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Toxicology in Vitro : An International... Dec 2023Deuterium oxide (DO) or heavy water is known to have diverse biological activities and have a few therapeutic applications due to its limited toxicity to human subjects....
Heavy water (DO) induces autophagy-dependent apoptotic cell death in non-small cell lung cancer A549 cells by generating reactive oxygen species (ROS) upon microtubule disruption.
OBJECTIVE
Deuterium oxide (DO) or heavy water is known to have diverse biological activities and have a few therapeutic applications due to its limited toxicity to human subjects. In the present study, we investigated the mechanism of DO-induced cytotoxicity in non-small cell lung cancer A549 cells.
RESULTS
We found that DO-treatment resulted in cytotoxicity, cell cycle arrest, and apoptosis in A549 cells in a dose-dependent fashion. In contrast, limited cytotoxicity was observed in lung fibroblasts WI38 cells. Moreover, DO-treatment resulted in the disruption of the cellular microtubule network, accompanied by the generation of ROS. On further investigation, we observed that the intracellular ROS triggered autophagic responses in DO-treated cells, leading to apoptosis by inhibiting the oncogenic PI3K/ Akt/ mTOR signaling. DO-treatment was also found to enhance the efficacy of paclitaxel in A549 cells.
SIGNIFICANCE
DO induces autophagy-dependent apoptosis in A549 cells via ROS generation upon microtubule depolymerization and inhibition of PI3K/ Akt/ mTOR signaling. It augments the efficacy of other microtubule-targeting anticancer drug taxol, which indicates the potential therapeutic importance of DO as an anticancer agent either alone or in combination with other chemotherapeutic drugs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Reactive Oxygen Species; A549 Cells; Deuterium Oxide; Proto-Oncogene Proteins c-akt; Lung Neoplasms; TOR Serine-Threonine Kinases; Apoptosis; Autophagy; Microtubules; Phosphatidylinositol 3-Kinases
PubMed: 37751786
DOI: 10.1016/j.tiv.2023.105703 -
Gut Microbes Dec 2023Maternal secretor status has been shown to be associated with the presence of specific fucosylated human milk oligosaccharides (HMOs), and the impact of maternal...
Maternal secretor status has been shown to be associated with the presence of specific fucosylated human milk oligosaccharides (HMOs), and the impact of maternal secretor status on infant gut microbiota measured through 16s sequencing has previously been reported. None of those studies have confirmed exclusive breastfeeding nor investigated the impact of maternal secretor status on gut microbial fermentation products. The present study focused on exclusively breastfed (EBF) Indonesian infants, with exclusive breastfeeding validated through the stable isotope deuterium oxide dose-to-mother (DTM) technique, and the impact of maternal secretor status on the infant fecal microbiome and metabolome. Maternal secretor status did not alter the within-community (alpha) diversity, between-community (beta) diversity, or the relative abundance of bacterial taxa at the genus level. However, infants fed milk from secretor (Se+) mothers exhibited a lower level of fecal succinate, amino acids and their derivatives, and a higher level of 1,2-propanediol when compared to infants fed milk from non-secretor (Se-) mothers. Interestingly, for infants consuming milk from Se+ mothers, there was a correlation between the relative abundance of and , and between each of these genera and fecal metabolites that was not observed in infants receiving milk from Se- mothers. Our findings indicate that the secretor status of the mother impacts the gut microbiome of the exclusively breastfed infant.
Topics: Infant; Female; Humans; Breast Feeding; Gastrointestinal Microbiome; Milk, Human; Microbiota; Oligosaccharides; Metabolome
PubMed: 37741856
DOI: 10.1080/19490976.2023.2257273 -
Scientific Data Sep 2023Metabolic stable isotope labeling with heavy water followed by liquid chromatography coupled with mass spectrometry (LC-MS) is a powerful tool for in vivo protein...
Metabolic stable isotope labeling with heavy water followed by liquid chromatography coupled with mass spectrometry (LC-MS) is a powerful tool for in vivo protein turnover studies. Several algorithms and tools have been developed to determine the turnover rates of peptides and proteins from time-course stable isotope labeling experiments. The availability of benchmark mass spectrometry data is crucial to compare and validate the effectiveness of newly developed techniques and algorithms. In this work, we report a heavy water-labeled LC-MS dataset from the murine liver for protein turnover rate analysis. The dataset contains eighteen mass spectral data with their corresponding database search results from nine different labeling durations and quantification outputs from d2ome+ software. The dataset also contains eight mass spectral data from two-dimensional fractionation experiments on unlabeled samples.
Topics: Animals; Mice; Chromatography, Liquid; Deuterium Oxide; Liver; Proteome; Tandem Mass Spectrometry
PubMed: 37726365
DOI: 10.1038/s41597-023-02537-w -
ACS Sensors Oct 2023Distinguishing between heavy water and regular water has been a continuing challenge since these isotopologues of water have very similar physical and chemical...
Distinguishing between heavy water and regular water has been a continuing challenge since these isotopologues of water have very similar physical and chemical properties. We report the development and evaluation of a simple, inexpensive sensor capable of detecting liquid DO and other isotopologues of liquid water through the measurement of electrical signals generated from a nanoporous alumina film. This electrical output, consisting of a sharp voltage pulse followed by a separate broad voltage pulse, is present during the application of microliter volumes of liquid. The amplitude and temporal characteristics of these pulses have been combined to enable four diagnostic parameters for sensing DO and HO. The sensing mechanism is based on different modification effects on the alumina surface by HO and DO, spatially localized variations in the surface potential of alumina induced by isotopically substituted water molecules, combined with the effect of isotopic composition on charge transfer. As a proof-of-concept demonstration, a sensing system has been developed that provides real-time detection of liquid DO in a stand-alone system.
Topics: Water; Deuterium Oxide; Aluminum Oxide
PubMed: 37725347
DOI: 10.1021/acssensors.3c01772 -
The Journal of Physical Chemistry. B Sep 2023DO is commonly used as a solvent instead of HO in spectroscopic studies of proteins, in particular, in infrared and nuclear-magnetic-resonance spectroscopy. DO is... (Review)
Review
DO is commonly used as a solvent instead of HO in spectroscopic studies of proteins, in particular, in infrared and nuclear-magnetic-resonance spectroscopy. DO is chemically equivalent to HO, and the differences, particularly in hydrogen-bond strength, are often ignored. However, replacing solvent water with DO can affect not only the kinetics but also the structure and stability of biomolecules. Recent experiments have shown that even the mesoscopic structures and the elastic properties of biomolecular assemblies, such as amyloids and protein networks, can be very different in DO and HO. We discuss these findings, which probably are just the tip of the iceberg, and which seem to call for obtaining a better understanding of the HO/DO-isotope effect on water-water and water-protein interactions. Such improved understanding may change the differences between HO and DO as biomolecular solvents from an elephant in the room to an opportunity for protein research.
Topics: Water; Proteins; Solvents; Isotopes; Deuterium Oxide
PubMed: 37722111
DOI: 10.1021/acs.jpcb.3c04385 -
Chemical Science Sep 2023Cucurbit[7]uril (CB[7]) encapsulates adamantyl and trimethylsilyl substituents of positively charged guests in dimethyl sulfoxide (DMSO). Unlike in water or deuterium...
Cucurbit[7]uril (CB[7]) encapsulates adamantyl and trimethylsilyl substituents of positively charged guests in dimethyl sulfoxide (DMSO). Unlike in water or deuterium oxide, addition of a selection of alkali and alkali-earth cations with van der Waals radii between 1.0 and 1.4 Å (Na, K, Ca, Sr, Ba and Eu) to the CB[7]/guest complexes triggers their cation-mediated trimerization, a process that is very slow on the nuclear magnetic resonance (NMR) time scale. Smaller (Li, Mg) or larger cations (Rb, Cs or NH) are inert. The trimers display extensive CH-O interactions between the equatorial and pseudo-equatorial hydrogens of CB[7] and the carbonyl rim of the neighboring CB[7] unit in the trimer, and a deeply nested cation between the three interacting carbonylated CB[7] rims; a counteranion is likely perched in the shallow cavity formed by the three outer walls of CB[7] in the trimer. Remarkably, a guest must occupy the cavity of CB[7] for trimerization to take place. Using a combination of semi-empirical and density functional theory techniques in conjunction with continuum solvation models, we showed that trimerization is favored in DMSO, and not in water, because the penalty for the partial desolvation of three of the six CB[7] portals upon aggregation into a trimer is less unfavorable in DMSO compared to water.
PubMed: 37712024
DOI: 10.1039/d3sc02032k -
Angewandte Chemie (International Ed. in... Nov 2023Despite widespread use of the deuterium isotope effect, selective deuterium labeling of chemical molecules remains a major challenge. Herein, a facile and general...
Despite widespread use of the deuterium isotope effect, selective deuterium labeling of chemical molecules remains a major challenge. Herein, a facile and general electrochemically driven, organic mediator enabled deuteration of styrenes with deuterium oxide (D O) as the economical deuterium source was reported. Importantly, this transformation could be suitable for various electron rich styrenes mediated by triphenylphosphine (TPP). The reaction proceeded under mild conditions without transition-metal catalysts, affording the desired products in good yields with excellent D-incorporation (D-inc, up to >99 %). Mechanistic investigations by means of isotope labeling experiments and cyclic voltammetry tests provided sufficient support for this transformation. Notably, this method proved to be a powerful tool for late-stage deuteration of biorelevant compounds.
PubMed: 37698174
DOI: 10.1002/anie.202312803 -
The Journal of Chemical Physics Sep 2023A model zwitterionic polysulfobetaine, poly(3-(acrylamidopropyl-dimethyl-ammonium) propyl-1-sulfonate) (pAPAPS), phase separates upon cooling and exhibits an upper...
A model zwitterionic polysulfobetaine, poly(3-(acrylamidopropyl-dimethyl-ammonium) propyl-1-sulfonate) (pAPAPS), phase separates upon cooling and exhibits an upper critical solution temperature (UCST) behavior with no added salt in deuterium oxide solutions. Dynamic light scattering measurements indicate the presence of distinct fast and slow diffusive modes, where the fast mode is interpreted as a collective diffusion coefficient and the slow mode is attributed to the diffusion of multi-chain dynamic clusters. The relative population of fast and slow modes varies systematically with temperature and concentration. A clustering temperature (T*) was assigned when the slow mode first appeared upon cooling. The slow mode then increases in relative scattering amplitude as the phase boundary is approached. The fast mode exhibits a concentration dependence above T* consistent with the virial expansion in the collective diffusion. The sign of the virial coefficient (kd) is negative, even in the good solvent region above the expected Flory temperature (Θ ≈ 39 °C), a behavior distinct from synthetic neutral polymers in organic solvents. The onset of multi-chain clustering at T < T* coincides with the poor solvent regime (T < Θ). Attractive dipolar interactions due to the zwitterionic sulfobetaine groups in pAPAPS are suggested as the origin of the multi-chain clusters with no salt. Upon the addition of 100 mM NaCl, the slow mode is suppressed, and the hydrodynamic radius is consistent with polyzwitterion chain dimensions in a dilute solution. We find that concentration dependent diffusion is highly linked to the theta temperature and the emergence of dynamic clusters as the polymer goes from good to poor solvent on approach to the UCST. The slow mode in the semidilute regime is reported along with preliminary small-angle neutron scattering data that show salt reduces clustering and leads to predominantly chain scattering.
PubMed: 37694748
DOI: 10.1063/5.0162376 -
Frontiers in Nutrition 2023To date, body composition assessments in Hispanics, computed via bioimpedance devices, have primarily focused on body fat percent, fat mass, and fat-free mass instead of...
BACKGROUND
To date, body composition assessments in Hispanics, computed via bioimpedance devices, have primarily focused on body fat percent, fat mass, and fat-free mass instead of total body water (TBW). Additionally, virtually no information is available on which type of bioimpedance device is preferred for TBW assessments in Hispanic populations.
PURPOSE
The purpose of this study was to validate two bioimpedance devices for the estimate of TBW in Hispanics adults when using a criterion deuterium oxide (DO) technique.
METHODS
One-hundred thirty individuals (males: = 70; females: = 60) of Hispanic descent had TBW estimated via DO, single-frequency bioimpedance analysis ([SF-BIA] Quantum V, RJL Systems) and bioimpedance spectroscopy ([BIS] SFB7 Impedimed).
RESULTS
The mean values for SF-BIA were significantly lower than DO when evaluating the entire sample (37.4 L and 38.2 L, respectively; < 0.05). In contrast, TBW values were not statistically significant when comparing DO against BIS (38.4 L, > 0.05). Bland-Altman analysis indicated no proportional bias when evaluating the entire sample for SF-BIA or BIS. The standard error of estimate and total error values were ≤ 2.3 L and Lin's concordance correlation coefficient were ≥ 0.96 for all comparisons.
CONCLUSION
The SF-BIA and BIS devices evaluated in the current study hold promise for accurate estimation of TBW in Hispanic adults. While both methods demonstrated relatively low errors relative to the DO criterion, BIS exhibited a more consistent performance, particularly at the group level. These findings provide essential information for researchers and clinical nutrition practitioners assessing TBW in Hispanic adults.
PubMed: 37693242
DOI: 10.3389/fnut.2023.1221774 -
Infection and Drug Resistance 2023Antibiotic resistance represents a serious global health challenge, particularly with the emergence of strains resistant to last-resort antibiotics such as tigecycline,...
BACKGROUND
Antibiotic resistance represents a serious global health challenge, particularly with the emergence of strains resistant to last-resort antibiotics such as tigecycline, polymyxin B, and vancomycin. Urgent measures are required to alleviate this situation. To facilitate the judicious use of antibiotics, rapid and precise antimicrobial susceptibility testing (AST) is essential. Heavy water (deuterium oxide, DO)-labeled Raman spectroscopy has emerged as a promising time-saving tool for microbiological testing.
METHODS
Deuterium incorporation and experimental conditions were examined to develop and apply a Raman-based AST method to evaluate the efficacy of last-resort antibiotics, including tigecycline, polymyxin B, and vancomycin, against , and . Essential agreement and categorical agreement were used to assess the metabolism inactivation concentration based on Raman spectroscopy (R-MIC)-a new metric developed in this study-and minimum inhibitory concentration (MIC) determined via the traditional microdilution broth method. Spearman's rank correlation coefficient was employed to measure the association between R-MIC and MIC values.
RESULTS
The Raman-based AST method achieved a 100% categorical agreement (92/92) with the traditional microdilution broth method within five hours, while the traditional method required approximately 24 h. The R-MIC values shared 68.5% (63/92) consistency with the MIC values. In addition, the R-MIC and MIC values were highly correlated (Spearman's r=0.96), resulting in an essential agreement of 100%.
CONCLUSION
Our optimized experimental method and conditions indicate that Raman-based AST holds great promise as a solution to overcome the time-consuming challenges of traditional AST methods.
PubMed: 37638072
DOI: 10.2147/IDR.S404732