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Advances and prospects in deuterium metabolic imaging (DMI): a systematic review of in vivo studies.European Radiology Experimental Jun 2024Deuterium metabolic imaging (DMI) has emerged as a promising non-invasive technique for studying metabolism in vivo. This review aims to summarize the current... (Review)
Review
BACKGROUND
Deuterium metabolic imaging (DMI) has emerged as a promising non-invasive technique for studying metabolism in vivo. This review aims to summarize the current developments and discuss the futures in DMI technique in vivo.
METHODS
A systematic literature review was conducted based on the PRISMA 2020 statement by two authors. Specific technical details and potential applications of DMI in vivo were summarized, including strategies of deuterated metabolites detection, deuterium-labeled tracers and corresponding metabolic pathways in vivo, potential clinical applications, routes of tracer administration, quantitative evaluations of metabolisms, and spatial resolution.
RESULTS
Of the 2,248 articles initially retrieved, 34 were finally included, highlighting 2 strategies for detecting deuterated metabolites: direct and indirect DMI. Various deuterated tracers (e.g., [6,6'-H2]glucose, [2,2,2'-H3]acetate) were utilized in DMI to detect and quantify different metabolic pathways such as glycolysis, tricarboxylic acid cycle, and fatty acid oxidation. The quantifications (e.g., lactate level, lactate/glutamine and glutamate ratio) hold promise for diagnosing malignancies and assessing early anti-tumor treatment responses. Tracers can be administered orally, intravenously, or intraperitoneally, either through bolus administration or continuous infusion. For metabolic quantification, both serial time point methods (including kinetic analysis and calculation of area under the curves) and single time point quantifications are viable. However, insufficient spatial resolution remains a major challenge in DMI (e.g., 3.3-mL spatial resolution with 10-min acquisition at 3 T).
CONCLUSIONS
Enhancing spatial resolution can facilitate the clinical translation of DMI. Furthermore, optimizing tracer synthesis, administration protocols, and quantification methodologies will further enhance their clinical applicability.
RELEVANCE STATEMENT
Deuterium metabolic imaging, a promising non-invasive technique, is systematically discussed in this review for its current progression, limitations, and future directions in studying in vivo energetic metabolism, displaying a relevant clinical potential.
KEY POINTS
• Deuterium metabolic imaging (DMI) shows promise for studying in vivo energetic metabolism. • This review explores DMI's current state, limits, and future research directions comprehensively. • The clinical translation of DMI is mainly impeded by limitations in spatial resolution.
Topics: Humans; Deuterium; Animals
PubMed: 38825658
DOI: 10.1186/s41747-024-00464-y -
Polymers May 2023The work reports a number of results on the dynamics of swelling and inferred nanostructure of the ion-exchange polymer membrane Nafion in different aqueous solutions.... (Review)
Review
The work reports a number of results on the dynamics of swelling and inferred nanostructure of the ion-exchange polymer membrane Nafion in different aqueous solutions. The techniques used were photoluminescent and Fourier transform IR (FTIR) spectroscopy. The centers of photoluminescence were identified as the sulfonic groups localized at the ends of the perfluorovinyl ether (Teflon) groups that form the backbone of Nafion. Changes in deuterium content of water induced unexpected results revealed in the process of polymer swelling. In these experiments, deionized (DI) water (deuterium content 157 ppm) and deuterium depleted water (DDW) with deuterium content 3 PPM, were investigated. The strong hydration of sulfonic groups involves a competition between ortho- and para-magnetic forms of a water molecule. Deuterium, as it seems, adsorbs competitively on the sulfonic groups and thus can change the geometry of the sulfate bonds. With photoluminescent spectroscopy experiments, this is reflected in the unwinding of the polymer fibers into the bulk of the adjoining water on swelling. The unwound fibers do not tear off from the polymer substrate. They form a vastly extended "brush" type structure normal to the membrane surface. This may have implications for specificity of ion transport in biology, where the ubiquitous glycocalyx of cells and tissues invariably involves highly sulfated polymers such asheparan and chondroitin sulfate.
PubMed: 37177360
DOI: 10.3390/polym15092214 -
Acta Neuropathologica Communications Dec 2020Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and...
Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson's disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.
Topics: Animals; Axonal Transport; Behavior, Animal; Brain; Deuterium; Dopaminergic Neurons; Exploratory Behavior; Humans; Inflammation; Linoleic Acid; Mitochondria; Oxidative Stress; Parkinson Disease; Postural Balance; Rats; Rats, Transgenic; Substantia Nigra; alpha-Linolenic Acid; alpha-Synuclein
PubMed: 33308320
DOI: 10.1186/s40478-020-01090-6 -
Angewandte Chemie (International Ed. in... Jul 2022There is a constant need for deuterium-labelled products for multiple applications in life sciences and beyond. Here, a new class of heterogeneous catalysts is reported...
There is a constant need for deuterium-labelled products for multiple applications in life sciences and beyond. Here, a new class of heterogeneous catalysts is reported for practical deuterium incorporation in anilines, phenols, and heterocyclic substrates. The optimal material can be conveniently synthesised and allows for high deuterium incorporation using deuterium oxide as isotope source. This new catalyst has been fully characterised and successfully applied to the labelling of natural products as well as marketed drugs.
Topics: Aniline Compounds; Catalysis; Deuterium; Electrons; Manganese
PubMed: 35484978
DOI: 10.1002/anie.202202423 -
Trends in Biochemical Sciences Oct 2020Methodological improvements in both single particle cryo-electron microscopy (cryo-EM) and hydrogen/deuterium exchange mass spectrometry (HDX-MS) mean that the two... (Review)
Review
Methodological improvements in both single particle cryo-electron microscopy (cryo-EM) and hydrogen/deuterium exchange mass spectrometry (HDX-MS) mean that the two methods are being more frequently used together to tackle complex problems in structural biology. There are many benefits to this combination, including for the analysis of low-resolution density, for structural validation, in the analysis of individual proteins versus the same proteins in large complexes, studies of allostery, protein quality control during cryo-EM construct optimization, and in the study of protein movements/dynamics during function. As will be highlighted in this review, through careful considerations of potential sample and conformational heterogeneity, many joint studies have recently been demonstrated, and many future studies using this combination are anticipated.
Topics: Cryoelectron Microscopy; Hydrogen Deuterium Exchange-Mass Spectrometry; Proteins
PubMed: 32487353
DOI: 10.1016/j.tibs.2020.05.005 -
Journal of Inherited Metabolic Disease Jul 2022X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and...
X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C-ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to-date for ALD. Pioglitazone, an anti-diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPARγ agonism) and nongenomic (mitochondrial pyruvate carrier-MPC, long-chain acyl-CoA synthetase 4-ACSL4, inhibition). However, its use is limited by PPARγ-driven side effects (e.g. weight gain, edema). PXL065 is a clinical-stage deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonism but retains MPC activity. Here, we show that incubation of ALD patient-derived cells (both AMN and C-ALD) and glial cells from Abcd1-null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1-null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPARγ agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Animals; Deuterium; Fatty Acids; Fatty Acids, Nonesterified; Inflammation; Mice; Mice, Knockout; PPAR gamma; Pioglitazone
PubMed: 35510808
DOI: 10.1002/jimd.12510 -
Clinical Cancer Research : An Official... Dec 2023An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic...
PURPOSE
An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field MRI using deuterium-labeled molecules. The study aim was to use 2H tissue labeling and deuterium MRI at clinical field strength for tumor visualization and assessment of three anticancer therapies in pancreatic cancer model mice.
EXPERIMENTAL DESIGN
MIA PaCa-2 pancreatic carcinoma and C26 colorectal carcinoma models of BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days of free drinking of 30% D2O to track 2H distribution in tissues. 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration was also measured in MIA PaCa-2-bearing mice. Confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS, and histopathology were performed.
RESULTS
The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI, and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments.
CONCLUSIONS
Deuterium MRI at 1.5T proved feasible to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for preliminary assessment of radiotherapy and chemotherapy of cancer.
Topics: Humans; Mice; Animals; Water; Deuterium; Protons; Bevacizumab; Gemcitabine; Magnetic Resonance Imaging; Neoplasms
PubMed: 37732903
DOI: 10.1158/1078-0432.CCR-23-1635 -
Nature Communications Jun 2022Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using DO as the economical...
Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using DO as the economical deuterium source was reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external catalysts and tolerates high current, showing possible use in industrial applications.
Topics: Catalysis; Deuterium
PubMed: 35773255
DOI: 10.1038/s41467-022-31435-9 -
Molecules (Basel, Switzerland) Oct 2022The functional structure of proteins results from marginally stable folded conformations. Reversible unfolding, irreversible denaturation, and deterioration can be... (Review)
Review
The functional structure of proteins results from marginally stable folded conformations. Reversible unfolding, irreversible denaturation, and deterioration can be caused by chemical and physical agents due to changes in the physicochemical conditions of pH, ionic strength, temperature, pressure, and electric field or due to the presence of a cosolvent that perturbs the delicate balance between stabilizing and destabilizing interactions and eventually induces chemical modifications. For most proteins, denaturation is a complex process involving transient intermediates in several reversible and eventually irreversible steps. Knowledge of protein stability and denaturation processes is mandatory for the development of enzymes as industrial catalysts, biopharmaceuticals, analytical and medical bioreagents, and safe industrial food. Electrophoresis techniques operating under extreme conditions are convenient tools for analyzing unfolding transitions, trapping transient intermediates, and gaining insight into the mechanisms of denaturation processes. Moreover, quantitative analysis of electrophoretic mobility transition curves allows the estimation of the conformational stability of proteins. These approaches include polyacrylamide gel electrophoresis and capillary zone electrophoresis under cold, heat, and hydrostatic pressure and in the presence of non-ionic denaturing agents or stabilizers such as polyols and heavy water. Lastly, after exposure to extremes of physical conditions, electrophoresis under standard conditions provides information on irreversible processes, slow conformational drifts, and slow renaturation processes. The impressive developments of enzyme technology with multiple applications in fine chemistry, biopharmaceutics, and nanomedicine prompted us to revisit the potentialities of these electrophoretic approaches. This feature review is illustrated with published and unpublished results obtained by the authors on cholinesterases and paraoxonase, two physiologically and toxicologically important enzymes.
Topics: Protein Denaturation; Protein Conformation; Deuterium Oxide; Aryldialkylphosphatase; Electrophoresis, Polyacrylamide Gel; Cholinesterases; Biological Products; Thermodynamics; Protein Folding
PubMed: 36296453
DOI: 10.3390/molecules27206861 -
Nature May 2020The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine. Beyond their widespread use in spectroscopy, mass...
The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug, these processes are often unselective and the stereoisotopic purity can be difficult to measure. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.
Topics: Benzene; Chemistry Techniques, Synthetic; Cyclohexenes; Databases, Chemical; Deuterium; Kinetics; Molecular Structure; Pharmaceutical Preparations; Stereoisomerism; Tetrabenazine; Tungsten
PubMed: 32433618
DOI: 10.1038/s41586-020-2268-y