RESUMO
OBJECTIVES: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD. METHODS: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance. RESULTS: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer. CONCLUSIONS: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.
Assuntos
Artrite Reumatoide , Metaboloma , Neoplasias , Síndromes Paraneoplásicas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Neoplasias/sangue , Neoplasias/complicações , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/diagnóstico , Idoso , Adulto , Doenças Reumáticas/sangue , Doenças Reumáticas/complicações , Sensibilidade e Especificidade , Biomarcadores Tumorais/sangueRESUMO
BACKGROUND: Hyperglycaemia is frequent in acute ischemic stroke and denotes a bad prognosis, even in the absence of pre-existing diabetes. However, in clinical trials treatment of elevated glucose levels with insulin did not improve stroke outcome, suggesting that collateral effects rather than hyperglycaemia itself aggravate ischemic brain damage. As reactive glucose metabolites, glyoxal and methylglyoxal are candidates for mediating the deleterious effects of hyperglycaemia in acute stroke. METHODS: In 135 patients with acute stroke, we used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to measure glyoxal, methylglyoxal and several of their glycated amino acid derivatives in serum. Results were verified in a second cohort of 61 stroke patients. The association of serum concentrations with standard stroke outcome scales (NIHSS, mRS) was tested. RESULTS: Glucose, glyoxal, methylglyoxal, and the glyoxal-derived glycated amino acid Nδ-(5-hydro-4-imidazolon-2-yl)ornithine (G-H1) were positively correlated with a bad stroke outcome at 3 months as measured by mRS90, at least in one of the two cohorts. However, the glycated amino acids Nε-carboxyethyllysine (CEL) and in one cohort pyrraline showed an inverse correlation with stroke outcome probably reflecting lower food intake in severe stroke. Patients with a poor outcome had higher serum concentrations of glyoxal and methylglyoxal. CONCLUSIONS: The glucose-derived α-dicarbonyl glyoxal and glycated amino acids arising from a reaction with glyoxal are associated with a poor outcome in ischemic stroke. Thus, lowering α-dicarbonyls or counteracting their action could be a therapeutic strategy for hyperglycaemic stroke.
Assuntos
Antifibrinolíticos , Hiperglicemia , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/diagnóstico , Glioxal , Aldeído Pirúvico , Estudos de Coortes , Hiperglicemia/diagnóstico , Cromatografia Líquida , Espectrometria de Massas em Tandem , Acidente Vascular Cerebral/diagnóstico , Aminoácidos , Glucose , GlicopirrolatoRESUMO
OBJECTIVES: Rheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8+ T cell (CD8) function, but CD8 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients. METHODS: Peripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing 13C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified. RESULTS: CD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838. CONCLUSIONS: Our study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.
RESUMO
Half-sandwich Ru(II) complexes belong to group of biologically active metallo-compounds with promising antimicrobial and anticancer activity. Herein, we report the synthesis and characterization of arene ruthenium complexes containing benzimidazole moiety, namely, [(η6-p-cymene)RuCl(bimCOO)] (1) and [(η6-p-cymene)RuCl2(bim)] (2) (where bimCOO = benzimidazole-2-carboxylate and bim = 1-H-benzimidazole). The compounds were characterized by 1H NMR, 13C NMR, IR, UV-vis and CV. Molecular structures of the complexes were determined by SC-XRD analysis, and the results indicated the presence of a pseudo-tetrahedral (piano stool) geometry. Interactions in the crystals of the Ru complexes using the Hirshfeld surface analysis were also examined. In addition, the biological studies of the complexes, such as antimicrobial assays (against planktonic and adherent microbes), cytotoxicity and lipophilicity, were performed. Antibacterial activity of the complexes was evaluated against S. aureus, E. coli, P. aeruginosa PAO1 and LES B58. Cytotoxic activity was tested against primary human fibroblasts and adenocarcinoma human alveolar basal epithelial cells. Obtained biological results show that the ruthenium compounds have bacteriostatic activity toward Pseudomonas aeruginosa PAO1 strain and are not toxic to normal cells. A molecular docking study was applied as a predictive source of information about the plausibility of examined structures binding with HSA as a transporting system.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Humanos , Rutênio/química , Simulação de Acoplamento Molecular , Escherichia coli/metabolismo , Staphylococcus aureus/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Antibacterianos/química , Benzimidazóis/farmacologia , Complexos de Coordenação/químicaRESUMO
In radiopharmaceutical syntheses, maleimide is commonly used for linking thiol-bearing bioactive molecules to metal-complexing ligands (chelators). However, due to instability of the resulting linkage, phenyloxadiazolyl methylsulfone (PODS) was developed as an alternative to maleimide. This coupling strategy has never been attempted with HBED which is a powerful chelator for gallium-radiolabeling especially at ambient temperature. Here we present HBED-CC-PODS as a bifunctional chelator scaffold for the site-selective conjugation of thiol-bearing vectors and [68Ga]Ga-radiolabeling.
Assuntos
Quelantes/química , Oxidiazóis/química , Peptídeos/química , Compostos Radiofarmacêuticos/química , Sulfonas/química , Quelantes/síntese química , Radioisótopos de Gálio/química , Marcação por Isótopo , Oxidiazóis/síntese química , Peptídeos/síntese química , Compostos Radiofarmacêuticos/síntese química , Sulfonas/síntese químicaRESUMO
The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation.
RESUMO
We wish to draw attention to an important issue concerning scientific practice with regard to enhancing the quality of publications in Molecules (as well as for other journals) [...].
RESUMO
OBJECTIVES: The differential diagnosis of seronegative rheumatoid arthritis (negRA) and psoriasis arthritis (PsA) is often difficult due to the similarity of symptoms and the unavailability of reliable clinical markers. Since chronic inflammation induces major changes in the serum metabolome and lipidome, we tested whether differences in serum metabolites and lipids could aid in improving the differential diagnosis of these diseases. METHODS: Sera from negRA and PsA patients with established diagnosis were collected to build a biomarker-discovery cohort and a blinded validation cohort. Samples were analysed by proton nuclear magnetic resonance. Metabolite concentrations were calculated from the spectra and used to select the variables to build a multivariate diagnostic model. RESULTS: Univariate analysis demonstrated differences in serological concentrations of amino acids: alanine, threonine, leucine, phenylalanine and valine; organic compounds: acetate, creatine, lactate and choline; and lipid ratios L3/L1, L5/L1 and L6/L1, but yielded area under the curve (AUC) values lower than 70%, indicating poor specificity and sensitivity. A multivariate diagnostic model that included age, gender, the concentrations of alanine, succinate and creatine phosphate and the lipid ratios L2/L1, L5/L1 and L6/L1 improved the sensitivity and specificity of the diagnosis with an AUC of 84.5%. Using this biomarker model, 71% of patients from a blinded validation cohort were correctly classified. CONCLUSIONS: PsA and negRA have distinct serum metabolomic and lipidomic signatures that can be used as biomarkers to discriminate between them. After validation in larger multiethnic cohorts this diagnostic model may become a valuable tool for a definite diagnosis of negRA or PsA patients.
Assuntos
Artrite Psoriásica/sangue , Artrite Reumatoide/sangue , Acetatos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina/sangue , Aminoácidos/sangue , Artrite Psoriásica/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Colina/sangue , Creatina/sangue , Diagnóstico Diferencial , Feminino , Humanos , Ácido Láctico/sangue , Lipidômica , Lipídeos/sangue , Masculino , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Fosfocreatina/sangue , Espectroscopia de Prótons por Ressonância Magnética , Ácido Succínico/sangueRESUMO
A commonly presented account of the structural elucidation of a natural product consists of an initial, highly detailed and fastidious NMR analysis together with HR-MS data, followed by an X-ray analysis, followed then by a postulated biosynthetic pathway with perhaps some bioassay results, which may be apt or appear gratuitous. But an X-ray crystallographic-determined structure renders any prior NMR-based structural elucidation redundant, and moreover, an exhaustive and detailed examination of NMR contacts seems tiresome in light of an X-ray analysis. Suggestions are therefore proffered on how the description of a structural elucidation of a natural product might alternatively be approached rather than seemingly blindly following a prescribed formula, particularly with respect to NMR and (HR-)MS data. Also considered is which information should be in the manuscript proper and which material is better placed in the Supporting Information.
Assuntos
Produtos Biológicos/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura MolecularRESUMO
Multidrug-resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site-specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000-fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d-Ala-d-Ala revealed a mode of action beyond inhibition of cell-wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an inâ vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos/química , Resistência a Vancomicina/efeitos dos fármacos , Vancomicina/química , Vancomicina/farmacologia , Animais , Antibacterianos/farmacocinética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Ratos , Ratos Wistar , Distribuição Tecidual , Vancomicina/farmacocinéticaRESUMO
PURPOSE: Relaxation-compensated CEST-MRI (i.e., the inverse metrics magnetization transfer ratio and apparent exchange-dependent relaxation) has already been shown to provide valuable information for brain tumor diagnosis at ultrahigh magnetic field strengths. This study aims at translating the established acquisition protocol at 7 T to a clinically relevant magnetic field strength of 3 T. METHODS: Protein model solutions were analyzed at multiple magnetic field strengths to assess the spectral widths of the amide proton transfer and relayed nuclear Overhauser effect (rNOE) signals at 3 T. This prior knowledge of the spectral range of CEST signals enabled a reliable and stable Lorentzian-fitting also at 3 T where distinct peaks are no longer resolved in the Z-spectrum. In comparison to the established acquisition protocol at 7 T, also the image readout was extended to three dimensions. RESULTS: The observed spectral range of CEST signals at 3 T was approximately ±15 ppm. Final relaxation-compensated amide proton transfer and relayed nuclear Overhauser effect contrasts were in line with previous results at 7 T. Examination of a patient with glioblastoma demonstrated the applicability of this acquisition protocol in a clinical setting. CONCLUSION: The presented acquisition protocol allows relaxation-compensated CEST-MRI at 3 T with a 3D coverage of the human brain. Translation to a clinically relevant magnetic field strength of 3 T opens the door to trials with a large number of participants, thus enabling a comprehensive assessment of the clinical relevance of relaxation compensation in CEST-MRI.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Humanos , Razão Sinal-RuídoRESUMO
This commentary discusses an important, though not widely appreciated, chiral phenomenon of molecular chirality that effectively always occurs whenever nonracemic samples are subjected to practically any physicochemical process (e.g., force field, recrystallization, sublimation, even distillation, etc.) under totally achiral conditions external to the sample itself. The phenomenon is termed as the self-disproportionation of enantiomers (SDE) and though ubiquitous, its presence may not always be readily apparent, or workers may be otherwise oblivious to its effects. In the particular case of chromatography, when the SDE is apparent, the enantiomeric excess (ee) of the chiral compound is observed to vary across an eluted peak, with anterior eluted portions either enantioenriched or enantiodepleted relative to the ee of the starting material, and conversely for the posterior eluted portions. Herein, we highlight various aspects of the SDE phenomenon as it pertains to chromatography and, in particular, the effect of scaling down chromatographic systems, the potential risk of problems that the SDE can cause, as well as opportunities for practical applications of the phenomenon, possible new occurrences of the SDE phenomenon to be searched for, and unrealized opportunities.
Assuntos
Técnicas de Química Analítica , Fracionamento Químico , Eletroforese , Modelos Moleculares , EstereoisomerismoRESUMO
This review covers the phenomenon of the self-disproportionation of enantiomers (SDE) of amino acids and their derivatives in all its guises from phase transformations (recrystallization, sublimation, and distillation), to the application of force fields, through to chromatography including HPLC, MPLC, gravity-driven column chromatography, and SEC. The relevance of the SDE phenomenon to amino acid research and to marketed pharmaceuticals is clear given the potential for alteration of the enantiomeric excess of a portion of a scalemic sample. In addition, the possible contribution of the SDE phenomenon to the genesis of prebiotic homochirality is considered.
Assuntos
Aminoácidos/química , Sublimação Química , Fracionamento Químico , Cromatografia , Cristalização , EstereoisomerismoRESUMO
This work presents the first study of the self-disproportionation of enantiomers via chromatography (SDEvC) of ß-aminophosphonic acid esters, several of which have been synthesized for the first time. Three types of structures were examined, N-acetylated, dipeptide construction with N-Cbz glycine, and a free amine. In the latter case, this is the first time that SDEvC has been reported for free amine amino acids. In all the three types of structures, significant SDE magnitudes (Δee's up to 55%) were exhibited underscoring the ubiquitous nature of the SDE phenomenon. Chemical models of homo- versus heterochiral intermolecular interactions are proposed to rationalize the SDE magnitude differences amongst these new ß-aminophosphonic acid derivatives. In addition, the incorporation of additional, competing binding modes to a molecule, was found to lead to a reduction of the SDE magnitude by shifting the intermolecular binding away from the stereogenic center and/or by leading to a convoluted binding system that disrupts the structured and relatively stable assemblies that give rise to the SDE.
Assuntos
Aminoácidos/química , Cromatografia/métodos , Fluoretos/química , Ácidos Fosfóricos/química , Acetilação , Dipeptídeos/química , Ésteres/síntese química , Ésteres/química , Ligação de Hidrogênio , EstereoisomerismoRESUMO
α-Amino acids (α-AAs) are in extremely high demand in nearly every sector of the food and health-related chemical industries and continue to be the subject of intense multidisciplinary research. The self-disproportionation of enantiomers (SDE) is an emerging and one of the least studied areas of α-AA or enantiomeric properties, critically important for their production and application. In the present work, we report a detailed study of the SDE via achiral, gravity-driven column chromatography for a set of N-acylated, N-carbonylated, N-fluoroacylated, and N-thioacylated α-amino acid esters. As well as thioacylation, attention was paid to the effect of altering the R group of the ester functionality, the side chain, or that of the acyl group attached to the amide nitrogen, whereby it was found that electron-withdrawing groups in the latter moiety had a pronounced effect on the magnitude and behavior of the resulting SDE phenomenon. Intriguingly, in the case of N-fluoroacylated derivatives, by favoring the formation of dimeric associates and effecting a strong bias toward homochiral associates over heterochiral associates, the SDE magnitude was greatly reduced contrary to intuitive expectations. Energy estimates resulted from DFT calculations.
Assuntos
Aminoácidos/química , Ésteres/química , Ésteres/síntese química , Acilação , Amidas/química , Cromatografia , Ligação de Hidrogênio , Concentração Osmolar , Solventes/química , EstereoisomerismoRESUMO
Radiometal-based radiopharmaceuticals bearing bifunctional HBED chelators are powerful radiotracers for cancer diagnosis and therapy. Bifunctional HBED chelators make strong complexes with trivalent gallium and are able to bind to bioactive molecules through covalent bonds. However, thus far, no bifunctional HBED chelator capable of direct conjugation via click chemistry has been reported. We hereby introduce HBED-NN as a structurally new bifunctional HBED chelator for direct click coupling. We also investigated the complex chemistry of [Ga-(HBED-NN)] for potential use in gallium-based radiopharmaceuticals.
Assuntos
Quelantes/química , Ácido Edético/análogos & derivados , Gálio/química , Neoplasias/diagnóstico , Compostos Radiofarmacêuticos/química , Quelantes/síntese química , Ácido Edético/química , Humanos , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese químicaRESUMO
Chiral sulfoxides are in extremely high demand in nearly every sector of the chemical industry concerned with the design and development of new synthetic reagents, drugs, and functional materials. The primary objective of this review is to update readers on the latest developments from the past five years (2011-2016) in the preparation of optically active sulfoxides. Methodologies covered include catalytic asymmetric sulfoxidation using either chemical, enzymatic, or hybrid biocatalytic means; kinetic resolution involving oxidation to sulfones, reduction to sulfides, modification of side chains, and imidation to sulfoximines; as well as various other methods including nucleophilic displacement at the sulfur atom for the desymmetrization of achiral sulfoxides, enantioselective recognition and separation based on either metal-organic frameworks (MOF's) or host-guest chemistry, and the Horner-Wadsworth-Emmons reaction. A second goal of this work concerns a critical discussion of the problem of the accurate determination of the stereochemical outcome of a reaction due to the self-disproportionation of enantiomers (SDE) phenomenon, particularly as it relates to chiral sulfoxides. The SDE is a little-appreciated phenomenon that can readily and spontaneously occur for scalemic samples when subjected to practically any physicochemical process. It has now been unequivocally demonstrated that ignorance in the SDE phenomenon inevitably leads to erroneous interpretation of the stereochemical outcome of catalytic enantioselective reactions, in particular, for the synthesis of chiral sulfoxides. It is hoped that this two-pronged approach to covering the chemistry of chiral sulfoxides will be appealing, engaging, and motivating for current research-active authors to respond to in their future publications in this exciting area of current research.
RESUMO
BACKGROUND/AIMS: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. METHODS: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. RESULTS: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. CONCLUSION: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.
Assuntos
Carnosina/química , Carnosina/metabolismo , Polímeros/química , Aldeído Pirúvico/química , Animais , Anserina/análise , Anserina/química , Anserina/metabolismo , Carnosina/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Glutationa/análise , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Transportador 1 de Peptídeos/genética , Transportador 1 de Peptídeos/metabolismo , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Polímeros/metabolismo , Aldeído Pirúvico/toxicidade , Albumina Sérica/química , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Simportadores/genética , Simportadores/metabolismoRESUMO
A novel MRI contrast is proposed which enables the selective detection of endogenous bulk mobile proteins in vivo. Such a non-invasive imaging technique may be of particular interest for many diseases associated with pathological alterations of protein expression, such as cancer and neurodegenerative disorders. Specificity to mobile proteins was achieved by the selective measurement of intramolecular spin diffusion and the removal of semi-solid macromolecular signal components by a correction procedure. For this purpose, the approach of chemical exchange saturation transfer (CEST) was extended to a radiofrequency (RF) irradiation scheme at two different frequency offsets (dualCEST). Using protein model solutions, it was demonstrated that the dualCEST technique allows the calculation of an image contrast which is exclusively sensitive to changes in concentration, molecular size and the folding state of mobile proteins. With respect to application in humans, dualCEST overcomes the selectivity limitations at relatively low magnetic field strengths, and thus enables examinations on clinical MR scanners. The feasibility of dualCEST examinations in humans was verified by a proof-of-principle examination of a brain tumor patient at 3 T. With its specificity for the mobile fraction of the proteome, its comparable sensitivity to conventional water proton MRI and its applicability to clinical MR scanners, this technique represents a further step towards the non-invasive imaging of proteomic changes in humans.
Assuntos
Imageamento por Ressonância Magnética , Proteínas/análise , Humanos , Substâncias Macromoleculares/análise , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por ComputadorRESUMO
The R/S system, universally applied for indicating the absolute configuration of a structure, is extremely adept for conveying the absolute configuration unequivocally. However, it suffers from one limitation, viz that due to CIP priority rules the rankings of the ligands attached to an asymmetric center can be altered upon a change in a ligand leading to a change in the designated configuration even if bonds to the asymmetric center were not actually formed or broken. This means that the sense of stereochemistry in situations such as within a set of compounds where family relationships are of focus or where the sense of the stereochemical course of a reaction is of interest can be lost or confusion may occur. This shortcoming is easily remedied though by defining a fixed ranking for a particular ligand in the system under study, eg, the ligand at which the change has occurred. The configurations are then expressed as iR or iS, akin to the R and S descriptors, for sp3 -hybridized tetrahedral chiral structures and similarly, as ire and isi faces, akin to the re and si descriptors, for sp2 -hybridized trigonal prochiral structures. All in all, the notation can be considered as an auxiliary to extend the usefulness of the R/S system. Thus, the proposed iR/iS notation could find profitable use in comparative studies where there is a need to avoid confusion arising from changing assignments due to priority rules or to expedite the ease of comprehension. Moreover, in the current digital age, the facile retrieval of stereochemically clear data by machines is highly desirable-something that the iR/iS notation is readily amenable to.