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1.
Proc Natl Acad Sci U S A ; 121(4): e2309628121, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38227660

RESUMO

Human bone marrow failure (BMF) syndromes result from the loss of hematopoietic stem and progenitor cells (HSPC), and this loss has been attributed to cell death; however, the cell death triggers, and mechanisms remain unknown. During BMF, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) increase. These ligands are known to induce necroptosis, an inflammatory form of cell death mediated by RIPK1, RIPK3, and MLKL. We previously discovered that mice with a hematopoietic RIPK1 deficiency (Ripk1HEM KO) exhibit inflammation, HSPC loss, and BMF, which is partially ameliorated by a RIPK3 deficiency; however, whether RIPK3 exerts its effects through its function in mediating necroptosis or other forms of cell death remains unclear. Here, we demonstrate that similar to a RIPK3 deficiency, an MLKL deficiency significantly extends survival and like Ripk3 deficiency partially restores hematopoiesis in Ripk1HEM KO mice revealing that both necroptosis and apoptosis contribute to BMF in these mice. Using mouse models, we show that the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) is up-regulated in mouse RIPK1-deficient bone marrow cells and that ZBP1's function in endogenous nucleic acid sensing is necessary for HSPC death and contributes to BMF. We also provide evidence that IFNγ mediates HSPC death in Ripk1HEM KO mice, as ablation of IFNγ but not TNFα receptor signaling significantly extends survival of these mice. Together, these data suggest that RIPK1 maintains hematopoietic homeostasis by preventing ZBP1 activation and induction of HSPC death.


Assuntos
Ácidos Nucleicos , Pancitopenia , Animais , Humanos , Camundongos , Apoptose/genética , Transtornos da Insuficiência da Medula Óssea , Morte Celular/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Necrose/metabolismo , Ácidos Nucleicos/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
2.
Environ Sci Technol ; 57(47): 18658-18667, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36706342

RESUMO

Bromine radical (Br•) has been hypothesized to be a key intermediate of bromate formation during ozonation. Once formed, Br• further reacts with ozone to eventually form bromate. However, this reaction competes with the reaction of Br• with dissolved organic matter (DOM), of which reactivity and reaction mechanisms are less studied to date. To fill this gap, this study determined the second-order rate constant (k) of the reactions of selected organic model compounds, a DOM isolate, and monochloramine (NH2Cl) with Br• using γ-radiolysis. The kBr• of all model compounds were high (kBr• > 108 M-1 s-1) and well correlated with quantum-chemically computed free energies of activation, indicating a selectivity of Br• toward electron-rich compounds, governed by electron transfer. The reaction of phenol (a representative DOM moiety) with Br• yielded p-benzoquinone as a major product with a yield of 59% per consumed phenol, suggesting an electron transfer mechanism. Finally, the potential of NH2Cl to quench Br• was tested based on the fast reaction (kBr•, NH2Cl = 4.4 × 109 M-1 s-1, this study), resulting in reduced bromate formation of up to 77% during ozonation of bromide-containing lake water. Overall, our study demonstrated that Br• quenching by NH2Cl can substantially suppress bromate formation, especially in waters containing low DOC concentrations (1-2 mgC/L).


Assuntos
Ozônio , Poluentes Químicos da Água , Purificação da Água , Bromo , Matéria Orgânica Dissolvida , Bromatos/química , Fenol/química , Compostos Orgânicos , Purificação da Água/métodos , Poluentes Químicos da Água/análise
3.
bioRxiv ; 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39386657

RESUMO

Embryonic hematopoietic stem and progenitor cells (HSPCs) have the unique ability to undergo rapid proliferation while maintaining multipotency, a clinically-valuable quality which currently cannot be replicated in vitro. Here, we show that embryonic HSPCs achieve this state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of Tg(ubi:mitoQC) zebrafish indicate that mitophagy initiates as HSPCs undergo endothelial-to-hematopoietic transition and colonize the caudal hematopoietic tissue (CHT). Knockdown of bnip3lb reduced mitophagy and HSPC numbers in the CHT by promoting myeloid-biased differentiation and apoptosis, which was rescued by anti-oxidant exposure. Conversely, induction of mitophagy enhanced both embryonic HSPC and lymphoid progenitor numbers. Significantly, mitophagy activation improved ex vivo functional capacity of hematopoietic progenitors derived from human-induced pluripotent stem cells (hiPSCs), enhancing serial-replating hematopoietic colony forming potential. HIGHLIGHTS: ROS promotes HSPC formation in the dorsal aorta but negatively affects maintenance thereafter.HSPCs colonizing secondary niches control ROS levels via Bnip3lb-directed mitophagy.Mitophagy protects nascent HSPCs from ROS-associated apoptosis and maintains multipotency.Induction of mitophagy enhances long-term hematopoietic potential of iPSC-derived HSPCs.

4.
Water Res ; 213: 118053, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35196612

RESUMO

Ozonation has been applied in water treatment for more than a century, first for disinfection, later for oxidation of inorganic and organic pollutants. In recent years, ozone has been increasingly applied for enhanced municipal wastewater treatment for ecosystem protection and for potable water reuse. These applications triggered significant research efforts on the abatement efficiency of organic contaminants and the ensuing formation of transformation products. This endeavor was accompanied by developments in analytical and computational chemistry, which allowed to improve the mechanistic understanding of ozone reactions. This critical review assesses the challenges of ozonation of impaired water qualities such as wastewaters and provides an up-to-date compilation of the recent kinetic and mechanistic findings of ozone reactions with dissolved organic matter, various functional groups (olefins, aromatic compounds, heterocyclic compounds, aliphatic nitrogen-containing compounds, sulfur-containing compounds, hydrocarbons, carbanions, ß-diketones) and antibiotic resistance genes.

5.
Dev Biol ; 331(2): 350-60, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19427847

RESUMO

The subdivision of mesodermal cells into muscle and non-muscle cells is crucial to animal development. In the C. elegans postembryonic mesoderm, this subdivision is a result of an asymmetric cell division that leads to the formation of striated body wall muscles and non-muscle coelomocytes. Here we report that the Six homeodomain protein CEH-34 and its cofactor Eyes Absent, EYA-1, function synergistically to promote the non-muscle fate in cells also competent to form muscles. We further show that the asymmetric expression of ceh-34 and eya-1 is regulated by a combination of 1) mesodermal intrinsic factors MAB-5, HLH-1 and FOZI-1, 2) differential POP-1 (TCF/LEF) transcriptional activity along the anterior-posterior axis, and 3) coelomocyte competence factor(s). These factors are conserved in both vertebrates and invertebrates, suggesting a conserved paradigm for mesoderm development in metazoans.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Homeodomínio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mesoderma/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Wnt/metabolismo , Animais , Animais Geneticamente Modificados , Antígenos de Diferenciação/metabolismo , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/crescimento & desenvolvimento , Desenvolvimento Muscular , Músculos/citologia , Músculos/embriologia , Transdução de Sinais/fisiologia
6.
Water Res ; 157: 514-528, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30986698

RESUMO

Aliphatic amines are common constituents in micropollutants and dissolved organic matter and present in elevated concentrations in wastewater-impacted source waters. Due to high reactivity, reactions of aliphatic amines with ozone are likely to occur during ozonation in water and wastewater treatment. We investigated the kinetics and mechanisms of the reactions of ozone with ethylamine, diethylamine, and triethylamine as model nitrogenous compounds. Species-specific second-order rate constants for the neutral parent amines ranged from 9.3 × 104 to 2.2 × 106 M-1s-1 and the apparent second-order rate constants at pH 7 for potential or identified transformation products were 6.8 × 105 M-1s-1 for N,N-diethylhydroxylamine, ∼105 M-1s-1 for N-ethylhydroxylamine, 1.9 × 103 M-1s-1 for N-ethylethanimine oxide, and 3.4 M-1s-1 for nitroethane. Product analyses revealed that all amines were transformed to products containing a nitrogen-oxygen bond (e.g., triethylamine N-oxide and nitroethane) with high yields, i.e., 64-100% with regard to the abated target amines. These findings could be confirmed by measurements of singlet oxygen and hydroxyl radical which are formed during the amine-ozone reactions. Based on the high yields of nitroethane from ethylamine and diethylamine, a significant formation of nitroalkanes can be expected during ozonation of waters containing high levels of dissolved organic nitrogen, as expected in wastewaters or wastewater-impaired source waters. This may pose adverse effects on the aquatic environment and human health.


Assuntos
Ozônio , Poluentes Químicos da Água , Purificação da Água , Aminas , Cinética , Oxirredução , Águas Residuárias
7.
Exp Hematol ; 46: 83-95.e6, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27751871

RESUMO

Hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate each of the mature blood cell lineages and thereby reconstitute the entire blood system. Therefore, HSCs are therapeutically valuable for treatment of hematological malignances and bone marrow failure. We showed recently that transient glucose elevation elicited dose-dependent effects on HSCs through elevated metabolic activity and subsequent reactive oxygen species-mediated induction of Hypoxia-Inducible Factor 1α (Hif1α). Platelet-Derived Growth Factor B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic stimulation. Although the function of PDGF signaling is well established in vascular development, its role in hematopoiesis is less understood. Exposure to either a pan-PDGF inhibitor or a PDGFRß-selective antagonist in the context of Hif1α stimulation blocked elevations in hematopoietic stem and progenitor cell (HSPC) formation as determined by runx1;cmyb whole-mount in situ hybridization (WISH) and HSPC-reporter flow cytometry analysis. Similar results were observed for morpholino (MO) knockdown of pdgfrb or dominant-negative pdgfrb expression, indicating that PDGFRß signaling is a key downstream mediator of Hif1α-mediated induction of HSPCs. Notably, overexpression of Pdgfb ligand enhanced HSPC numbers in the aorta-gonado-mesonephros (AGM) at 36 hours postfertilization (hpf) and in the caudal hematopoietic tissue at 48 hpf. A survey of known PDGF-B/PDGFRß regulatory targets by expression analysis revealed a significant increase in inflammatory intermediates, including Interleukin 6 (IL-6) and its receptor (IL-6R). MO-mediated knockdown of il6 or chemical inhibition of IL-6R antagonized the effect of Pdgfb overexpression. Furthermore, epistatic analysis of IL-6/IL-6R function confirmed activity downstream of Hif1α. Together, these findings define a Hif1α-regulated signaling axis mediated through PBFGB/PDGFRß and IL-6/IL-6R that acts to control embryonic HSPC production.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Interleucina-6/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Proliferação de Células , Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Imuno-Histoquímica , Estabilidade Proteica , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Peixe-Zebra
8.
Water Res ; 105: 119-128, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27611639

RESUMO

Compounds with N,N-dimethylhydrazine moieties ((CH3)2N-N-) form N-nitrosodimethylamine (NDMA) during ozonation, but the relevant reaction chemistry is hitherto poorly understood. This study investigated the reaction kinetics and mechanisms of NDMA formation during ozonation of unsymmetrical dimethylhydrazine (UDMH) and daminozide (DMZ) as structural model N,N-dimethylhydrazine compounds. The reaction of ozone with these NDMA precursor compounds was fast, and kO3 at pH 7 was 2 × 106 M-1 s-1 for UDMH and 5 × 105 M-1 s-1 for DMZ. Molar NDMA yields (i.e., Δ[NDMA]/Δ[precursor] × 100) were 84% and 100% for UDMH and DMZ, respectively, determined at molar ozone dose ratio ([O3]0/[precursor]0) of ≥4 in the presence of tert-butanol as hydroxyl radical (OH) scavenger. The molar NDMA yields decreased significantly in the absence of tert-butanol, indicating OH formation and its subsequent reaction with the parent precursors forming negligible NDMA. The kOH at pH 7 was 4.9 × 109 M-1 s-1 and 3.4 × 109 M-1 s-1 for UDMH and DMZ, respectively. Reaction mechanisms are proposed in which an ozone adduct is formed at the nitrogen next to N,N-dimethylamine which decomposes via homolytic and heterolytic cleavages of the -N+-O-O-O- bond, forming NDMA as a final product. The heterolytic cleavage pathway explains the significant OH formation via radical intermediates. Overall, significant NDMA formation was found to be unavoidable during ozonation or even O3/H2O2 treatment of waters containing N,N-dimethylhydrazine compounds due to their rapid reaction with ozone forming NDMA with high yield. Thus, source control or pre-treatment of N,N-dimethylhydrazine precursors and post-treatment of NDMA are proposed as the mitigation options.


Assuntos
Dimetilnitrosamina/química , Peróxido de Hidrogênio/química , Dimetilidrazinas , Cinética , Ozônio/química
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