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Deuterium-Depleted Water in Cancer Therapy: A Systematic Review of Clinical and Experimental Trials.Nutrients May 2024Chemotherapy exhibits numerous side effects in anti-tumour therapy. The clinical experiments indicated that deuterium-depleted water (DDW) monotherapy or in combination... (Review)
Review
Chemotherapy exhibits numerous side effects in anti-tumour therapy. The clinical experiments indicated that deuterium-depleted water (DDW) monotherapy or in combination with chemotherapy was beneficial in inhibiting cancer development. To further understand the potential mechanism of DDW in cancer therapy, we performed a systematic review. The data from experiments published over the past 15 years were included. PubMed, Cochrane and Web of Science (January 2008 to November 2023) were systemically searched. Fifteen studies qualified for review, including fourteen in vivo and in vitro trials and one interventional trial. The results showed that DDW alone or in combination with chemotherapy effectively inhibited cancer progression in most experiments. The combination treatment enhances the therapeutic effect on cancer compared with chemotherapeutic monotherapy. The inhibitory role of DDW in tumours is through regulating the reactive oxygen species (ROS)-related genes in Kelch-like ECH-associated protein 1 (Keap 1) and Nuclear erythroid 2-related factor 2 (Nrf2) signalling pathways, further controlling ROS production. An abnormal amount of ROS can inhibit the tumour progression. More extensive randomized controlled trials should be conducted to evaluate the accurate effect of DDW in Keap1-Nrf2 signalling pathways.
Topics: Humans; Neoplasms; Deuterium; Water; Reactive Oxygen Species; Antineoplastic Agents; NF-E2-Related Factor 2; Signal Transduction; Kelch-Like ECH-Associated Protein 1; Animals; Clinical Trials as Topic
PubMed: 38732643
DOI: 10.3390/nu16091397 -
Water Research Jun 2024High-valent metal-oxo species (HMOS) have been extensively recognized in advanced oxidation processes (AOPs) owing to their high selectivity and high chemical...
High-valent metal-oxo species (HMOS) have been extensively recognized in advanced oxidation processes (AOPs) owing to their high selectivity and high chemical utilization efficiency. However, the interactions between HMOS and halide ions in sewage wastewater are complicated, leading to ongoing debates on the intrinsic reactive species and impacts on remediation. Herein, we prepared three typical HMOS, including Fe(IV), Mn(V)-nitrilotriacetic acid complex (Mn(V)NTA) and Co(IV) through peroxymonosulfate (PMS) activation and comparatively studied their interactions with Cl to reveal different reactive chlorine species (RCS) and the effects of HMOS types on RCS generation pathways. Our results show that the presence of Cl alters the cleavage behavior of the peroxide OO bond in PMS and prohibits the generation of Fe(IV), spontaneously promoting SO production and its subsequent transformation to secondary radicals like Cl and Cl. The generation and oxidation capacity of Mn(V)NTA was scarcely influenced by Cl, while Cl would substantially consume Co(IV) and promote HOCl generation through an oxygen-transfer reaction, evidenced by density functional theory (DFT) and deuterium oxide solvent exchange experiment. The two-electron-transfer standard redox potentials of Fe(IV), Mn(V)NTA and Co(IV) were calculated as 2.43, 2.55 and 2.85 V, respectively. Due to the different reactive species and pathways in the presence of Cl, the amounts of chlorinated by-products followed the order of Co(II)/PMS > Fe(II)/PMS > Mn(II)NTA/PMS. Thus, this work renovates the knowledge of halide chemistry in HMOS-based systems and sheds light on the impact on the treatment of salinity-containing wastewater.
Topics: Oxidation-Reduction; Chlorides; Chlorine; Metals; Halogenation; Water Pollutants, Chemical; Wastewater
PubMed: 38728779
DOI: 10.1016/j.watres.2024.121715 -
Oecologia May 2024Migratory bird populations are declining globally at alarming rates. Non-breeding site conditions affect breeding populations, but generalising non-breeding habitat...
Migratory bird populations are declining globally at alarming rates. Non-breeding site conditions affect breeding populations, but generalising non-breeding habitat conditions over large spatial regions cannot address potential fine-scale differences across landscapes or local populations. Plumage characteristics can mediate the effects of environmental conditions on individual fitness. However, whether different phenotypes use distinctive non-breeding sites, and whether they respond to non-breeding site conditions differently remains largely unknown. Stable isotopes (δC, δN, δH) of inert tissues are useful to infer habitat characteristics and geographic origins where those tissues were grown. We collected winter-grown feathers from pied flycatchers (Ficedula hypoleuca) on their breeding grounds over several years from males whose dorsal plumage colouration ranged continuously from brown to black and assessed their stable isotope values as proxies of local habitat conditions. Based on feather δH profiles we found that browner males spent their non-breeding season in drier habitats than black males. Assignment to origin analysis shows potential regional non-breeding ground separation between differently coloured males. High within-individual repeatability of both δC and δN indicate the pied flycatcher males return yearly to similar areas. Blacker males were more likely to return to the breeding grounds after dry years compared with brown males. The opposite was found in wet years. Our study demonstrates that different phenotypes are exposed to different non-breeding site conditions which can differentially affect individual survivorship. This has important ramifications for population dynamics under predicted climate change scenarios where especially brown phenotype pied flycatcher males may be under a risk of decreasing.
Topics: Animals; Animal Migration; Seasons; Ecosystem; Feathers; Phenotype; Male; Passeriformes; Songbirds; Birds
PubMed: 38724708
DOI: 10.1007/s00442-024-05561-8 -
Proceedings of the National Academy of... May 2024Shifts in the hydrogen stable isotopic composition (H/H ratio) of lipids relative to water (lipid/water H-fractionation) at natural abundances reflect different sources...
Shifts in the hydrogen stable isotopic composition (H/H ratio) of lipids relative to water (lipid/water H-fractionation) at natural abundances reflect different sources of the central cellular reductant, NADPH, in bacteria. Here, we demonstrate that lipid/water H-fractionation (ε) can also constrain the relative importance of key NADPH pathways in eukaryotes. We used the metabolically flexible yeast a microbial model for respiratory and fermentative metabolism in industry and medicine, to investigate ε. In chemostats, fatty acids from glycerol-respiring cells were >550‰ H-enriched compared to those from cells aerobically fermenting sugars via overflow metabolism, a hallmark feature in cancer. Faster growth decreased H/H ratios, particularly in glycerol-respiring cells by 200‰. Variations in the activities and kinetic isotope effects among NADP-reducing enzymes indicate cytosolic NADPH supply as the primary control on ε. Contributions of cytosolic isocitrate dehydrogenase (cIDH) to NAPDH production drive large H-enrichments with substrate metabolism (cIDH is absent during fermentation but contributes up to 20 percent NAPDH during respiration) and slower growth on glycerol (11 percent more NADPH from cIDH). Shifts in NADPH demand associated with cellular lipid abundance explain smaller ε variations (<30‰) with growth rate during fermentation. Consistent with these results, tests of murine liver cells had H-enriched lipids from slower-growing, healthy respiring cells relative to fast-growing, fermenting hepatocellular carcinoma. Our findings point to the broad potential of lipid H/H ratios as a passive natural tracker of eukaryotic metabolism with applications to distinguish health and disease, complementing studies that rely on complex isotope-tracer addition methods.
Topics: Saccharomyces cerevisiae; Fermentation; Fatty Acids; NADP; Aerobiosis; Deuterium; Humans; Glycerol; Isocitrate Dehydrogenase
PubMed: 38709917
DOI: 10.1073/pnas.2310771121 -
ACS Omega Apr 2024Chromium(III) complexes bearing bidentate {NH(CH)PPh: PN, ()-[NH(CHPh)PPh]: P'N} and tridentate [PhP(CH)N(H)(CH)PPh: P-NH-P, ()-(Pr)PCHCHN(H)CH(Ph)CH(Ph)PPh: P-NH-P']...
Chromium(III) complexes bearing bidentate {NH(CH)PPh: PN, ()-[NH(CHPh)PPh]: P'N} and tridentate [PhP(CH)N(H)(CH)PPh: P-NH-P, ()-(Pr)PCHCHN(H)CH(Ph)CH(Ph)PPh: P-NH-P'] ligands have been synthesized using a mechanochemical approach. The complexes {-[Cr(PN)Cl]Cl (), -[Cr(P'N)Cl]Cl (), -Cr(P-NH-P)Cl (), and -Cr(P-NH-P')Cl ()} were obtained in high yield (95-97%) the grinding of the respective ligands andthe solid Cr(III) ion precursor [CrCl(THF)] with the aid of a pestle and mortar, followed by recrystallization in acetonitrile. The isolated complexes are high spin. A single-crystal X-ray diffraction study of revealed a cationic chromium complex with two P'N ligands in a configuration with P' to P' with chloride as the counteranion. The X-ray study of shows a neutral Cr(III) complex with the P-NH-P' ligand in a configuration. The difference in molecular structures and bulkiness of the ligands influence the electronic, magnetic, and electrochemical properties of the complexes as exhibited by the bathochromic shifts in the electronic absorption peaks of the complexes and the relative increase in the magnetic moment of (4.19 μ) and (4.15 μ) above the spin only value (3.88 μ) for a d electronic configuration. Complexes - were found to be inactive in the hydrogenation of an aldimine [()-1-(4-fluorophenyl)--phenylmethanimine] under a variety of activating conditions. The addition of magnesium and trimethylsilyl chloride in THF did cause hydrogenation at room temperature, but this occurred even in the absence of the chromium complex. The hydrogen in the amine product came from the THF solvent in this novel reaction, as determined by deuterium incorporation into the product when deuterated THF was used.
PubMed: 38708235
DOI: 10.1021/acsomega.4c02076 -
Analytical Chemistry Jun 2024An important element of antibody-guided vaccine design is the use of neutralizing or opsonic monoclonal antibodies to define protective epitopes in their native...
An important element of antibody-guided vaccine design is the use of neutralizing or opsonic monoclonal antibodies to define protective epitopes in their native three-dimensional conformation. Here, we demonstrate a multimodal mass spectrometry-based strategy for in-depth characterization of antigen-antibody complexes to enable the identification of protective epitopes using the cytolytic exotoxin Streptolysin O (SLO) from as a showcase. We first discovered a monoclonal antibody with an undisclosed sequence capable of neutralizing SLO-mediated cytolysis. The amino acid sequence of both the antibody light and the heavy chain was determined using mass-spectrometry-based sequencing, followed by chemical cross-linking mass spectrometry to generate distance constraints between the antibody fragment antigen-binding region and SLO. Subsequent integrative computational modeling revealed a discontinuous epitope located in domain 3 of SLO that was experimentally validated by hydrogen-deuterium exchange mass spectrometry and reverse engineering of the targeted epitope. The results show that the antibody inhibits SLO-mediated cytolysis by binding to a discontinuous epitope in domain 3, likely preventing oligomerization and subsequent secondary structure transitions critical for pore-formation. The epitope is highly conserved across >98% of the characterized isolates, making it an attractive target for antibody-based therapy and vaccine design against severe streptococcal infections.
Topics: Streptococcus pyogenes; Streptolysins; Bacterial Proteins; Epitopes; Mass Spectrometry; Antibodies, Monoclonal; Amino Acid Sequence; Models, Molecular
PubMed: 38701337
DOI: 10.1021/acs.analchem.4c00596 -
Nature Communications May 2024Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the...
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the role of the HPK1 kinase domain (KD) has been extensively characterized, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterize the structure-function of CHD in relationship to KD. Crystallography and hydrogen-deuterium exchange mass spectrometry reveal that CHD adopts a seven-bladed β-propellor fold that binds to KD. Mutagenesis associated with binding and functional studies show a direct correlation between domain-domain interaction and negative regulation of kinase activity. We further demonstrate that the CHD provides stability to HPK1 protein in cells as well as contributes to the docking of its substrate SLP76. Altogether, this study highlights the importance of the CHD in the direct and indirect regulation of HPK1 function.
Topics: Phosphorylation; Protein Serine-Threonine Kinases; Humans; Adaptor Proteins, Signal Transducing; Phosphoproteins; Protein Binding; Protein Domains; Crystallography, X-Ray; HEK293 Cells
PubMed: 38697971
DOI: 10.1038/s41467-024-48014-9 -
Viruses Apr 2024The higher-order structure (HOS) is a critical quality attribute of recombinant adeno-associated viruses (rAAVs). Evaluating the HOS of the entire rAAV capsid is...
The higher-order structure (HOS) is a critical quality attribute of recombinant adeno-associated viruses (rAAVs). Evaluating the HOS of the entire rAAV capsid is challenging because of the flexibility and/or less folded nature of the VP1 unique (VP1u) and VP1/VP2 common regions, which are structural features essential for these regions to exert their functions following viral infection. In this study, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was used for the structural analysis of full and empty rAAV8 capsids. We obtained 486 peptides representing 85% sequence coverage. Surprisingly, the VP1u region showed rapid deuterium uptake even though this region contains the phospholipase A2 domain composed primarily of α-helices. The comparison of deuterium uptake between full and empty capsids showed significant protection from hydrogen/deuterium exchange in the full capsid at the channel structure of the 5-fold symmetry axis. This corresponds to cryo-electron microscopy studies in which the extended densities were observed only in the full capsid. In addition, deuterium uptake was reduced in the VP1u region of the full capsid, suggesting the folding and/or interaction of this region with the encapsidated genome. This study demonstrated HDX-MS as a powerful method for probing the structure of the entire rAAV capsid.
Topics: Dependovirus; Capsid Proteins; Capsid; Serogroup; Deuterium Exchange Measurement; Hydrogen Deuterium Exchange-Mass Spectrometry; Humans; Deuterium; Mass Spectrometry; Cryoelectron Microscopy; Models, Molecular
PubMed: 38675928
DOI: 10.3390/v16040585 -
Pharmaceutics Apr 2024New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A...
New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange-mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.
PubMed: 38675197
DOI: 10.3390/pharmaceutics16040536 -
International Journal of Environmental... Apr 2024Regular physical activity (PA) is known to promote the physical and mental health of children and adolescents and further prevent the development of health problems in...
Regular physical activity (PA) is known to promote the physical and mental health of children and adolescents and further prevent the development of health problems in adulthood. Information on body composition and PA is crucial for health promotion strategies and for epidemiological studies informing policies. However, there is limited data on the association between body composition and PA in Namibia. This dearth of published data is a significant shortcoming in the development of strategies and policies to promote PA in Namibia. Therefore, this cross-sectional study was conducted to determine the association between PA as a dependent variable and independent variables such as high blood pressure and body fatness as measured by different methods (gold standard deuterium dilution, body mass index, mid upper arm circumference, and waist circumference). The study included 206 healthy adolescent girls aged 13-19 years and 207 young adult females aged 20-40 years from Windhoek, Namibia. PA was measured using the PACE+ questionnaire in adolescents, and the GPAQ questionnaire was used for adults. In adolescents, only 33% of the participants met the recommended guidelines for PA, compared to only 2% for adults. Nevertheless, the study found no statistically significant association between PA and blood pressure indices (-value < 0.05) among adolescents and adults. However, there was a significant association between PA and high body fatness (-value < 0.001) and waist circumference (-value = 0.014) in adolescents. Among adults, PA was significantly related to waist circumference only. In conclusion, failure to meet recommended PA guidelines is strongly associated with abdominal obesity and high body fatness. The knowledge gained from this study may be used by policymakers in the development of strategic policies and interventions aimed at promoting PA as a public priority and improving health outcomes.
Topics: Humans; Female; Adolescent; Adult; Young Adult; Cross-Sectional Studies; Namibia; Hypertension; Body Mass Index; Exercise; Waist Circumference; Blood Pressure
PubMed: 38673357
DOI: 10.3390/ijerph21040446