phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) imaging (MRSI) is an important non-invasive imaging tool for studying cerebral energy metabolism, intracellular nicotinamide adenine dinucleotide (NAD) and redox ratio, and mitochondrial function. However, it is challenging to achieve high signal-to-noise ratio (SNR) 31P MRS/MRSI results owing to low phosphorus metabolites concentration and low phosphorous gyromagnetic ratio (γ). Many works have demonstrated that ultrahigh field (UHF) could significantly improve the 31P-MRS SNR. However, there is a lack of studies of the 31P MRSI SNR in the 10.5 Tesla (T) human scanner. In this study, we designed and constructed a novel 31P-1H dual-frequency loop-dipole probe that can operate at both 7T and 10.5T for a quantitative comparison of 31P MRSI SNR between the two magnetic fields, taking into account the RF coil B1 fields (RF coil receive and transmit fields) and relaxation times. We found that the SNR of the 31P MRS signal is 1.5 times higher at 10.5T as compared to 7T, and the power dependence of SNR on magnetic field strength (B0) is 1.9.
Asunto(s)
Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Fósforo , Relación Señal-Ruido , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/instrumentación , Espectroscopía de Resonancia Magnética/métodos , Fósforo/química , Ondas de Radio , Isótopos de Fósforo , Fantasmas de ImagenRESUMEN
BACKGROUND: Biothiols are important for numerous cellular processes, such as resisting oxidative stress and protecting cell health. Their abnormal levels and molecular configurations have been associated with various diseases. So, establishing an effective and reliable method for the specific detection and enantiomeric discrimination of diverse biothiols is highly meaningful. RESULTS: We have developed a new NMR and CD probe using 1,4-dinitroimidazole, specifically targeting the thiol group. This probe allows for the specific detection and enantiomeric recognition of biothiols in complex mixtures. We achieved this by identifying the distinguishable 1H NMR signals of 2nd in imidazole-ring of the resulting 4NI-biothiols in the downfield region at 7-8 ppm and newly discovered induced CD signals within 290-430 nm. Using this probe, the limits of detection of Cys, GSH, and Hcy, the recovery rates, and the concentration of GSH extracted from HEK293T cells were determined by measuring the unique downfield 1H NMR signals. Moreover, Cys, GSH, and Hcy can be discriminated simultaneously in complicated samples at a pH range of 2-3.5. Furthermore, this probe can also be utilized to sense chiral thiol-drugs. SIGNIFICANCE: This method offers a cost-effective and accurate sensing solution for the specific detection of biothiols in complex mixtures, with stereochemical recognition.
Asunto(s)
Imidazoles , Compuestos de Sulfhidrilo , Humanos , Estereoisomerismo , Imidazoles/química , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/análisis , Células HEK293 , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Cisteína/análisis , Glutatión/análisis , Glutatión/química , Homocisteína/análisis , Límite de Detección , Estructura MolecularRESUMEN
Recently, the growth of consumer demand for functional foods with potential nutritional and health benefits led to rapid growth of analytical tools for profiling of bioactive metabolites and assure quality. Bee propolis is one of the most important bee products owing to its myriad health value. As a gummy exudate produced in beehives after harvesting from different plant species, bee propolis contains bioactive secondary metabolites. The current study aims to profiling the chemical composition of propolis samples from Nigeria using HPLC-UV-ELSD and with the aid of NMR-based analysis for assignment of metabolites classes abundant in Nigerian propolis. Red Nigerian propolis samples were subjected to phytochemical analysis using HPLC-UV-ELSD and NMR. Further chromatographic separation of promising fractions was performed by column chromatography and size exclusion chromatography. Screening of the antitrypanosomal and cytotoxic activities against Trypanosoma brucei and human leukemia cell lines (U937), respectively, was performed. The performance of LC-MS permitted identification of the different components from which 13 compound were identified and allowed combination of fractions to afford 9 fractions from which two isoflavonoids were isolated and identified using 1D and 2D NMR analysis with MS as isosativan and Medicarpin. Red Nigerian propolis crude extract showed the highest inhibitory activity at 6.5 µg/ml compared to moderate activity for the isolated compounds with MIC of 7.6 µg/ml and 12.1 µg/ml for medicarpin and isosativan, respectively. Moreover, the fraction RN-6 from the total extract showed the potent cytotoxic effect with IC50 = 26.5 µg/ml compared to standard diminazen which showed IC50 = 29.5 µg/ml.
Asunto(s)
Antiprotozoarios , Flavonoides , Fitoquímicos , Própolis , Trypanosoma brucei brucei , Própolis/química , Própolis/farmacología , Antiprotozoarios/farmacología , Antiprotozoarios/química , Humanos , Trypanosoma brucei brucei/efectos de los fármacos , Flavonoides/química , Flavonoides/farmacología , Flavonoides/análisis , Fitoquímicos/farmacología , Fitoquímicos/química , Nigeria , Animales , Cromatografía Líquida de Alta Presión , Línea Celular Tumoral , Espectroscopía de Resonancia Magnética , AbejasRESUMEN
Protein dynamics play a crucial role in biological function, encompassing motions ranging from atomic vibrations to large-scale conformational changes. Recent advancements in experimental techniques, computational methods, and artificial intelligence have revolutionized our understanding of protein dynamics. Nuclear magnetic resonance spectroscopy provides atomic-resolution insights, while molecular dynamics simulations offer detailed trajectories of protein motions. Computational methods applied to X-ray crystallography and cryo-electron microscopy (cryo-EM) have enabled the exploration of protein dynamics, capturing conformational ensembles that were previously unattainable. The integration of machine learning, exemplified by AlphaFold2, has accelerated structure prediction and dynamics analysis. These approaches have revealed the importance of protein dynamics in allosteric regulation, enzyme catalysis, and intrinsically disordered proteins. The shift towards ensemble representations of protein structures and the application of single-molecule techniques have further enhanced our ability to capture the dynamic nature of proteins. Understanding protein dynamics is essential for elucidating biological mechanisms, designing drugs, and developing novel biocatalysts, marking a significant paradigm shift in structural biology and drug discovery.
Asunto(s)
Microscopía por Crioelectrón , Aprendizaje Automático , Simulación de Dinámica Molecular , Proteínas , Microscopía por Crioelectrón/métodos , Proteínas/química , Proteínas/metabolismo , Conformación Proteica , Humanos , Resonancia Magnética Nuclear Biomolecular/métodos , Espectroscopía de Resonancia Magnética/métodosRESUMEN
Considering that maize (Zea mays L.) is a staple food for a large segment of the population worldwide, many attempts have been made to improve the nutritional value of its grain and at the same time to achieve sustainable cropping systems. The present study aimed to characterize the composition and nutritional value of maize grain as influenced by cropping system, genetic background (variety), and growing year using untargeted NMR metabolomics. The composition of both water- (sugars and polyols, organic acids, and amino acids) and liposoluble metabolites (free and esterified fatty acids, sterols, and lipids) extracted from the maize grain was determined. Multivariate statistical analyses (PCA and ANOVA) pointed to the growing year and the variety as the most important random and fixed factors, respectively, influencing the metabolite profile. The samples were separated along PC1 and PC3 according to the growing year and the variety, respectively. A higher content of citric acid and diunsaturated fatty acids and a lower content of tyrosine, trigonelline, and monounsaturated fatty acids was observed in the organic with respect to the conventional variety. The effect of the cropping system was overwhelmed by the random effect of the growing year. The results provide novel knowledge on the influence of agronomic practices on maize micronutrient contents.
Asunto(s)
Espectroscopía de Resonancia Magnética , Metabolómica , Zea mays , Zea mays/metabolismo , Zea mays/crecimiento & desarrollo , Zea mays/química , Espectroscopía de Resonancia Magnética/métodos , Metabolómica/métodos , Grano Comestible/metabolismo , Grano Comestible/crecimiento & desarrollo , Grano Comestible/química , Ácidos Grasos/metabolismo , Ácidos Grasos/análisis , Metaboloma , Aminoácidos/metabolismo , Aminoácidos/análisis , Valor NutritivoRESUMEN
This study investigated the structural composition and antioxidant properties of pectic polysaccharides extracted from Rohdea japonica (Thunb.) Roth. Pectins, which belong to a complex category of acidic polysaccharides, possess a wide range of biological effects stemming from their distinctive structural domains. The polysaccharides were extracted using water, and were subsequently purified through ion exchange and gel permeation chromatography. In order to elucidate their structural features, Fourier Transform Infrared Spectroscopy and Nuclear Magnetic Resonance techniques were applied. Two specific polysaccharides, WRJP-A2a and WRJP-A3b, with molecular weights of 42.7 kDa and 64.1 kDa, respectively, were identified to contain varying proportions of homogalacturonan, rhamnogalacturonan I, and rhamnogalacturonan II domains. Regarding antioxidant capacity, WRJP-A3b exhibited superior scavenging capabilities against DPPH, ABTS, and hydroxyl radicals, potentially attributed to its higher galacturonic acid content and abundance of homogalacturonan domains. These results enhance our comprehension of the structure-activity interplay of pectic polysaccharides sourced from Rohdea japonica (Thunb.) Roth and their potential utility in the healthcare and functional food sectors.
Asunto(s)
Antioxidantes , Pectinas , Polisacáridos , Pectinas/química , Pectinas/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Polisacáridos/química , Polisacáridos/farmacología , Peso Molecular , Espectroscopía Infrarroja por Transformada de Fourier , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Espectroscopía de Resonancia Magnética , Picratos/química , Picratos/antagonistas & inhibidores , Ácidos HexurónicosRESUMEN
The control of metabolic networks is incompletely understood, even for glycolysis in highly studied model organisms. Direct real-time observations of metabolic pathways can be achieved in cellular systems with 13C NMR using dissolution Dynamic Nuclear Polarization (dDNP NMR). The method relies on a short-lived boost of NMR sensitivity using a redistribution of nuclear spin states to increase the alignment of the magnetic moments by more than four orders of magnitude. This temporary boost in sensitivity allows detection of metabolism with sub-second time resolution. Here, we hypothesized that dDNP NMR would be able to investigate molecular phenotypes that are not easily accessible with more conventional methods. The use of dDNP NMR allows real-time insight into carbohydrate metabolism in a Gram-positive bacterium (Lactoccocus lactis), and comparison to other bacterial, yeast and mammalian cells shows differences in the kinetic barriers of glycolysis across the kingdoms of life. Nevertheless, the accumulation of non-toxic precursors for biomass at kinetic barriers is found to be shared across the kingdoms of life. We further find that the visualization of glycolysis using dDNP NMR reveals kinetic characteristics in transgenic strains that are not evident when monitoring the overall glycolytic rate only. Finally, dDNP NMR reveals that resting Lactococcus lactis cells use the influx of carbohydrate substrate to produce acetoin rather than lactate during the start of glycolysis. This metabolic regime can be emulated using suitably designed substrate mixtures to enhance the formation of the C4 product acetoin more than 400-fold. Overall, we find that dDNP NMR provides analytical capabilities that may help to clarify the intertwined mechanistic determinants of metabolism and the optimal usage of biotechnologically important bacteria.
Asunto(s)
Glucólisis , Lactococcus lactis , Lactococcus lactis/metabolismo , Redes y Vías Metabólicas , Espectroscopía de Resonancia Magnética con Carbono-13/métodos , Espectroscopía de Resonancia Magnética/métodos , Isótopos de CarbonoRESUMEN
Two new sulfur glycosides, bursapastoris A-B (3-4), were extracted and isolated from shepherd's purse seed, along with two new natural products, 11-(methylsulfinyl)undecanoic acid (2) and 10-(methylsulfinyl)decanoic acid (1). Their structures were determined though infrared spectroscopy, one-dimensional nuclear magnetic resonance (1H and 13C), and electrospray ionization mass spectrometry. Additionally, the structures of 3-4 were further identified by two-dimensional nuclear magnetic resonance (HMBC, HSQC, 1H-1H COSY, and NOESY). Compounds 1-4 showed relatively favorable docking to NF-κB. Unfortunately, we only discovered that compound 1-4 had weak anti-radiation activity at present. Therefore, further research regarding the biological activity of these organosulfur compounds is required at a later stage.
Asunto(s)
Productos Biológicos , Glicósidos , Fitoquímicos , Semillas , Semillas/química , Glicósidos/química , Glicósidos/farmacología , Fitoquímicos/química , Fitoquímicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Estructura Molecular , Azufre/química , Simulación del Acoplamiento Molecular , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
The goal of preparative chromatography is to isolate suitable amounts of compound(s) at the required purity in the most cost-effective way. This study analyses the power of High-performance thin-layer chromatography (HPTLC) guided preparative flash chromatography to separate and isolate bioactive compounds from an olive flower extract for their further characterisation via spectroscopy. The structure and purity of isolated bioactive compounds were assessed using Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Flash chromatography of the olive flower extract successfully isolated pure oleanolic and maslinic acids. Moreover, the flash chromatography of the extract allowed isolation and phytochemical analysis of the most lipophilic fraction of the extract, which was found to contain n-eicosane and n-(Z)-eicos-5-ene, that has not been isolated previously with preparative TLC.
Asunto(s)
Flores , Espectroscopía de Resonancia Magnética , Olea , Extractos Vegetales , Flores/química , Cromatografía en Capa Delgada/métodos , Olea/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Espectroscopía Infrarroja por Transformada de Fourier , Triterpenos/análisis , Triterpenos/aislamiento & purificación , Triterpenos/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análisis , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Prolyl-hydroxylation is an oxygen-dependent posttranslational modification (PTM) that is known to regulate fibril formation of collagenous proteins and modulate cellular expression of hypoxia-inducible factor (HIF) α subunits. However, our understanding of this important but relatively rare PTM has remained incomplete due to the lack of biophysical methodologies that can directly measure multiple prolyl-hydroxylation events within intrinsically disordered proteins. Here, we describe a real-time 13C-direct detection NMR-based assay for studying the hydroxylation of two evolutionarily conserved prolines (P402 and P564) simultaneously in the intrinsically disordered oxygen-dependent degradation domain of hypoxic-inducible factor 1α by exploiting the "proton-less" nature of prolines. We show unambiguously that P564 is rapidly hydroxylated in a time-resolved manner while P402 hydroxylation lags significantly behind that of P564. The differential hydroxylation rate was negligibly influenced by the binding affinity to prolyl-hydroxylase enzyme, but rather by the surrounding amino acid composition, particularly the conserved tyrosine residue at the +1 position to P564. These findings support the unanticipated notion that the evolutionarily conserved P402 seemingly has a minimal impact in normal oxygen-sensing pathway.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia , Proteínas Intrínsecamente Desordenadas , Prolina , Hidroxilación , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Prolina/metabolismo , Proteínas Intrínsecamente Desordenadas/metabolismo , Proteínas Intrínsecamente Desordenadas/química , Humanos , Procesamiento Proteico-Postraduccional , Espectroscopía de Resonancia Magnética/métodosRESUMEN
We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.
Asunto(s)
Glutaratos , Isocitrato Deshidrogenasa , Mutación , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/química , Cristalografía por Rayos X , Humanos , Glutaratos/metabolismo , Glutaratos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Regulación Alostérica , Modelos MolecularesRESUMEN
The Jurassic relict Royal fern, Osmunda regalis L., is widely distributed across temperate zones in the Northern and Southern hemispheres. Even though this species has been utilised for centuries as a medicinal plant, its phytochemical composition mainly remains unknown. As part of our ongoing research to identify potential lead compounds for future anticancer drugs, 17 natural products were characterised from the aerial parts of Osmunda regalis L. Fifteen of these compounds were identified in this species for the first time, including the six previously undescribed compounds kaempferol 3-O-(2''-O-(2'''-α-rhamnopyranosyl)-ß-glucopyranosyl)-ß-glucopyranoside, quercetin 3-O-(2''-O-(2'''-α-rhamnopyranosyl)-ß-glucopyranosyl)-ß-glucopyranoside, kaempferol 3-O-(2''-O-(2'''-α-rhamnopyranosyl-6'''-O-(E)-caffeoyl-)-ß-glucopyranosyl)-ß-glucopyranoside, 3-methoxy-5-hydroxy-4-olide, 4-hydroxy-3-(3'-hydroxy-4'-(hydroxyethyl)-oxotetrafuranone-5-methyl tetrahydropyranone, and 4-O-(5-hydroxy-4-oxohexanoyl) osmundalactone. The molecular structures were determined by combining several 1D and 2D NMR experiments, circular dichroism spectroscopy, and HRMS. Determination of cytotoxicity against AML MOLM-13, H9c2, and NRK cell lines showed that two isolated lactones exhibited significant cytotoxic activity.
Asunto(s)
Productos Biológicos , Productos Biológicos/química , Productos Biológicos/farmacología , Humanos , Helechos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Espectroscopía de Resonancia MagnéticaRESUMEN
PURPOSE: Metabolic vulnerabilities can exacerbate inflammatory injury and inhibit repair in multiple sclerosis (MS). The purpose was to evaluate whether blood biomarkers of inflammatory and metabolic vulnerability are associated with MS disability and neurodegeneration. METHODS: Proton nuclear magnetic resonance spectra were obtained from serum samples from 153 healthy controls, 187 relapsing-remitting, and 91 progressive MS patients. The spectra were analyzed to obtain concentrations of lipoprotein sub-classes, glycated acute-phase proteins, and small-molecule metabolites, including leucine, valine, isoleucine, alanine, and citrate. Composite indices for inflammatory vulnerability, metabolic malnutrition, and metabolic vulnerability were computed. MS disability was measured on the Expanded Disability Status Scale. MRI measures of lesions and whole-brain and tissue-specific volumes were acquired. RESULTS: Valine, leucine, isoleucine, alanine, the Inflammatory Vulnerability Index, the Metabolic Malnutrition Index, and the Metabolic Vulnerability Index differed between healthy control and MS groups in regression analyses adjusted for age, sex, and body mass index. The Expanded Disability Status Scale was associated with small HDL particle levels, inflammatory vulnerability, and metabolic vulnerability. Timed ambulation was associated with inflammatory vulnerability and metabolic vulnerability. Greater metabolic vulnerability and inflammatory vulnerability were associated with lower gray matter, deep gray matter volumes, and greater lateral ventricle volume. CONCLUSIONS: Serum-biomarker-derived indices of inflammatory and metabolic vulnerability are associated with disability and neurodegeneration in MS.
Asunto(s)
Biomarcadores , Humanos , Femenino , Masculino , Biomarcadores/sangre , Persona de Mediana Edad , Adulto , Imagen por Resonancia Magnética , Esclerosis Múltiple/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Estudios de Casos y Controles , Espectroscopía de Resonancia Magnética , Inflamación/sangre , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Esclerosis Múltiple Crónica Progresiva/sangre , Evaluación de la Discapacidad , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
INTRODUÇÃO:O lúpus eritematoso sistêmico (LES) é uma doença autoimune crônica que afeta predominantemente mulheres jovens, caracterizada por alterações sistêmicas e serosites. O envolvimento cardíaco ocorre em 30-50% dos pacientes, com o comprometimento miocárdico em cerca de 10%. A miocardite lúpica (ML) é uma complicação grave, exigindo tratamento imediato devido ao risco de arritmias, distúrbios de condução e insuficiência cardíaca (IC). Apresentamos um caso raro de LES com miocardite como sua primeira manifestação em um paciente masculino de 60 anos, sem diagnóstico prévio da doença. RELATO DE CASO: Homem, 60 anos, sem histórico médico relevante, foi admitido com Insuficiência Cardíaca perfil C, apresentando congestão pulmonar e sistêmica progressiva há 2 meses. O eletrocardiograma mostrou ritmo sinusal e bloqueio de ramo esquerdo. O ecocardiograma revelou fração de ejeção de 32%, hipocinesia difusa do ventrículo esquerdo e derrame pericárdico moderado. Exames laboratoriais indicaram proteinúria e pancitopenia. A investigação reumatológica resultou no diagnóstico de LES, evidenciado por comprometimento miocárdico, nefrite lúpica grau IV, FAN positivo (1/1280), anti-DNA positivo e consumo de complemento. O tratamento iniciado incluiu corticoterapia, ciclofosfamida e terapia para IC com fração de ejeção reduzida (ICFER). Ressonância cardíaca realizada 6 meses depois mostrou FEVE de 58%, sem isquemia e ausência de inflamação. Atualmente, o paciente está em acompanhamento ambulatorial de Cardiologia, em classe funcional I. DISCUSSÃO: O envolvimento cardíaco no LES é relevante, podendo levar a arritmias e insuficiência cardíaca. Embora mais frequente em mulheres jovens, o LES pode também afetar homens e indivíduos mais velhos, ainda que com menor incidência. No caso apresentado, a ressonância cardíaca evidenciou melhora na fração de ejeção ventricular esquerda após o tratamento, porém não confirmou miocardite devido à evolução temporal e à intervenção terapêutica. O diagnóstico de miocardite lúpica foi estabelecido com base em achados clínicos, laboratoriais e de imagem, corroborados pela resposta à terapia. A identificação precoce e o tratamento adequado são cruciais para prevenir complicações e melhorar o prognóstico no LES.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Espectroscopía de Resonancia MagnéticaRESUMEN
INTRODUÇÃO Os mixomas são tumores primários cardíacos correspondendo em sua grande maioria de natureza benigna e de constituição sólida, sendo a prevalência mais comum no lado esquerdo (75 a 80% dos casos), com predomínio no sexo feminino. Apesar da histogênese mais comum ser benigna deve-se prosseguir com exérese precoce devido às possíveis complicações, em especial morte súbita e acidentes vasculares. O ecocardiograma é o exame diagnóstico de escolha pois caracteriza tamanho, localização e mobilidade da tumoração assim como a capacidade de obstrução e/ou de formação de êmbolos. Outra opção é a ressonância magnética cardíaca pois além das características anatômicas nos fornece dados de características do microambiente do tumor. DESCRIÇÃO DO CASO Paciente do sexo feminino, 40 anos, proveniente de São Paulo (SP). Deu entrada neste Serviço referenciada de hospital secundário com história de palpitações em precórdio associada a dispneia e astenia intensa com duração de 20 minutos há cerca de 3 meses. Nega queixas durante o período interepisódio assim como nega dor torácica. Como antecedentes patológicos possui fibrilação atrial (FA) paroxística com controle de frequência cardíaca com propranolol 40mg/dia e hipertensão arterial sistêmica (HAS) em uso de losartana 50mg/dia. Nega internações prévios devido o quadro supracitado. Em ECOTT realizado no serviço de origem presença de imagem hiperecoica, homogênea, aderida ao septo interatrial em átrio esquerdo medindo em seus maiores diâmetros aproximadamente 2,6x2,2cm sugestiva de mixoma atrial esquerdo. Prosseguindo investigação realizou novo ECOTT no Instituto Dante Pazzanese de Cardiologia (IDPC) onde observou-se imagem sugestiva de linha de dissecção que se inicia logo após a emergência da artéria subclávia esquerda que se estende até a aorta abdominal proximal. Atualmente recebendo propranolol 40mg/dia e losartana 50mg/dia, evoluindo com bons controles pressóricos e frequência cardíaca sendo programado a exérese de mixoma localizado em atrial esquerdo pela equipe do miocárdio do IDPC e posterior acompanhamento no ambulatório da equipe. CONCLUSÃO Apesar de se tratar de tumores raros e possuírem histologia benigna, os mixomas devem ser investigados e prosseguir com ressecção tumoral com brevidade, devido aos riscos de embolização. Idealmente a investigação deve ser iniciada com o ecocardiograma, seja o transesofágico ou transtorácico, como foi no caso relatado acima onde flagrou-se o mixoma em átrio esquerdo.