-
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 -
Angewandte Chemie (International Ed. in... Jul 2023Different from classical allylic substitutions that require a vicinal leaving group, an olefin bearing a remote leaving group is scarcely viewed as a potential...
Different from classical allylic substitutions that require a vicinal leaving group, an olefin bearing a remote leaving group is scarcely viewed as a potential allylation substrate. Herein, we describe feasible protocols to achieve regiodivergent allylic C-H functionalizations via palladium-catalyzed remote substitution, which provides a novel strategy for the seldomly studied migratory Tsuji-Trost reaction. Dictated by a suitable ligand, a process that involved 4,3-hydrofunctionalization of the generated conjugated diene intermediate via metal walking is observed in generally >20 : 1 regioselectivity. Unexpectedly, a related 1,4-hydrofunctionalization pathway is found to be a major route with a newly synthesized electron-rich bisphosphine ligand, which challenges the conventional viewpoint on the potential regioselectivity of hydrofunctionalizations of linear internal conjugated dienes via η -substitution. A series of deuterium experiments and kinetic studies provide a preliminary insight into the potential catalytic cycle.
PubMed: 36920655
DOI: 10.1002/anie.202301556 -
Magnetic Resonance in Medicine Dec 2023X-nuclei (also called non-proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of...
PURPOSE
X-nuclei (also called non-proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of x-nuclei examination warrants the need of a robust and versatile tool improving image quality for diagnostic use. In this work, we compare a novel denoising method with fewer inputs to the current state-of-the-art denoising method.
METHODS
Denoising approaches were compared on human acquisitions of sodium ( Na) brain, deuterium ( H) brain, carbon ( C) heart and brain, and simulated dynamic hyperpolarized C brain scans, with and without additional noise. The current state-of-the-art denoising method Global-local higher order singular value decomposition (GL-HOSVD) was compared to the few-input method tensor Marchenko-Pastur principal component analysis (tMPPCA). Noise-removal was quantified by residual distributions, and statistical analyses evaluated the differences in mean-square-error and Bland-Altman analysis to quantify agreement between original and denoised results of noise-added data.
RESULTS
GL-HOSVD and tMPPCA showed similar performance for the variety of x-nuclei data analyzed in this work, with tMPPCA removing ˜5% more noise on average over GL-HOSVD. The mean ratio between noise-added and denoising reproducibility coefficients of the Bland-Altman analysis when compared to the original are also similar for the two methods with 3.09 ± 1.03 and 2.83 ± 0.79 for GL-HOSVD and tMPPCA, respectively.
CONCLUSION
The strength of tMPPCA lies in the few-input approach, which generalizes well to different data sources. This makes the use of tMPPCA denoising a robust and versatile tool in x-nuclei imaging improvements and the preferred denoising method.
PubMed: 37526128
DOI: 10.1002/mrm.29817 -
Chemical Communications (Cambridge,... Oct 2023All aromatic C-H bonds of triphenylphosphine (PPh) were efficiently replaced by C-D bonds using Ru/C and Ir/C co-catalysts in 2-PrOH and DO, an inexpensive deuterium...
All aromatic C-H bonds of triphenylphosphine (PPh) were efficiently replaced by C-D bonds using Ru/C and Ir/C co-catalysts in 2-PrOH and DO, an inexpensive deuterium source. Furthermore, non-radioactive and safe deuterium-incorporated Mito-Q (drug candidate) was prepared from deuterated PPh and used for the live-cell Raman imaging to evaluate the mitochondrial uptake.
PubMed: 37721453
DOI: 10.1039/d3cc04410f -
PeerJ 2023Hydrogen sulfide (HS), as an endogenous gas signaling molecule, plays an important role in plant growth regulation and resistance to abiotic stress. This study aims to...
Hydrogen sulfide (HS), as an endogenous gas signaling molecule, plays an important role in plant growth regulation and resistance to abiotic stress. This study aims to investigate the mechanism of exogenous HS on the growth and development of seedlings under salt stress and to determine the optimal concentration for foliar application. To investigate the regulatory effects of exogenous HS (donor sodium hydrosulfide, NaHS) at concentrations ranging from 0 to 1 mM on reactive oxygen species (ROS), antioxidant system, and osmoregulation in seedlings under 300 mM NaCl stress. The growth of seedlings was inhibited by salt stress, which resulted in a decrease in the leaf relative water content (LRWC), specific leaf area (SLA), and soluble sugar content in leaves, elevated activity levels of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and accumulated superoxide anion (O), proline, malondialdehyde (MDA), and soluble protein content in leaves; and increased L-cysteine desulfhydrase (LCD) activity and endogenous HS content. This indicated that a high level of ROS was produced in the leaves of seedlings and seriously affected the growth and development of seedlings. The exogenous application of different concentrations of NaHS reduced the content of O , proline and MDA, increased the activity of antioxidant enzymes and the content of osmoregulators (soluble sugars and soluble proteins), while the LCD enzyme activity and the content of endogenous HS were further increased with the continuous application of exogenous HS. The inhibitory effects of salt stress on the growth rate of plant height and ground diameter, the LRWC, biomass, and SLA were effectively alleviated. A comprehensive analysis showed that the LRWC, POD, and proline could be used as the main indicators to evaluate the alleviating effect of exogenous HS on seedlings under salt stress. The optimal concentration of exogenous HS for seedlings under salt stress was 0.025 mM. This study provides an important theoretical foundation for understanding the salt tolerance mechanism of and for cultivating high-quality germplasm resources.
Topics: Salt Tolerance; Hydrogen Sulfide; Reactive Oxygen Species; Seedlings; Antioxidants; Salt Stress; Peroxidase; Peroxidases; Coloring Agents; Deuterium
PubMed: 37641597
DOI: 10.7717/peerj.15881 -
Talanta Dec 2023Deuterium substitution provides various benefits in drug molecules, including improvement in pharmacokinetic properties, reduction of toxicity, reduction of...
Deuterium substitution provides various benefits in drug molecules, including improvement in pharmacokinetic properties, reduction of toxicity, reduction of epimerization, etc. Also, it has been shown that the position of deuterium substitution affects the properties of drug molecules. Therefore, it is important to study low molecular weight deuterated isotopologues which constitute the deuterated pool and are building blocks of larger deuterated molecules. The effect of the position and number of deuterium atoms on the retention of 23 deuterated isotopologues on two gas chromatography stationary phases of different polarities was evaluated. It was observed that the ratio of calculated chromatographic isotope effects resulting from a deuterium atom connected to an sp vs. an sp hybridized carbon was more on the polar IL-111i stationary phase compared to the nonpolar PDMS-5, for each group of isotopologues. Also, a compound with a deuterium atom connected to an sp hybridized carbon always had greater retention than the analogous compound where deuterium was connected to an sp hybridized carbon. The van't Hoff plots for all analytes showed that the effect of entropy was almost negligible in the separation of deuterated vs. protiated isotopologues, thus these separations were mainly enthalpy driven.
PubMed: 37442006
DOI: 10.1016/j.talanta.2023.124857 -
BioRxiv : the Preprint Server For... Oct 2023The folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain...
UNLABELLED
The folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. The ABCC transporters core consists of two nucleotide binding domains (NBD1,2) and transmembrane domains (TMD1,2). Using molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization of NBD1-TMD1/2 interfaces can compromise or facilitate the CFTR(ABCC7)-, MRP1(ABCC1)-, and ABCC6-transporters posttranslational coupled domain-folding in the endoplasmic reticulum. Allosteric or orthosteric binding of VX-809 and/or VX-445 folding correctors to TMD1/2 can rescue kinetically trapped CFTR post-translational folding intermediates of cystic fibrosis (CF) mutants of NBD1 or TMD1 by global rewiring inter-domain allosteric-networks. We propose that dynamic allosteric domain-domain communications not only regulate ABCC-transporters function but are indispensable to tune the folding landscape of their post-translational intermediates. These allosteric networks can be compromised by CF-mutations, and reinstated by correctors, offering a framework for mechanistic understanding of ABCC-transporters (mis)folding.
ONE-SENTENCE SUMMARY
Allosteric interdomain communication and its modulation are critical determinants of ABCC-transporters post-translational conformational biogenesis, misfolding, and pharmacological rescue.
PubMed: 37905074
DOI: 10.1101/2023.10.19.563107 -
Anti-cancer Drugs Nov 2023Colorectal cancer is one of the most common types of cancer in the world and the study of the role of nutrients in preventing or inhibiting the growth of this cancer is...
Colorectal cancer is one of the most common types of cancer in the world and the study of the role of nutrients in preventing or inhibiting the growth of this cancer is of interest to scientists. In this article, the synergistic effect of deuterium-depleted water(DDW) and crocin at specific concentrations on HT-29 cells was investigated. In this regard, HT-29 cells were grown in RPMI medium containing DDW, alone and in combination with crocin for 24, 48 and 72 h. Cell viability, cell cycle changes and antioxidant enzymes status were determined by MTT assay, flow cytometry and quantitative luminescence methods, respectively. The results of these analyses proved the cell growth inhibitory effect of deuterium alone and its synergistic effect in combination with crocin. The cell cycle analysis showed an increase in the number of cells in the G0 and G1 phases whereas there was a decrease in the number of cells in the S, G2 and M phases. The activities of superoxide dismutase and catalase enzymes also decreased compared to the control group that is a reason to increase Malonyl dialdehyde factor. The results suggested that a combination of DDW and crocin can open a new strategic approach in the prevention and treatment of colorectal cancer.
Topics: Humans; Deuterium; HT29 Cells; Water; Colorectal Neoplasms
PubMed: 36847076
DOI: 10.1097/CAD.0000000000001512 -
Chirality Mar 2024Synthetic therapeutic peptides are a complex and popular class of pharmaceuticals. In recent years, peptides with proven therapeutic activity have gained significant... (Review)
Review
Synthetic therapeutic peptides are a complex and popular class of pharmaceuticals. In recent years, peptides with proven therapeutic activity have gained significant interest in the market. The determination of synthetic peptide enantiomeric purity plays a critical role in the evaluation of the quality of the medicine. Since racemization is one of the most common side reactions occurring in AAs or peptides, enantiomeric impurities such as D-isomers can form during the peptide synthesis or can be introduced from the starting materials (e.g., AAs). The therapeutic effect of a synthetic or semi-synthetic bioactive peptide molecule depends on its AA enantiomeric purity and secondary/tertiary structure. Therefore, the enantiomeric purity determination for synthetic peptides is supportive for interpreting unwanted therapeutic effects and determining the quality of synthetic peptide therapeutics. However, enantiomeric purity analysis encounters formidable analytical challenges during chromatographic separation, as D/L isomers have identical physical-chemical properties except stereochemical configuration. To ensure peptides AA stereochemical configuration whether in the free or bound state, sensitive and reproducible quantitative analytical method is mandatory. In this regard, numerous analytical techniques were emerged for the quantification of D-isomeric impurities in synthetic peptides, but still, very few reports are available in the literature. Thus, the purpose of this paper is to provide an overview of the importance, regulatory requirements, and various analytical methods used for peptide enantiomeric purity determination. In addition, we discussed the available literature in terms of enantiomeric impurity detection, common hydrolysis procedural aspects, and different analytical strategies used for sample preparation.
Topics: Stereoisomerism; Isomerism; Hydrolysis; Peptides
PubMed: 38448043
DOI: 10.1002/chir.23652 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2023The ability of various hydrogen-bonded resorcinarene-based capsules to bind α,ω-alkylbisDABCOnium (DnD) guests of different lengths was investigated in solution and in...
The ability of various hydrogen-bonded resorcinarene-based capsules to bind α,ω-alkylbisDABCOnium (DnD) guests of different lengths was investigated in solution and in the gas-phase. While no host-guest interactions were detected in solution, encapsulation could be achieved in the charged droplets formed during electrospray ionisation (ESI). This included guests, which are far too long in their most stable conformation to fit inside the cavity of the capsules. A combination of three mass spectrometric techniques, namely, collision-induced dissociation, hydrogen/deuterium exchange, and ion-mobility mass spectrometry, together with computational modelling allow us to determine the binding mode of the DnD guests inside the cavity of the capsules. Significant distortions of the guest into horseshoe-like arrangements are required to optimise cation-π interactions with the host, which also adopt distorted geometries with partially open hydrogen-bonding seams when binding longer guests. Such quasi "spring-loaded" capsules can form in the charged droplets during the ESI process as there is no competition between guest encapsulation and ion pair formation with the counterions that preclude encapsulation in solution. The encapsulation complexes are sufficiently stable in the gas-phase - even when strained - because non-covalent interactions significantly strengthen in the absence of solvent.
PubMed: 37724745
DOI: 10.1002/chem.202302112