-
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 -
Magnetic Resonance in Medicine Jun 2023To quantify the variations of the power-law dependences on diffusion time t or gradient frequency of extracellular water diffusion measured by diffusion MRI (dMRI).
PURPOSE
To quantify the variations of the power-law dependences on diffusion time t or gradient frequency of extracellular water diffusion measured by diffusion MRI (dMRI).
METHODS
Model cellular systems containing only extracellular water were used to investigate the dependence of , the extracellular diffusion coefficient. Computer simulations used a randomly packed tissue model with realistic intracellular volume fractions and cell sizes. DMRI measurements were performed on samples consisting of liposomes containing heavy water(D O, deuterium oxide) dispersed in regular water (H O). was obtained over a broad range (∼1-1000 ms) and then fit power-law equations and .
RESULTS
Both simulated and experimental results suggest that no single power-law adequately describes the behavior of over the range of diffusion times of most interest in practical dMRI. Previous theoretical predictions are accurate over only limited ranges; for example, is valid only for short times, whereas or is valid only for long times but cannot describe other ranges simultaneously. For the specific range of 5-70 ms used in typical human dMRI measurements, matches the data well empirically.
CONCLUSION
The optimal power-law fit of extracellular diffusion varies with diffusion time. The dependency obtained at short or long limits cannot be applied to typical dMRI measurements in human cancer or liver. It is essential to determine the appropriate diffusion time range when modeling extracellular diffusion in dMRI-based quantitative microstructural imaging.
Topics: Humans; Diffusion Magnetic Resonance Imaging; Neoplasms; Diffusion; Models, Biological; Computer Simulation
PubMed: 36740894
DOI: 10.1002/mrm.29594 -
RSC Advances Aug 2022Deuterium oxide (DO) is a special variety of water that serves as a crucial resource in a range of applications, but it is a costly and unusual resource. We therefore...
Deuterium oxide (DO) is a special variety of water that serves as a crucial resource in a range of applications, but it is a costly and unusual resource. We therefore developed a new DO concentration system that combines a polymer electrolyte water electrolyzer and a catalytic combustor for recycling used DO. In this study, 1.6 L of used DO, with a concentration of 93.1%, was electrolyzed for 13.6 h to obtain 0.62 L of DO, with a concentration of 99.3%. In addition, the recombined water obtained by burning electrolytic gas using the catalytic combustor was also electrolyzed for 8.8 h to obtain 0.22 L of DO, with a concentration of 99.0%. The estimated separation factor of this electrolyzer at 25 °C was 3.6, which is very close to the equilibrium constant of the water/hydrogen isotope exchange reaction. Recycled DO was used as a deuterium source for the deuteration reaction of sodium octanoate, and 93.6% deuterated sodium octanoate was obtained. It is concluded that there were no impurities in the recycled DO that interfered with the deuteration reaction. These results can lead to the development of a cost-effective deuteration method for these materials.
PubMed: 36128371
DOI: 10.1039/d2ra04369f -
Cancers Feb 2021There are two stable isotopes of hydrogen, protium (H) and deuterium (H; D). Cellular stress response dysregulation in cancer represents both a major pathological...
There are two stable isotopes of hydrogen, protium (H) and deuterium (H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact of deuterium (H)-stress on cancer cells remain largely unexplored. We have examined the anti-proliferative and apoptogenic effects of deuterium oxide (DO; 'heavy water') together with stress response gene expression profiling in panels of malignant melanoma (A375, A375, G361, LOX-IMVI), and pancreatic ductal adenocarcinoma (PANC-1, Capan-2, or MIA PaCa-2) cells with inclusion of human diploid Hs27 skin fibroblasts. Moreover, we have examined the efficacy of DO-based pharmacological intervention in murine models of human melanoma tumor growth and metastasis. DO-induction of apoptosis was substantiated by AV-PI flow cytometry, immunodetection of PARP-1, and pro-caspase 3 cleavage, and rescue by pan-caspase inhibition. Differential array analysis revealed early modulation of stress response gene expression in both A375 melanoma and PANC-1 adenocarcinoma cells elicited by DO (90%; ≤6 h) (upregulated: , , , , , , or (up to 9-fold; < 0.01)) confirmed by independent RT-qPCR analysis. Immunoblot analysis revealed rapid onset of DO-induced stress response phospho-protein activation (p-ERK, p-JNK, p-eIF2α, or p-H2AX) or attenuation (p-AKT). Feasibility of DO-based chemotherapeutic intervention (drinking water (30% w/w)) was demonstrated in a severe combined immunodeficiency (SCID) mouse melanoma metastasis model using luciferase-expressing A375-Luc2 cells. Lung tumor burden (visualized by bioluminescence imaging) was attenuated by DO, and inhibition of invasiveness was also confirmed in an in vitro Matrigel transwell invasion assay. DO supplementation also suppressed tumor growth in a murine xenograft model of human melanoma, and median survival was significantly increased without causing adverse effects. These data demonstrate for the first time that systemic DO administration impairs growth and metastasis of malignant melanoma through the pharmacological induction of deuterium (H)-stress.
PubMed: 33546433
DOI: 10.3390/cancers13040605 -
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 -
Translational Exercise Biomedicine May 2024'OMICs encapsulates study of scaled data acquisition, at the levels of DNA, RNA, protein, and metabolite species. The broad objectives of OMICs in biomedical exercise... (Review)
Review
OBJECTIVES
'OMICs encapsulates study of scaled data acquisition, at the levels of DNA, RNA, protein, and metabolite species. The broad objectives of OMICs in biomedical exercise research are multifarious, but commonly relate to biomarker development and understanding features of exercise adaptation in health, ageing and metabolic diseases.
METHODS
This field is one of exponential technical (i.e., depth of feature coverage) and scientific (i.e., in health, metabolic conditions and ageing, multi-OMICs) progress adopting and approaches.
RESULTS
Key findings in exercise biomedicine have led to the identification of OMIC features linking to heritability or adaptive responses to exercise e.g., the forging of GWAS/proteome/metabolome links to cardiovascular fitness and metabolic health adaptations. The recent addition of stable isotope tracing to proteomics ('dynamic proteomics') and metabolomics ('fluxomics') represents the next phase of state-of-the-art in 'OMICS.
CONCLUSIONS
These methods overcome limitations associated with point-in-time 'OMICs and can be achieved using substrate-specific tracers or deuterium oxide (DO), depending on the question; these methods could help identify how individual protein turnover and metabolite flux may explain exercise responses. We contend application of these methods will shed new light in translational exercise biomedicine.
PubMed: 38660119
DOI: 10.1515/teb-2024-2006 -
Deuterium oxide dilution and body composition in overweight and obese schoolchildren aged 6-9 years.Jornal de Pediatria 2016To correlate different methods of body composition assessment in overweight or obese schoolchildren, using deuterium oxide (D2O) dilution as a reference.
OBJECTIVE
To correlate different methods of body composition assessment in overweight or obese schoolchildren, using deuterium oxide (D2O) dilution as a reference.
METHODS
Percentage of total body water (%TBW), fat free mass (%FFM), and body fat (%BF) were assessed by D2O and tetrapolar electrical bioimpedance analysis (BIA) in 54 obese and overweight students aged 6-9 years. Skinfold thickness (ST), body mass index (BMI), conicity index (CI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip (WHR) ratio were also used.
RESULTS
Mean values for body composition were 38.4%±8.4% BF, 44.9%±6.1% TBW and 61.6%±8.4% FFM. There was no significant difference in body weight, body fat mass (FM), TBW, and FFM between genders. Regarding D2O, ST underestimated %BF, and overestimated %FFM in both genders (p<0.05). BIA overestimated %TBW in the group as a whole and in males (p<0.05). The only positive and strong correlations occurred in females regarding the WC (σ=0.679), CI (r=0.634), and WHtR (r=0.666).
CONCLUSIONS
In this sample of obese and overweight children, there were strong correlations between body composition measured by D2O and some indices and anthropometric indicators in females, but there was no positive and strong correlation of fat tissue with the indices/indicators at all ages and in both genders.
Topics: Anthropometry; Body Composition; Body Mass Index; Body Water; Child; Deuterium Oxide; Electric Impedance; Female; Humans; Indicator Dilution Techniques; Male; Obesity; Overweight; Sex Factors; Skinfold Thickness; Waist Circumference; Waist-Height Ratio
PubMed: 26247920
DOI: 10.1016/j.jped.2015.03.007 -
The Journal of Physiology May 2017Stable isotope tracers have been invaluable assets in physiological research for over 80 years. The application of substrate-specific stable isotope tracers has... (Review)
Review
Stable isotope tracers have been invaluable assets in physiological research for over 80 years. The application of substrate-specific stable isotope tracers has permitted exquisite insight into amino acid, fatty-acid and carbohydrate metabolic regulation (i.e. incorporation, flux, and oxidation, in a tissue-specific and whole-body fashion) in health, disease and response to acute and chronic exercise. Yet, despite many breakthroughs, there are limitations to 'substrate-specific' stable isotope tracers, which limit physiological insight, e.g. the need for intravenous infusions and restriction to short-term studies (hours) in controlled laboratory settings. In recent years significant interest has developed in alternative stable isotope tracer techniques that overcome these limitations, in particular deuterium oxide (D O or heavy water). The unique properties of this tracer mean that through oral administration, the turnover and flux through a number of different substrates (muscle proteins, lipids, glucose, DNA (satellite cells)) can be monitored simultaneously and flexibly (hours/weeks/months) without the need for restrictive experimental control. This makes it uniquely suited for the study of 'real world' human exercise physiology (amongst many other applications). Moreover, using D O permits evaluation of turnover of plasma and muscle proteins (e.g. dynamic proteomics) in addition to metabolomics (e.g. fluxomics) to seek molecular underpinnings, e.g. of exercise adaptation. Here, we provide insight into the role of stable isotope tracers, from substrate-specific to novel D O approaches, in facilitating our understanding of metabolism. Further novel potential applications of stable isotope tracers are also discussed in the context of integration with the snowballing field of 'omic' technologies.
Topics: Deuterium Oxide; Exercise; Gas Chromatography-Mass Spectrometry; Humans; Magnetic Resonance Imaging; Metabolomics; Muscle, Skeletal; Renal Elimination; Tissue Distribution
PubMed: 27610950
DOI: 10.1113/JP272277 -
Ageing Research Reviews Nov 2014Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or... (Review)
Review
Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or proteostasis) is important for slowing the aging process. Since proteostasis is a dynamic process, monitoring it is not a simple task and requires use of appropriate methods. This review will introduce methods to assess protein and DNA synthesis using deuterium oxide (D2O), and how protein and DNA synthesis outcomes provide insight into proteostatic mechanisms. Finally, we provide a discussion on how these assessments of protein and DNA synthesis are "mechanistic" investigations and provide an appropriate framework for the further development of slowed aging treatments.
Topics: Age Factors; Aging; Animals; Caloric Restriction; DNA Replication; Deuterium Oxide; Homeostasis; Humans; Litter Size; Protein Biosynthesis; Proteins; Sirolimus; Time Factors
PubMed: 25283966
DOI: 10.1016/j.arr.2014.09.005 -
Chemico-biological Interactions Aug 2019Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the... (Review)
Review
Carbamates are esters of substituted carbamic acids that react with acetylcholinesterase (AChE) by initially transferring the carbamoyl group to a serine residue in the enzyme active site accompanied by loss of the carbamate leaving group followed by hydrolysis of the carbamoyl enzyme. This hydrolysis, or decarbamoylation, is relatively slow, and half-lives of carbamoylated AChEs range from 4 min to more than 30 days. Therefore, carbamates are effective AChE inhibitors that have been developed as insecticides and as therapeutic agents. In this report, we review recent data showing that decarbamoylation rate constants are independent of the ester leaving group for a series of carbamic acid esters with the same carbamoyl group and that decarbamoylation rate constants decreased by 800-fold when the alkyl substituents on the carbamoyl group increased in size from N-monomethyl- to N,N-diethyl-. We also review data showing that solvent deuterium oxide isotope effects for decarbamoylation decreased from 2.8 for N-monomethylcarbamoyl AChE to 1.1 for N,N-diethylcarbamoyl AChE, indicating a shift in the rate-limiting step from general acid-base catalysis to a likely conformational change in the distorted active site in N,N-diethylcarbamoyl AChE. The nature of such a conformational change is suggested from X-ray crystal structures of AChE phosphorylated by paraoxon.
Topics: Acetylcholinesterase; Carbamates; Catalytic Domain; Crystallography, X-Ray; Kinetics; Paraoxon
PubMed: 31175846
DOI: 10.1016/j.cbi.2019.06.004