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Cardoso, Sara, Telma Afonso, Marcelo Maraschin et Miguel Rocha. « WebSpecmine : A Website for Metabolomics Data Analysis and Mining ». Metabolites 9, no 10 (19 octobre 2019) : 237. http://dx.doi.org/10.3390/metabo9100237.
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Metabolomics data analysis is an important task in biomedical research. The available tools do not provide a wide variety of methods and data types, nor ways to store and share data and results generated. Thus, we have developed WebSpecmine to overcome the aforementioned limitations. WebSpecmine is a web-based application designed to perform the analysis of metabolomics data based on spectroscopic and chromatographic techniques (NMR, Infrared, UV-visible, and Raman, and LC/GC-MS) and compound concentrations. Users, even those not possessing programming skills, can access several analysis methods including univariate, unsupervised and supervised multivariate statistical analysis, as well as metabolite identification and pathway analysis, also being able to create accounts to store their data and results, either privately or publicly. The tool’s implementation is based in the R project, including its shiny web-based framework. Webspecmine is freely available, supporting all major browsers. We provide abundant documentation, including tutorials and a user guide with case studies.
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Nandania, Jatin, Gopal Peddinti, Alberto Pessia, Meri Kokkonen et Vidya Velagapudi. « Validation and Automation of a High-Throughput Multitargeted Method for Semiquantification of Endogenous Metabolites from Different Biological Matrices Using Tandem Mass Spectrometry ». Metabolites 8, no 3 (5 août 2018) : 44. http://dx.doi.org/10.3390/metabo8030044.
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The use of metabolomics profiling to understand the metabolism under different physiological states has increased in recent years, which created the need for robust analytical platforms. Here, we present a validated method for targeted and semiquantitative analysis of 102 polar metabolites that cover major metabolic pathways from 24 classes in a single 17.5-min assay. The method has been optimized for a wide range of biological matrices from various organisms, and involves automated sample preparation and data processing using an inhouse developed R-package. To ensure reliability, the method was validated for accuracy, precision, selectivity, specificity, linearity, recovery, and stability according to European Medicines Agency guidelines. We demonstrated an excellent repeatability of retention times (CV < 4%), calibration curves (R2 ≥ 0.980) in their respective wide dynamic concentration ranges (CV < 3%), and concentrations (CV < 25%) of quality control samples interspersed within 25 batches analyzed over a period of one year. The robustness was demonstrated through a high correlation between metabolite concentrations measured using our method and the NIST reference values (R2 = 0.967), including cross-platform comparability against the BIOCRATES AbsoluteIDQp180 kit (R2 = 0.975) and NMR analyses (R2 = 0.884). We have shown that our method can be successfully applied in many biomedical research fields and clinical trials, including epidemiological studies for biomarker discovery. In summary, a thorough validation demonstrated that our method is reproducible, robust, reliable, and suitable for metabolomics studies.
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Emwas, Abdul-Hamid, Raja Roy, Ryan T. McKay, Leonardo Tenori, Edoardo Saccenti, G. A. Nagana Gowda, Daniel Raftery et al. « NMR Spectroscopy for Metabolomics Research ». Metabolites 9, no 7 (27 juin 2019) : 123. http://dx.doi.org/10.3390/metabo9070123.
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Over the past two decades, nuclear magnetic resonance (NMR) has emerged as one of the three principal analytical techniques used in metabolomics (the other two being gas chromatography coupled to mass spectrometry (GC-MS) and liquid chromatography coupled with single-stage mass spectrometry (LC-MS)). The relative ease of sample preparation, the ability to quantify metabolite levels, the high level of experimental reproducibility, and the inherently nondestructive nature of NMR spectroscopy have made it the preferred platform for long-term or large-scale clinical metabolomic studies. These advantages, however, are often outweighed by the fact that most other analytical techniques, including both LC-MS and GC-MS, are inherently more sensitive than NMR, with lower limits of detection typically being 10 to 100 times better. This review is intended to introduce readers to the field of NMR-based metabolomics and to highlight both the advantages and disadvantages of NMR spectroscopy for metabolomic studies. It will also explore some of the unique strengths of NMR-based metabolomics, particularly with regard to isotope selection/detection, mixture deconvolution via 2D spectroscopy, automation, and the ability to noninvasively analyze native tissue specimens. Finally, this review will highlight a number of emerging NMR techniques and technologies that are being used to strengthen its utility and overcome its inherent limitations in metabolomic applications.
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Yilmaz, Ali, et Marcel Utz. « Characterisation of oxygen permeation into a microfluidic device for cell culture by in situ NMR spectroscopy ». Lab on a Chip 16, no 11 (2016) : 2079–85. http://dx.doi.org/10.1039/c6lc00396f.
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Date, Yasuhiro, Chiaki Ishikawa, Makoto Umeda, Yusuke Tarumoto, Megumi Okubo, Yasuaki Tamura et Hiroshi Ono. « Sugarcane Metabolome Compositional Stability in Pretreatment Processes for NMR Measurements ». Metabolites 12, no 9 (14 septembre 2022) : 862. http://dx.doi.org/10.3390/metabo12090862.
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Sugarcane is essential for global sugar production and its compressed juice is a key raw material for industrial products. Sugarcane juice includes various metabolites with abundances and compositional balances influencing product qualities and functionalities. Therefore, understanding the characteristic features of the sugarcane metabolome is important. However, sugarcane compositional variability and stability, even in pretreatment processes for nuclear magnetic resonance (NMR)-based metabolomic studies, remains elusive. The objective of this study is to evaluate sugarcane juice metabolomic variability affected by centrifugation, filtration, and thermal pretreatments, as well as the time-course changes for determining optimal conditions for NMR-based metabolomic approach. The pretreatment processes left the metabolomic compositions unchanged, indicating that these pretreatments are compatible with one another and the studied metabolomes are comparable. The thermal processing provided stability to the metabolome for more than 32 h at room temperature. Based on the determined analytical conditions, we conducted an NMR-based metabolomic study to discriminate the differences in the harvest period and allowed for successfully identifying the characteristic metabolome. Our findings denote that NMR-based sugarcane metabolomics enable us to provide an opportunity to collect a massive amount of data upon collaboration between multiple researchers, resulting in the rapid construction of useful databases for both research purposes and industrial use.
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Bazzano, Marilena, Luca Laghi, Chenglin Zhu, Enrica Lotito, Stefano Sgariglia, Beniamino Tesei et Fulvio Laus. « Exercise Induced Changes in Salivary and Serum Metabolome in Trained Standardbred, Assessed by 1H-NMR ». Metabolites 10, no 7 (21 juillet 2020) : 298. http://dx.doi.org/10.3390/metabo10070298.
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In the present study, data related to the metabolomics of saliva and serum in trained standardbred horses are provided for the first time. Metabolomic analysis allows to analyze all the metabolites within selected biofluids, providing a better understanding of biochemistry modifications related to exercise. On the basis of the current advances observed in metabolomic research on human athletes, we aimed to investigate the metabolites’ profile of serum and saliva samples collected from healthy standardbred horses and the relationship with physical exercise. Twelve trained standardbred horses were sampled for blood and saliva before (T0) and immediately after (T1) standardized exercise. Metabolomic analysis of both samples was performed by 1H-NMR spectroscopy. Forty-six metabolites in serum and 62 metabolites in saliva were detected, including alcohols, amino acids, organic acids, carbohydrates and purine derivatives. Twenty-six and 14 metabolites resulted to be significantly changed between T0 and T1 in serum and saliva, respectively. The findings of 2-hydroxyisobutyrate and 3-hydroxybutyrate in serum and GABA in equine saliva, as well as their modifications following exercise, provide new insights about the physiology of exercise in athletic horses. Glycerol might represent a novel biomarker for fitness evaluation in sport horses.
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Brennan, Lorraine. « Metabolomics in nutrition research–a powerful window into nutritional metabolism ». Essays in Biochemistry 60, no 5 (15 décembre 2016) : 451–58. http://dx.doi.org/10.1042/ebc20160029.
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Metabolomics is the study of small molecules present in biological samples. In recent years it has become evident that such small molecules, called metabolites, play a key role in the development of disease states. Furthermore, metabolomic applications can reveal information about alterations in certain metabolic pathways under different conditions. Data acquisition in metabolomics is usually performed using nuclear magnetic resonance (NMR)-based approaches or mass spectrometry (MS)-based approaches with a more recent trend including the application of multiple platforms in order to maximise the coverage in terms of metabolites measured. The application of metabolomics is rapidly increasing and the present review will highlight applications in nutrition research.
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Huang, Katherine, Natalie Thomas, Paul R. Gooley et Christopher W. Armstrong. « Systematic Review of NMR-Based Metabolomics Practices in Human Disease Research ». Metabolites 12, no 10 (12 octobre 2022) : 963. http://dx.doi.org/10.3390/metabo12100963.
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Nuclear magnetic resonance (NMR) spectroscopy is one of the principal analytical techniques for metabolomics. It has the advantages of minimal sample preparation and high reproducibility, making it an ideal technique for generating large amounts of metabolomics data for biobanks and large-scale studies. Metabolomics is a popular “omics” technology and has established itself as a comprehensive exploratory biomarker tool; however, it has yet to reach its collaborative potential in data collation due to the lack of standardisation of the metabolomics workflow seen across small-scale studies. This systematic review compiles the different NMR metabolomics methods used for serum, plasma, and urine studies, from sample collection to data analysis, that were most popularly employed over a two-year period in 2019 and 2020. It also outlines how these methods influence the raw data and the downstream interpretations, and the importance of reporting for reproducibility and result validation. This review can act as a valuable summary of NMR metabolomic workflows that are actively used in human biofluid research and will help guide the workflow choice for future research.
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Alborghetti, Marcos Rodrigo, Maria Elvira P. Corrêa, Andreia Aparecida da Silva, Eliana C. M. Miranda, Carmino A. De Souza, Mauricio L. Sforça et Ana Carolina de Mattos Zeri. « Metabolomic Model For Chronic Gvhd Diagnosis ». Blood 122, no 21 (15 novembre 2013) : 3304. http://dx.doi.org/10.1182/blood.v122.21.3304.3304.
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Abstract Introduction Metabolomics is an essential tool for Translational Medicine, with a holistic non targeted approach, which provides information from the metabolic profile that can be used as a potential biomarker for a certain feature. The identification of biomarker profiles can be translated into simplified tests for the early diagnosis of diseases such as graft-versus-host disease (GVHD). Aim To evaluate the feasibility of a diagnostic protocol for chronic GVHD (cGVHD) based on the metabolic profile of blood serum from patients (pts) submitted to hematopoietic stem cell transplantation (HSCT). Methodology The study included a prospective, nested cohort of 41 adult pts who had undergone first full-match allogeneic HSCT at Hospital de Cl’nicas/ University of Campinas between August, 2011-January, 2013 and had signed the Consent Form. Blood serum samples were prospectively collected on the day of hospitalization (D-8), day of transplantation (D0), NADIR phase (D+10) and D+100 post-HSCT. The Nuclear Magnetic Resonance (NMR)-based metabolomic experiments were performed at the Brazilian Biosciences National Laboratory (LNBio/CNPEM). Samples were previously filtered on a 3 kDa cut off filter, diluted 3X on 100 mM phosphate buffer pH 7.4, referenced with 10% D2O and 0.5 mM DSS (4,4-dimethyl-4-silapentane-1-sulfonic acid) for further absolute quantification of metabolites. The acquisition of 1D spectra was performed on a Agilent/Varian INOVA spectrometer operating at 1H resonance frequency of 600MHz. The spectra processing, identification and quantification of metabolites were performed by using the application package Chenomx NMR Suite and the target profiling approach (Chenomx, Inc). Samples from pts who developed chronic GVHD, at anytime, were marked as “cGVHD group”, and those who did not develop chronic GVHD, “cGVHD-free group” . Blood samples from pts who died up to 200 days after HSCT and did not develop chronic GVHD were excluded from the analysis, as were also all samples from pts whose sample collection was lacking at least in one period. T-tests (p<0.05) were applied at each sampling time in order to select metabolites and perform Principal Component Analysis (PCA), hierarchical clustering and calculate Receiver Operating Characteristic (ROC) curve for cGVHD diagnosis model using the software Pirouette¨ 4.0 (Infometrix, Inc) and the web tools MetaboAnalyst 2.0 and ROCCET. Results Median age was 41(18-69) years old and 61% were male. 18/41(44%) pts matched the inclusion criteria for the study. 6/18 (33%) pts had undergone cGVHD therapy. Seventy-three metabolites were identified and quantified in the blood serum samples. 8 metabolites were selected by T-test application at each studied time (2 metabolites from D-8, 2 from D0, 3 from D+10 and 1 from D+100). Using the selected metabolites the PCA showed clear separation between pts from “cGVHD” and “cGVHD-free” groups as well as hierarchical clustering (Fig. 1), confirmed by ROC analysis as a high sensitivity and specificity model for cGVHD diagnosis (AUC 0.99 and CI 0.93-1.00) (Fig. 2). Conclusion Metabolic differences were found in both studied groups. These differences may be used as a biomarker profile for cGVHD diagnosis up 100 days post-HSCT. Our results demonstrated that the statistical model using combined prospective time-series analysis is a powerful metabolomic model for early cGVHD diagnosis. Disclosures: Alborghetti: Sao Paulo Research Foundation: Research Funding. da Silva:Coordination for the Improvement of Higher Education Personnel (CAPES): Research Funding.
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Eom, Jun Sik, Shin Ja Lee, Hyun Sang Kim, You Young Choi, Sang Ho Kim, Yoo Gyung Lee et Sung Sill Lee. « Metabolomics Comparison of Hanwoo (Bos taurus coreanae) Biofluids Using Proton Nuclear Magnetic Resonance Spectroscopy ». Metabolites 10, no 8 (14 août 2020) : 333. http://dx.doi.org/10.3390/metabo10080333.
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The aim of this study was to identify the metabolomic profiles of rumen fluid, serum, and urine from Hanwoo (Bos taurus coreanae), using proton nuclear magnetic resonance (1H-NMR) spectroscopy. In all, 189, 110, and 188 metabolites were identified in rumen fluid, serum, and urine, and 107, 49, and 99 were quantified, respectively. Organic acids, carbohydrates, and aliphatic acyclic compound metabolites were present at the highest concentrations in rumen fluid, serum, and urine, respectively. In addition, acetate, glucose, and urea were the most highly concentrated individual metabolites in rumen fluid, serum, and urine, respectively. In all, 77 metabolites were commonly identified, and 19 were quantified across three biofluids. Metabolic pathway analysis showed that the common quantified metabolites could provide relevant information about three main metabolic pathways, phenylalanine, tyrosine, and tryptophan biosynthesis; caffeine metabolism; and histidine metabolism. These results can be useful as reference values for future metabolomic research on Hanwoo biofluids in Korea.
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Rosolanka, Robert, Peter Liptak, Eva Baranovicova, Anna Bobcakova, Robert Vysehradsky, Martin Duricek, Andrea Kapinova et al. « Changes in the Urine Metabolomic Profile in Patients Recovering from Severe COVID-19 ». Metabolites 13, no 3 (28 février 2023) : 364. http://dx.doi.org/10.3390/metabo13030364.
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Metabolomics is a relatively new research area that focuses mostly on the profiling of selected molecules and metabolites within the organism. A SARS-CoV-2 infection itself can lead to major disturbances in the metabolite profile of the infected individuals. The aim of this study was to analyze metabolomic changes in the urine of patients during the acute phase of COVID-19 and approximately one month after infection in the recovery period. We discuss the observed changes in relation to the alterations resulting from changes in the blood plasma metabolome, as described in our previous study. The metabolome analysis was performed using NMR spectroscopy from the urine of patients and controls. The urine samples were collected at three timepoints, namely upon hospital admission, during hospitalization, and after discharge from the hospital. The acute COVID-19 phase induced massive alterations in the metabolic composition of urine was linked with various changes taking place in the organism. Discriminatory analyses showed the feasibility of successful discrimination of COVID-19 patients from healthy controls based on urinary metabolite levels, with the highest significance assigned to citrate, Hippurate, and pyruvate. Our results show that the metabolomic changes persist one month after the acute phase and that the organism is not fully recovered.
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Han, Seongyi, Haeni Lee, Chulhong Kim et Jeesu Kim. « Review on Multispectral Photoacoustic Analysis of Cancer : Thyroid and Breast ». Metabolites 12, no 5 (22 avril 2022) : 382. http://dx.doi.org/10.3390/metabo12050382.
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In recent decades, photoacoustic imaging has been used widely in biomedical research, providing molecular and functional information from biological tissues in vivo. In addition to being used for research in small animals, photoacoustic imaging has also been utilized for in vivo human studies, achieving a multispectral photoacoustic response in deep tissue. There have been several clinical trials for screening cancer patients by analyzing multispectral responses, which in turn provide metabolomic information about the underlying biological tissues. This review summarizes the methods and results of clinical photoacoustic trials available in the literature to date to classify cancerous tissues, specifically of the thyroid and breast. From the review, we can conclude that a great potential exists for photoacoustic imaging to be used as a complementary modality to improve diagnostic accuracy for suspicious tumors, thus significantly benefitting patients’ healthcare.
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Marx, D., L. Diekmann, K. Klika, H. M. Lorenz, K. Benesova et M. Souto-Carneiro. « POS0472 COMPARATIVE METABOLOMIC ANALYSIS OF SERUM SAMPLES FROM PATIENTS WITH COINCIDENTAL RHEUMATOLOGICAL AND MALIGNANT DISEASES ». Annals of the Rheumatic Diseases 80, Suppl 1 (19 mai 2021) : 467.2–468. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2484.
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Background:Rheumatic and musculoskeletal diseases (RMDs) and malignancies are both caused by a dysfunctional immune system and the probability of their coincidence in one individual is rising due to advances in cancer treatment and demographic changes. However, the lack of understanding of the complex interrelationship of both conditions often leads to undertreatment and high level of suffering in affected patients. Herein, the MalheuR project breaks new ground by systematic analysis of concomitant malignant and rheumatic diseases and closes the knowledge gaps on the clinical and molecular level.Objectives:To enable early diagnosis of concomitant malignancy and/or identification of patients at risk in the future, changes in serum metabolome were explored in order to create a diagnostic classification model.Methods:Serum samples from patients with concomitant RMD and cancer or obligate precancerous lesions (n=78, breast cancer (23), melanoma (14), MGUS (12), prostate cancer (8) and others (21)) were collected as a pilot study within the MalheuR project, a registry-based study initiated in 2018 at the university hospital Heidelberg, Germany. The following groups were defined by the underlying RMD: rheumatoid arthritis (n=42), psoriasis arthritis (n=23), spondylarthritis (n=9) and systemic lupus erythematosus (n=4). RMD patients without any malignancies were used as controls (n=280: 122 RA, 81 PsA, 46 SpA, 31 SLE).Samples were analyzed by 1H NMR spectroscopy. For all samples, regular 1H acquisition with presaturation and Carr-Purcell-Meiboom-Gill (CPMG) spectra were acquired using a 600 MHz Bruker NMR spectrometer. Spectra were processed with TopSpin using 0.2 Hz of line broadening and manual phasing. Molar concentrations of 26 metabolites were acquired by integration of NMR spectra. With GraphPad Prism, univariate and ANOVA statistical analysis was performed to find significant differences between each malignant group and their control group as well as between all four malignant groups.Results:Mean disease duration was 11.8 ±10.5 years for cancer and 12.8±10.8 years for RMDs since diagnosis. 1.4% received cancer treatment (6.4% of malignancy group), 69.3% csDMARDs, 42.3% b/tsDMARDs and 46.4% glucocorticoids at the time of sample collection.Most metabolites tested were significantly lower in the malignancy groups versus associated controls: Concentrations of amino acids V and L were significantly reduced in all malignancy samples. Additionally, T, D, N, Q, E, A, I were altered in RA, SpA and PsA, changes in G were seen in RA, PsA and SLE and P was altered in RA and PsA only. Furthermore, lower concentrations of short chain fatty acids and tricarboxylic acid cycle intermediates were present in the malignancy groups. In no case was a metabolite concentration significantly higher in the malignancy group than in the associated control. When comparing the metabolome within the four malignancy groups, only the concentrations of creatine, threonine and isoleucine were found higher in RA patients with malignancy.Conclusion:Significant differences between the metabolomic fingerprints of RMD patients with and without malignancies could be observed. These changes might be characteristic for cancer burden, as in most cases the underlying RMD was not relevant when comparing the concentrations between the malignancy groups. Our results may promote understanding of the interrelationships of both disease entities as well as prove useful as biomarkers for diagnostic and therapeutic purposes.Acknowledgements:Grant/research support from medical faculty (Olympia Morata Programme) and foundations commission (Herbert Daus estate) of University of HeidelbergDisclosure of Interests:None declared
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Abooshahab, Raziyeh, Hamidreza Ardalani, Maryam Zarkesh, Koroush Hooshmand, Ali Bakhshi, Crispin R. Dass et Mehdi Hedayati. « Metabolomics—A Tool to Find Metabolism of Endocrine Cancer ». Metabolites 12, no 11 (21 novembre 2022) : 1154. http://dx.doi.org/10.3390/metabo12111154.
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Clinical endocrinology entails an understanding of the mechanisms involved in the regulation of tumors that occur in the endocrine system. The exact cause of endocrine cancers remains an enigma, especially when discriminating malignant lesions from benign ones and early diagnosis. In the past few years, the concepts of personalized medicine and metabolomics have gained great popularity in cancer research. In this systematic review, we discussed the clinical metabolomics studies in the diagnosis of endocrine cancers within the last 12 years. Cancer metabolomic studies were largely conducted using nuclear magnetic resonance (NMR) and mass spectrometry (MS) combined with separation techniques such as gas chromatography (GC) and liquid chromatography (LC). Our findings revealed that the majority of the metabolomics studies were conducted on tissue, serum/plasma, and urine samples. Studies most frequently emphasized thyroid cancer, adrenal cancer, and pituitary cancer. Altogether, analytical hyphenated techniques and chemometrics are promising tools in unveiling biomarkers in endocrine cancer and its metabolism disorders.
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Burlikowska, Katarzyna, Iga Stryjak, Joanna Bogusiewicz, Bogumiła Kupcewicz, Karol Jaroch et Barbara Bojko. « Comparison of Metabolomic Profiles of Organs in Mice of Different Strains Based on SPME-LC-HRMS ». Metabolites 10, no 6 (17 juin 2020) : 255. http://dx.doi.org/10.3390/metabo10060255.
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Given that the extent to which genetics alters the metabolomic profile of tissues is still poorly understood, the current study aimed to characterize and investigate the metabolite profiles of brain, liver, kidney and skeletal muscle of two common mouse inbred strains (BALB/c, C57BL/6) and one outbred stock (CD1) for strain-specific differences. Male mice (n = 15) at the age of 12 weeks were used: BALB/c (n = 5), C57BL/6 (n = 5) and CD1 (n = 5). Solid phase microextraction (SPME) was applied for the extraction of analytes from the tissues. SPME fibers (approximately 0.2 mm in diameter) coated with a biocompatible sorbent (4 mm length of hydrophilic-lipophilic balanced particles) were inserted into each organ immediately after euthanasia. Samples were analyzed using liquid chromatography coupled to a Q-Exactive Focus Orbitrap mass spectrometer. Distinct interstrain differences in the metabolomic patterns of brain and liver tissue were revealed. The metabolome of kidney and muscle tissue in BALB/c mice differed greatly from C57BL/6 and CD1 strains. The main compounds differentiating all the targeted organs were alpha-amino acids, purine nucleotides and fatty acid esters. The results of the study indicate that the baseline metabolome of organs, as well as different metabolic pathways, vary widely among general-purpose models of laboratory mice commonly used in biomedical research.
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Chiocchetti, Gabriela de Matuoka e., Leisa Lopes-Aguiar, Natália Angelo da Silva Miyaguti, Lais Rosa Viana, Carla de Moraes Salgado, Ophelie Ocean Orvoën, Derly Florindo, Rogério Williams dos Santos et Maria Cristina Cintra Gomes-Marcondes. « A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life ». Metabolites 11, no 6 (20 juin 2021) : 404. http://dx.doi.org/10.3390/metabo11060404.
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Cancer cachexia is a severe wasting condition that needs further study to find ways to minimise the effects of damage and poor prognosis. Skeletal muscle is the most impacted tissue in cancer cachexia; thus, elucidation of its metabolic alterations could provide a direct clue for biomarker research and be applied to detect this syndrome earlier. In addition, concerning the significant changes in the host metabolism across life, this study aimed to compare the metabolic muscle changes in cachectic tumour-bearing hosts at different ages. We performed 1H-NMR metabolomics in the gastrocnemius muscle in weanling and young adult Walker-256 tumour-bearing rats at different stages of tumour evolution (initial, intermediate, and advanced). Among the 49 metabolites identified, 24 were significantly affected throughout tumour evolution and 21 were significantly affected regarding animal age. The altered metabolites were mainly related to increased amino acid levels and changed energetic metabolism in the skeletal muscle, suggesting an expressive catabolic process and diverted energy production, especially in advanced tumour stages in both groups. Moreover, these changes were more severe in weanling hosts throughout tumour evolution, suggesting the distinct impact of cancer cachexia regarding the host’s age, highlighting the need to adopting the right animal age when studying cancer cachexia.
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Wylie, Andrew, Joseph Schoepfer, Giuliano Berellini, Hongbo Cai, Giorgio Caravatti, Simona Cotesta, Stephanie Dodd et al. « ABL001, a Potent Allosteric Inhibitor of BCR-ABL, Prevents Emergence of Resistant Disease When Administered in Combination with Nilotinib in an in Vivo Murine Model of Chronic Myeloid Leukemia ». Blood 124, no 21 (6 décembre 2014) : 398. http://dx.doi.org/10.1182/blood.v124.21.398.398.
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Abstract Background: Chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) are caused by the t(9;22)(q34;q11.2) chromosome translocation, resulting in fusion of the BCR and ABL1 genes on the Philadelphia chromosome to encode constitutively active ABL1 kinase. Despite the dramatic progress made over the past decade with tyrosine kinase inhibitors (TKIs) in the treatment of CML, allogeneic stem cell transplant is considered the only proven curative therapy. To achieve cure or benefit from treatment-free remissions with pharmacologically-based therapies, it is estimated that patients will likely need to achieve a sustained reduction in tumor burden of 4 logs (MR4) or deeper (MR4.5). Currently, only 39% and 18% of patients achieve MR4 by 24 months of treatment with single agent nilotinib or imatinib, respectively. Furthermore, for a subset of CML patients and the majority of Ph+ ALL patients, resistance develops to current TKI’s as a result of emergence of point mutations in the ATP site of the kinase domain. ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action which recently entered Phase I development for the treatment of patients with CML and Ph+ ALL. ABL001 was developed to be dosed in combination with nilotinib to provide greater pharmacological coverage of BCR-ABL disease and prevent the emergence of resistance. Methods: Based on X-ray crystallography, NMR and molecular modeling, ABL001 is the result of a structure-guided medicinal chemistry program targeting the myristoyl pocket of the ABL1 kinase. In vitro cell based assays were performed using the Ba/F3 isogenic cell system and a panel of over 300 cell lines. KCL-22 cells were used to develop an in vivo xenograft model to assess the efficacy of ABL001 and the PD marker, pSTAT5, was used to monitor the inhibition of BCR-ABL signaling. Results: In contrast to TKIs that bind to the ATP-site of the ABL1 kinase domain, NMR and X-Ray crystallography studies confirmed that ABL001 binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity. Cell proliferation studies demonstrate that ABL001 selectively inhibited the growth of CML and Ph+ ALL cells with potencies ranging from 1-10nM range. In contrast, BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher. With resistance emerging in the clinic to current TKI’s as a result of point mutations in the ATP-site, ABL001 was tested for activity against clinically observed mutations and found to be active in the low nM range. In the KCL-22 mouse xenograft model, ABL001 displayed potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. The KCL-22 xenograft model was also used to compare the dosing of ABL001 and nilotinib as single agents to dosing a combination of ABL001 and nilotinib. Single agent dosing regimens led to tumor regressions; however, despite continuous dosing, all tumors relapsed within 30-60 days with evidence of point mutations in the resistant tumors. In contrast, animals treated with the combination of ABL001 and nilotinib achieved sustained tumor regression with no evidence of disease relapse either during the 70 days of treatment or for > 150 days after treatment stopped. Conclusion: ABL001 selectively inhibited the proliferation of cells expressing the BCR-ABL fusion gene and was active against clinically important mutations that arise with current TKI therapy in CML. In an in vivo model of CML, the combination of ABL001 and nilotinib resulted in complete and sustained tumor regression with no evidence of disease relapse. These results provide proof-of-principle that simultaneous targeting of the myristoyl pocket and ATP-pocket by ABL001 and nilotinib, respectively, promotes a more sustained overall efficacy and prevents the emergence of resistance via acquisition of point mutations in the respective binding sites. ABL001 is currently being evaluated in a Phase 1 study in patients with CML and Ph+ ALL. Disclosures Wylie: Novartis Institutes for Biomedical Research, Inc: Employment. Schoepfer:Novartis Institutes for Biomedical Research: Employment. Berellini:Novartis Institutes for Biomedical Research: Employment. Cai:Novartis Institutes for Biomedical Research: Employment. Caravatti:Novartis Institutes for Biomedical Research: Employment. Cotesta:Novartis Institues for Biomedical Research: Employment. Dodd:Novartis Institutes for Biomedical Research: Employment. Donovan:Novartis Institutes for Biomedical Research: Employment. Erb:Novartis Institutes for Biomedical Research: Employment. Furet:Novartis Institutes for Biomedical Research: Employment. Gangal:Novartis Institutes for Biomedical Research: Employment. Grotzfeld:Novartis Institutes for Biomedical Research: Employment. Hassan:Novartis Institutes for Biomedical Research: Employment. Hood:Novartis Institutes for Biomedical Research: Employment. Iyer:Novartis Institutes for Biomedical Research: Employment. Jacob:Novartis Institutes for Biomedical Research: Employment. Jahnke:Novartis Institutes for Biomedical Research: Employment. Lombardo:Novartis Institutes for Biomedical Research: Employment. Loo:Novartis Institutes for Biomedical Research: Employment. Manley:Novartis Institutes for Biomedical Research: Employment. Marzinzik:Novartis Institutes for Biomedical Research: Employment. Palmer:Novartis Institutes for Biomedical Research: Employment. Pelle:Novartis Institutes for Biomedical Research: Employment. Salem:Novartis Institutes for Biomedical Research: Employment. Sharma:Novartis Institutes for Biomedical Research: Employment. Thohan:Novartis Institutes for Biomedical Research: Employment. Zhu:Novartis Institutes for Biomedical Research: Employment. Keen:Novartis Institutes for Biomedical Research: Employment. Petruzzelli:Novartis Institutes for Biomedical Research: Employment. Vanasse:Novartis: Employment, Equity Ownership. Sellers:Novartis: Employment.
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Salzer, Liesa, et Michael Witting. « Quo Vadis Caenorhabditis elegans Metabolomics—A Review of Current Methods and Applications to Explore Metabolism in the Nematode ». Metabolites 11, no 5 (29 avril 2021) : 284. http://dx.doi.org/10.3390/metabo11050284.
Texte intégralRésumé :
Metabolomics and lipidomics recently gained interest in the model organism Caenorhabditis elegans (C. elegans). The fast development, easy cultivation and existing forward and reverse genetic tools make the small nematode an ideal organism for metabolic investigations in development, aging, different disease models, infection, or toxicology research. The conducted type of analysis is strongly depending on the biological question and requires different analytical approaches. Metabolomic analyses in C. elegans have been performed using nuclear magnetic resonance (NMR) spectroscopy, direct infusion mass spectrometry (DI-MS), gas-chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS) or combinations of them. In this review we provide general information on the employed techniques and their advantages and disadvantages in regard to C. elegans metabolomics. Additionally, we reviewed different fields of application, e.g., longevity, starvation, aging, development or metabolism of secondary metabolites such as ascarosides or maradolipids. We also summarised applied bioinformatic tools that recently have been used for the evaluation of metabolomics or lipidomics data from C. elegans. Lastly, we curated metabolites and lipids from the reviewed literature, enabling a prototypic collection which serves as basis for a future C. elegans specific metabolome database.
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Fanos, V., A. Noto, T. Xanthos, M. Lussu, F. Murgia, L. Barberini, G. Finco et al. « Metabolomics Network Characterization of Resuscitation after Normocapnic Hypoxia in a Newborn Piglet Model Supports the Hypothesis That Room Air Is Better ». BioMed Research International 2014 (2014) : 1–7. http://dx.doi.org/10.1155/2014/731620.
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Perinatal asphyxia is attributed to hypoxia and/or ischemia around the time of birth and may lead to multiorgan dysfunction. Aim of this research article is to investigate whether different metabolomic profiles occurred according to oxygen concentration administered at resuscitation. In order to perform the experiment, forty newborn piglets were subjected to normocapnic hypoxia and reoxygenation and were randomly allocated in 4 groups resuscitated with different oxygen concentrations, 18%, 21%, 40%, and 100%, respectively. Urine metabolic profiles at baseline and at hypoxia were analysed by1H-NMR spectroscopy and metabolites were also identified by multivariate statistical analysis. Metabolic pathways associations were also built up by ingenuity pathway analysis (IPA). Bioinformatics analysis of metabolites characterized the effect of metabolism in the 4 groups; it showed that the 21% of oxygen is the most “physiological” and appropriate concentration to be used for resuscitation. Our data indicate that resuscitation with 21% of oxygen seems to be optimal in terms of survival, rapidity of resuscitation, and metabolic profile in the present animal model. These findings need to be confirmed with metabolomics in human and, if so, the knowledge of the perinatal asphyxia condition may significantly improve.
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Reinhardt, Carsten. « “This Other Method” ». Historical Studies in the Natural Sciences 47, no 3 (1 juin 2017) : 389–422. http://dx.doi.org/10.1525/hsns.2017.47.3.389.
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Nuclear magnetic resonance (NMR) spectroscopy has been and continues to be one of the most widely spread research techniques in the physical and life sciences, including medicine, since the technique’s invention in 1945. There is no basis, however, to account for a linear success story. Although NMR was used for decades in biochemistry and molecular biology, it had not contributed substantially to solving the big scientific problems in these areas. The goal set by its early proponents—to find out about the dynamics and functions of large biomolecules—was not successfully tackled until the 1980s, when new technology became available. Much of the pre-1980s history of NMR is arguably a history of the dependence of NMR on a rival method, x-ray crystallography. In this paper I will discuss the epistemic and social processes that made the continuation of NMR as a dependent research method possible, perhaps even inevitable. Following a comparison of x-ray crystallography and NMR in the structural elucidation of large biomolecules, the paper analyzes three examples of the practices of biochemical and biomedical research using NMR from the 1950s to the 1970s in the United States: first is a fundamental, almost reductionist approach with a basis in physics and goals in technology; second, a pragmatic one with a strong bent toward biological problems; and third, a methods-oriented program, involving issues of the former two and proving the most fruitful in the long term. This essay is part of a special issue entitled THE BONDS OF HISTORY edited by Anita Guerrini.
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Janczuk, A., J. Li, W. Zhang, X. Chen, Y. Chen, J. Fang, J. Wang et P. G. Wang. « α-Gal Oligosaccharides : Chemistry and Potential Biomedical Application ». Current Medicinal Chemistry 6, no 2 (février 1999) : 155–64. http://dx.doi.org/10.2174/0929867306666220207213238.
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Abstract: This article focuses on the most recent research efforts by the Wang group in the field of a-Gal oligosaccharides. a-Gal oligosaccharides are carbohydrate structures bearing a Gala1-3Galterminus. This class of compounds are believed to act as xenoactive antigens that instigate the hyperacute rejection in xenotransplantation. Enzymatic methods using recombinant a1-3 galactosyltransferase were employed to synthesize several a- Gal oligosaccharides. In addition, a chemical synthetic scheme was devised in order to produce readily acessible amounts of a-Gal. Conformational analysis was done using both NMR techniques and molecular modeling protocols. These studies provide important information in the structure-function relationship of a-Gal and anti-a-Gal antibodies. The second part of this article deals with the use of a-Gal in immunotherapy. Based on the abundance of anti-a-Gal antibodies lgM and lgG in human blood serum, a-Gal conjugates may act as effective immunotheraputic drugs. Recent studies have discovered characteristic peptide sequences containing Arg-Giy-Asp (RGD) motif that binds to integrins on the surface of cancer cells. A a-Gal conjugate was developed by chemical coupling a a-Gal trisacchpride to a RGD peptide. Preliminary studies using the conjugate on prostate DU-145 cancer cells showed a reduction in the survival rate of the cells.
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Lonati, Caterina, Daniele Dondossola, Laimdota Zizmare, Michele Battistin, Leonie Wüst, Luigi Vivona, Margherita Carbonaro et al. « Quantitative Metabolomics of Tissue, Perfusate, and Bile from Rat Livers Subjected to Normothermic Machine Perfusion ». Biomedicines 10, no 3 (24 février 2022) : 538. http://dx.doi.org/10.3390/biomedicines10030538.
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Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used. Experiments were carried out with the addition of an oxygen carrier (OxC) to the perfusion fluid (OxC-NMP, n = 5) or without (h-NMP, n = 5). Bile and perfusate samples were collected throughout the procedure, while biopsies were only taken at the end of NMP. Two additional groups were: (1) Native, in which tissue or bile specimens were collected from rats in resting conditions; and (2) SCS, in which biopsies were taken from cold-stored livers. Generally, NMP groups showed a distinctive metabolomic signature in all the analyzed biological matrices. In particular, many of the differentially expressed metabolites were involved in mitochondrial biochemical pathways. Succinate, acetate, 3-hydroxybutyrate, creatine, and O-phosphocholine were deeply modulated in ex vivo perfused livers compared to both the Native and SCS groups. These novel results demonstrate a broad modulation of mitochondrial metabolism during NMP that exceeds energy production and redox balance maintenance.
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Colaco, K., K. A. Lee, S. Akhtari, R. Winer, P. Welsh, N. Sattar, I. Mcinnes et al. « OP0221 TARGETED METABOLOMIC PROFILING AND PREDICTION OF CARDIOVASCULAR EVENTS : A PROSPECTIVE STUDY OF PATIENTS WITH PSORIATIC ARTHRITIS AND PSORIASIS ». Annals of the Rheumatic Diseases 80, Suppl 1 (19 mai 2021) : 132–33. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1154.
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Background:Psoriatic arthritis and psoriasis, collectively termed psoriatic disease (PsD), are associated with increased cardiovascular (CV) risk. Metabolites comprise biomarkers that may add predictive value over traditional CV risk factors.Objectives:We aimed to identify metabolites associated with CV events (CVEs) and to determine whether they could improve CV risk prediction beyond traditional CV risk factors.Methods:Patients from a longitudinal PsD cohort without a prior history of CVEs were included. In the first available serum sample, a targeted nuclear magnetic resonance (NMR) metabolomics platform was used to quantify 64 metabolite measures comprised of lipoprotein subclasses, fatty acids, glycolysis precursors, ketone bodies and amino acids. The study outcome included any of the following CVEs occurring within the first 10 years of biomarker assessment: angina, myocardial infarction, congestive heart failure, transient ischemic attack, cerebrovascular accident, revascularization procedures and CV death. The association of each metabolite with incident CVEs were analyzed separately using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalization with boosting after adjusting for age and sex. The added predictive value of the selected metabolites to improve risk prediction beyond traditional CV risk factors was assessed using the area under the receiver operator characteristic curve (AUC).Results:A total of 977 patients with PsD, followed between 2002 and 2019, were analyzed (mean age 49.1 ± 12.6 years, 45.1% female). During a mean follow-up of 7.1 years, 70 (7.2%) patients developed incident CVEs. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, total high-density lipoprotein (HDL) cholesterol, medium and large HDL particles, and the degree of unsaturation of fatty acids were significantly associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B, remnant cholesterol, very low-density lipoprotein (VLDL) cholesterol, and very small VLDL particles were associated with an increased CV risk. In proportional sub-distribution hazards regression models adjusted for age and sex, 13 metabolites were selected (Table 1). The age- and sex-adjusted expanded model (base model + 13 metabolites) significantly improved prediction of CVEs beyond the base model (only age and sex) with an AUC of 79.9 vs. 72.6, respectively (p=0.019) (Figure 1).Table 1.Regression coefficients of the selected metabolites in a model adjusted for age and sex.CategoryMetaboliteModel adjusted for Age and SexAmino AcidsAlanine-0.1179Glycine-0.0339Tyrosine-0.1010Fatty acid ratios, relative to total fatty acidsDocosahexaenoic acid-0.0862Unsaturation degree, double bonds per fatty acid-0.1265Fluid BalanceAlbumin+0.0685GlyceridesTriglycerides in IDL cholesterol+0.1546Glycolysis precursorsGlucose+0.1391InflammationGlycoprotein acetyls+0.1478Ketone bodiesAcetoacetate+0.0464Lipoprotein subclassesHDL3 Cholesterol-0.0211Medium HDL-0.0296Large HDL-0.0309Figure 1.Predictive performance of a model with age and sex alone is compared to a model with age and sex plus selected metabolites.Conclusion:Using NMR metabolomics profiling, we identified a variety of metabolites associated with a lower and higher risk of developing CVEs in patients with PsD. Further study of their underlying association with CVEs is needed to clarify the clinical utility of these biomarkers to guide CV risk assessment in this population.References:[1]Eder L, Wu Y, Chandran V, et al. Incidence and predictors for cardiovascular events in patients with psoriatic arthritis. Ann Rheum Dis 2016;75(9):1680-6.[2]Soininen P, Kangas AJ, Wurtz P, et al. Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. Circ Cardiovasc Genet 2015;8(1):192-206.Acknowledgements:Keith Colaco is supported by the Enid Walker Estate, Women’s College Research Institute, Arthritis Society (TGP-19-0446), National Psoriasis Foundation (Early Career Grant) and the Edward Dunlop Foundation. Lihi Eder is supported by a Young Investigator Award from the Arthritis Society and an Early Researcher Award from the Ontario Ministry of Science and Innovation. The study was supported in part by a discovery grant from the National Psoriasis Foundation and an operating grant from the Arthritis Society (YIO-16-394).Disclosure of Interests:None declared
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Manolakou, T., I. Tsiara, D. Nikolopoulos, P. Garantziotis, D. Benaki, E. Gikas, E. Frangou, E. Mikroa et D. Boumpas. « POS0421 COMBINED ANALYSIS OF METABOLIC AND TRANSCRIPTOMIC KIDNEY PROFILES OF NZW/B-F1 MURINE LUPUS UNCOVERS BIOLOGICAL MECHANISMS PRECEDING THE ONSET OF NEPHRITIS ». Annals of the Rheumatic Diseases 80, Suppl 1 (19 mai 2021) : 439.2–440. http://dx.doi.org/10.1136/annrheumdis-2021-eular.4115.
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Background:Metabolic pathways are important regulators of immune differentiation and activation in kidneys. Kidneys directly impact systemic metabolism, circulating metabolite levels, and express intrinsic metabolic activity. The integration of renal metabolomic and transcriptomic profiles may unravel unique gene-metabolite pairs of biological significance in lupus nephritis (LN).Objectives:To decipher gene-metabolite signatures at both pre-nephritic and nephritic stages of lupus.Methods:Kidneys were isolated and snap-frozen after perfusion from female NZB/NZW-F1 lupus mice at the pre-nephritic (3-month-old) and nephritic (6-month-old exhibiting ≥100 ng/dL of urine protein) stage of lupus (n=6/group). Age-matched female C57BL/6 mice were used as healthy controls. Sample extracts were used for RNA sequencing and 1H-NMR spectroscopy metabolic profiling. DESeq2 was used to identify differentially expressed genes. Univariate analysis was used to reveal metabolic differences characteristic for nephritis.Results:Comparative transcriptomic analyses uncovered multiple transcripts related to metabolic pathways: In pre-nephritic kidneys, lipid metabolism, cellular respiration, TCA cycle, amino acid metabolism processes were overrepresented in the upregulated genes while in nephritic kidneys, amino acid metabolism processes were overrepresented among the downregulated genes (Figure 1). 1H-NMR analysis revealed a total of 49 metabolites. Comparison of the metabolic levels of nephritic and pre-nephritic animals revealed that ADP, ATP, NAD+, Taurine and Myo-inositol decreased, while Thr increased significantly. The comparison to corresponding control animals, demonstrated that only myo-inositol increased significantly. Integration of kidney metabolomics and transcriptomics indicated the involvement of processes related to glutathione metabolism, leukocyte trans-endothelial migration and antigen presentation during the established renal disease stage.Conclusion:The combined transcriptomics and metabolomics analysis revealed metabolic derangements in lupus-affected kidneys both during subclinical and overt LN. Deregulated tissue-levels of taurine and myo-inositol at the subclinical stage of the disease suggest aberrant renal biochemistry preceding the development of overt LN that may directly impact systemic metabolism and circulating metabolite levels.Figure 1.Pathways linked to cell metabolism were overrepresented among 3-month upregulated and 6-month lupus mice (F1) downregulated DEGS (differentially expressed genes) compared to controls (C57BL/6).Acknowledgements:This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390).Disclosure of Interests:None declared
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Bonartsev, A. P., G. A. Bonartseva, V. L. Myshkina, V. V. Voinova, T. K. Mahina, I. I. Zharkova, S. G. Yakovlev et al. « Biosynthesis of poly(3-hydroxybutyrateco-3-hydroxy-4-methylvalerate) by Strain Azotobacter chroococcum 7B ». Acta Naturae 8, no 3 (15 septembre 2016) : 77–87. http://dx.doi.org/10.32607/20758251-2016-8-3-77-87.
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Production of novel polyhydroxyalkanoates (PHAs), biodegradable polymers for biomedical applications, and biomaterials based on them is a promising trend in modern bioengineering. We studied the ability of an effective strain-producer Azotobacter chroococcum 7B to synthesize not only poly(3-hydroxybutyrate) homopolymer (PHB) and its main copolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), but also a novel copolymer, poly(3-hydroxybutyrate-co-3-hydroxy-4-methylvalerate) (PHB4MV). For the biosynthesis of PHB copolymers, we used carboxylic acids as additional carbon sources and monomer precursors in the chain of synthesized copolymers. The main parameters of these polymers biosynthesis were determined: strain-producer biomass yield, polymer yield, molecular weight and monomer composition of the synthesized polymers, as well as the morphology of A. chroococcum 7B bacterial cells. The physico-chemical properties of the polymers were studied using nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), contact angle test, and other methods. In vitro biocompatibility of the obtained polymers was investigated using stromal cells isolated from the bone marrow of rats with the XTT cell viability test. The synthesis of the novel copolymer PHB4MV and its chemical composition were demonstrated by NMR spectroscopy: the addition of 4-methylvaleric acid to the culture medium resulted in incorporation of 3-hydroxy-4-methylvalerate (3H4MV) monomers into the PHB polymer chain (0.6 mol%). Despite the low molar content of 3H4MV in the obtained copolymer, its physico-chemical properties were significantly different from those of the PHB homopolymer: it has lower crystallinity and a higher contact angle, i.e. the physico-chemical properties of the PHB4MV copolymer containing only 0.6 mol% of 3H4MV corresponded to a PHBV copolymer with a molar content ranging from 2.5% to 7.8%. In vitro biocompatibility of the obtained PHB4MV copolymer, measured in the XTT test, was not statistically different from the cell growth of PHB and PHBV polymers, which make its use possible in biomedical research and development.
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Geng, Huimin, Brice Tiret, Hua-Xin Gao, Cigall Kadoch, Ming Lu, Lingjing Chen, Ilwoo Park et al. « Application of Hyperpolarized 13C Magnetic Resonance Imaging to Detect Target Inhibition of NFkB Activation in Preclinical Patient-Derived Models of CNS Lymphoma ». Blood 132, Supplement 1 (29 novembre 2018) : 2840. http://dx.doi.org/10.1182/blood-2018-99-117625.
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Abstract To gain insights into the tumor microenvironment in primary and secondary CNS lymphomas, we applied LC/MS and GC/MS for differential metabolomic profiling of the cerebrospinal fluid (CSF) of CNS lymphoma patients compared to control subjects. Among 145 analytes identified, the majority were involved in energy metabolism; one of the most significantly upregulated metabolites in CNS lymphoma was lactate (1.8 fold, p<0.001). Subsequently we determined that baseline elevated CSF lactate, quantified by a Beckman Coulter Unicell Clinical Chemistry analyzer, correlated with short survival in three phase I investigations involving immunotherapy in relapsed CNS lymphoma (p<0.0001). (Blood Advances 2018). Given this, we hypothesize that tumor-associated lactate significantly contributes to the pathogenesis of CNS lymphoma as a potential mediator of tumor invasion as well as immunosuppression, and can serve as a novel biomarker in CNS lymphoma. To pursue this, we are testing the hypothesis that metabolic imaging techniques including proton magnetic resonance spectroscopy (MRS) and hyperpolarized (HP) 13C MRS can facilitate prognosis and response assessment to targeted therapies. Thus far we have applied these metabolic imaging approaches to preclinical murine models involving diffusely invasive, intracranial, patient-derived xenografts of CNS DLBCL in RAG-/- mice, to detect tumor-associated lactate production generated by infiltrating lymphoma. We demonstrated that each of these MRS approaches detect highly invasive lymphoma that is undetectable by conventional gadolinium-enhanced T1, T2 sequences, or diffusion-weighted imaging. Because of its ability to detect real-time changes in metabolic pathways, we focused on the application of HP13C pyruvate metabolic imaging as a non-invasive imaging tool for NF-kB pathway inhibition in CNS lymphoma using these models. We evaluated the metabolic response to AZ1495, a novel, CNS penetrant, orally-bioavailable inhibitor of IRAK4 kinase, comparing MYD88 wild type vs. MYD88 L265P mutant tumor models. Using a 14.1T imaging system for MR acquisition, we demonstrated similar tumor-associated production of HP 13C lactate in both MYD88wt and MY88 mutant tumors at 3 weeks post-implantation. We determined that while AZ1495 did not significantly impact lactate production in MYD88wt lymphoma, this agent significantly down-regulated tumor-associated HP pyruvate to lactate conversion (>47%) within 2 days in MYD88 mutant CNS lymphoma (p<0.02). (Figure 1). In parallel, we determined that AZ1495 potently antagonized phosphorylation of p65 REL-A selectively in intracranial xenografts harboring L265P MYD88 mutation. Transcriptional profiling by RNA-Seq demonstrated > 2-fold down-modulation of NF-kB gene expression at 4h of AZ1495 therapy, including transcripts encoding LDH-A as well as the catalytic subunit of PI3K, suggesting interaction with the B cell receptor pathway. Combination AZ1495 plus ibrutinib starting d+5 was synergistic in survival prolongation compared to AZ1495 monotherapy (p<0.003), ibrutinib monotherapy (p<0.005), or control gavage (p<0.002) in a MYD88 L265P mutant, clinically refractory patient-derived intracranial DLBCL xenograft model. Taken together, these data demonstrate the ability of HP13C MRI metabolic imaging to identify highly infiltrative CNS lymphoma, not detectable by conventional MR sequences, as well as its potential to provide an early, non-invasive pharmacodynamic biomarker of response in an NFkB pathway-specific manner, and to facilitate precision medicine in CNS lymphoma. Supported by the National Cancer Institute, the Leukemia and Lymphoma Society and by the Sandler Program for Breakthrough Biomedical Research. Disclosures Gao: Glaxo Smith Kline: Employment. Drew:AstraZeneca: Employment. Degorce:Astra Zeneca: Employment. Mayo:Astra Zeneca: Employment. Dillman:Astra Zeneca: Employment. Anjum:Astra Zeneca: Employment. Bloecher:Astra Zeneca: Employment. Rubenstein:Celgene: Research Funding; Genentech: Research Funding.
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Mishra, Vani, Gurudayal Prajapati, Vikas Baranwal et Rohit Kumar Mishra. « NMR-Based Metabolomic Imprinting Elucidates Macrophage Polarization of THP-1 Cell Lines Stimulated by Zinc Oxide Nanoparticles ». ACS Applied Bio Materials, 20 septembre 2022. http://dx.doi.org/10.1021/acsabm.2c00603.
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Li, Jinquan, Zhongxue Yuan, Huili Liu, Jianghua Feng et Zhong Chen. « Size-dependent tissue-specific biological effects of core–shell structured Fe3O4@SiO2–NH2 nanoparticles ». Journal of Nanobiotechnology 17, no 1 (décembre 2019). http://dx.doi.org/10.1186/s12951-019-0561-4.
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Abstract Background Understanding the in vivo size-dependent pharmacokinetics and toxicity of nanoparticles is crucial to determine their successful development. Systematic studies on the size-dependent biological effects of nanoparticles not only help to unravel unknown toxicological mechanism but also contribute to the possible biological applications of nanomaterial. Methods In this study, the biodistribution and the size-dependent biological effects of Fe3O4@SiO2–NH2 nanoparticles (Fe@Si-NPs) in three diameters (10, 20 and 40 nm) were investigated by ICP-AES, serum biochemistry analysis and NMR-based metabolomic analysis after intravenous administration in a rat model. Results Our findings indicated that biodistribution and biological activities of Fe@Si-NPs demonstrated the obvious size-dependent and tissue-specific effects. Spleen and liver are the target tissues of Fe@Si-NPs, and 20 nm of Fe@Si-NPs showed a possible longer blood circulation time. Quantitative biochemical analysis showed that the alterations of lactate dehydrogenase (LDH) and uric acid (UA) were correlated to some extent with the sizes of Fe@Si-NPs. The untargeted metabolomic analyses of tissue metabolomes (kidney, liver, lung, and spleen) indicated that different sizes of Fe@Si-NPs were involved in the different biochemical mechanisms. LDH, formate, uric acid, and GSH related metabolites were suggested as sensitive indicators for the size-dependent toxic effects of Fe@Si-NPs. The findings from serum biochemical analysis and metabolomic analysis corroborate each other. Thus we proposed a toxicity hypothesis that size-dependent NAD depletion may occur in vivo in response to nanoparticle exposure. To our knowledge, this is the first report that links size-dependent biological effects of nanoparticles with in vivo NAD depletion in rats. Conclusion The integrated metabolomic approach is an effective tool to understand physiological responses to the size-specific properties of nanoparticles. Our results can provide a direction for the future biological applications of Fe@Si-NPs.
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Al-Mutawa, Yousef K., Anne Herrmann, Catriona Corbishley, Paul D. Losty, Marie Phelan et Violaine Sée. « Effects of hypoxic preconditioning on neuroblastoma tumour oxygenation and metabolic signature in a chick embryo model ». Bioscience Reports 38, no 4 (29 août 2018). http://dx.doi.org/10.1042/bsr20180185.
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Hypoxia episodes and areas in tumours have been associated with metastatic dissemination and poor prognosis. Given the link between tumour tissue oxygen levels and cellular metabolic activity, we hypothesised that the metabolic profile between metastatic and non-metastatic tumours would reveal potential new biomarkers and signalling cues. We have used a previously established chick embryo model for neuroblastoma growth and metastasis, where the metastatic phenotype can be controlled by neuroblastoma cell hypoxic preconditioning (3 days at 1% O2). We measured, with fibre-optic oxygen sensors, the effects of the hypoxic preconditioning on the tumour oxygenation, within tumours formed by SK-N-AS cells on the chorioallantoic membrane (CAM) of chick embryos. We found that the difference between the metastatic and non-metastatic intratumoural oxygen levels was small (0.35% O2), with a mean below 1.5% O2 for most tumours. The metabolomic profiling, using NMR spectroscopy, of neuroblastoma cells cultured in normoxia or hypoxia for 3 days, and of the tumours formed by these cells showed that the effects of hypoxia in vitro did not compare with in vivo tumours. One notable difference was the high levels of the glycolytic end-products triggered by hypoxia in vitro, but not by hypoxia preconditioning in tumours, likely due to the very high basal levels of these metabolites in tumours compared with cells. In conclusion, we have identified high levels of ketones (3-hydroxybutyrate), lactate and phosphocholine in hypoxic preconditioned tumours, all known to fuel tumour growth, and we herein point to the poor relevance of in vitro metabolomic experiments for cancer research.
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Castellano-Escuder, Pol, Raúl González-Domínguez, David S. Wishart, Cristina Andrés-Lacueva et Alex Sánchez-Pla. « FOBI : an ontology to represent food intake data and associate it with metabolomic data ». Database 2020 (1 janvier 2020). http://dx.doi.org/10.1093/databa/baaa033.
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Abstract Nutrition research can be conducted by using two complementary approaches: (i) traditional self-reporting methods or (ii) via metabolomics techniques to analyze food intake biomarkers in biofluids. However, the complexity and heterogeneity of these two very different types of data often hinder their analysis and integration. To manage this challenge, we have developed a novel ontology that describes food and their associated metabolite entities in a hierarchical way. This ontology uses a formal naming system, category definitions, properties and relations between both types of data. The ontology presented is called FOBI (Food-Biomarker Ontology) and it is composed of two interconnected sub-ontologies. One is a ’Food Ontology’ consisting of raw foods and ‘multi-component foods’ while the second is a ‘Biomarker Ontology’ containing food intake biomarkers classified by their chemical classes. These two sub-ontologies are conceptually independent but interconnected by different properties. This allows data and information regarding foods and food biomarkers to be visualized in a bidirectional way, going from metabolomics to nutritional data or vice versa. Potential applications of this ontology include the annotation of foods and biomarkers using a well-defined and consistent nomenclature, the standardized reporting of metabolomics workflows (e.g. metabolite identification, experimental design) or the application of different enrichment analysis approaches to analyze nutrimetabolomic data. Availability: FOBI is freely available in both OWL (Web Ontology Language) and OBO (Open Biomedical Ontologies) formats at the project’s Github repository (https://github.com/pcastellanoescuder/FoodBiomarkerOntology) and FOBI visualization tool is available in https://polcastellano.shinyapps.io/FOBI_Visualization_Tool/.
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Korn, Sophie M., Roderick Lambertz, Boris Fürtig, Martin Hengesbach, Frank Löhr, Christian Richter, Harald Schwalbe, Julia E. Weigand, Jens Wöhnert et Andreas Schlundt. « 1H, 13C, and 15N backbone chemical shift assignments of the C-terminal dimerization domain of SARS-CoV-2 nucleocapsid protein ». Biomolecular NMR Assignments, 3 décembre 2020. http://dx.doi.org/10.1007/s12104-020-09995-y.
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AbstractThe current outbreak of the highly infectious COVID-19 respiratory disease is caused by the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). To fight the pandemic, the search for promising viral drug targets has become a cross-border common goal of the international biomedical research community. Within the international Covid19-NMR consortium, scientists support drug development against SARS-CoV-2 by providing publicly available NMR data on viral proteins and RNAs. The coronavirus nucleocapsid protein (N protein) is an RNA-binding protein involved in viral transcription and replication. Its primary function is the packaging of the viral RNA genome. The highly conserved architecture of the coronavirus N protein consists of an N-terminal RNA-binding domain (NTD), followed by an intrinsically disordered Serine/Arginine (SR)-rich linker and a C-terminal dimerization domain (CTD). Besides its involvement in oligomerization, the CTD of the N protein (N-CTD) is also able to bind to nucleic acids by itself, independent of the NTD. Here, we report the near-complete NMR backbone chemical shift assignments of the SARS-CoV-2 N-CTD to provide the basis for downstream applications, in particular site-resolved drug binding studies.
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Cacciatore, Stefano, Martha Wium, Cristina Licari, Aderonke Ajayi-Smith, Lorenzo Masieri, Chanelle Anderson, Azola Samkele Salukazana et al. « Inflammatory metabolic profile of South African patients with prostate cancer ». Cancer & ; Metabolism 9, no 1 (3 août 2021). http://dx.doi.org/10.1186/s40170-021-00265-6.
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Abstract Background Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail. Identification of new metabolic biomarkers of inflammation may improve diagnosis of patients with aggressive PCa. Methods Plasma samples were profiled from 41 South African men with PCa using nuclear magnetic resonance (NMR) spectroscopy. A total of 41 features, including metabolites, lipid classes, total protein, and the inflammatory NMR markers, GlycA, and GlycB, were quantified from each NMR spectrum. The Bruker’s B.I.-LISA protocols were used to characterize 114 parameters related to the lipoproteins. The unsupervised KODAMA method was used to stratify the patients of our cohort based on their metabolic profile. Results We found that the plasma of patients with very high risk, aggressive PCa and high level of C-reactive protein have a peculiar metabolic phenotype (metabotype) characterized by extremely high levels of GlycA and GlycB. The inflammatory processes linked to the higher level of GlycA and GlycB are characterized by a deep change of the plasma metabolome that may be used to improve the stratification of patients with PCa. We also identified a not previously known relationship between high values of VLDL and low level of GlycB in a different metabotype of patients characterized by lower-risk PCa. Conclusions For the first time, a portrait of the metabolic changes in African men with PCa has been delineated indicating a strong association between inflammation and metabolic profiles. Our findings indicate how the metabolic profile could be used to identify those patients with high level of inflammation, characterized by aggressive PCa and short life expectancy. Integrating a metabolomic analysis as a tool for patient stratification could be important for opening the door to the development of new therapies. Further investigations are needed to understand the prevalence of an inflammatory metabotype in patients with aggressive PCa.
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Chua, Kah-Ooi, Iqra Fatima, Yin Yin Lau, Kar Wai Hong, Wai-Fong Yin, Andrei Mardaryev, Kok-Gan Chan et Chien-Yi Chang. « Bacterial microbiome of faecal samples of naked mole-rat collected from the toilet chamber ». BMC Research Notes 15, no 1 (18 mars 2022). http://dx.doi.org/10.1186/s13104-022-06000-8.
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Abstract Objective The naked mole rats (NMRs, Heterocephalus glaber) are subterranean rodents that belong to the family Bathyergidae. They gained the attention of the scientific community for their exceptionally long lifespan of up to 30 years and have become an animal model of biomedical research on neurodegenerative diseases, aging and cancer. NMRs dig and survive in a maze of underground tunnels and chambers and demarcate toilet chambers for defecation and urination. Due to their coprophagic behaviours, we believed that the toilet chamber might play a role in maintaining optimal health of the NMRs. A 16S rRNA gene amplicon sequencing was performed to characterize the bacterial microbiome of faecal samples collected from the toilet chamber of a laboratory NMR colony. Results Four faecal samples were collected at different time points from the same toilet chamber of a laboratory NMR colony for analysis. The 16S rRNA gene amplicon sequencing revealed that bacterial phyla Firmicutes and Bacteroidetes were the dominant taxa in the bacterial microbiome of NMRs. The relative abundance of the bacterial taxa shifted substantially between time points, indicating a dynamic microbiome in the toilet chamber. The data provided an insight to the faecal microbiome of NMRs in the toilet chamber.
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Learte-Aymamí, Soraya, Pau Martin-Malpartida, Lorena Roldán-Martín, Giuseppe Sciortino, José R. Couceiro, Jean-Didier Maréchal, Maria J. Macias, José L. Mascareñas et M. Eugenio Vázquez. « Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide ». Communications Chemistry 5, no 1 (23 juin 2022). http://dx.doi.org/10.1038/s42004-022-00691-7.
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AbstractRAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II). NMR spectroscopy and MD studies demonstrate that Pd(II) has a nucleating effect that facilitates the access to the bioactive α-helical conformation. The binding can be suppressed by an external metal chelator and recovered again by the addition of more Pd(II), making this system the first switchable KRAS binder, and demonstrates that folding-upon-binding mechanisms can operate in metal-nucleated peptides. In vitro experiments show that the metallopeptide can efficiently internalize into living cells and inhibit the MAPK kinase cascade.