RESUMEN
The total synthesis of 1,4a-di-epi-ent-pancratistatin, a novel stereoisomer of the anti-tumor Amaryllidaceae alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The construction of the pancratistatin skeleton involved conjugate addition of organocuprate to a nitrosoolefin, which was generated in situ from inosose oxime. This was followed by stereoselective reduction of the oxime to an amine and site-selective formylation. Biological evaluations revealed that the newly synthesized compounds exhibit cytotoxicity toward cancer cells and significant ferroptosis inhibitory activity. These compounds constitute a promising small-molecule library for the development of potent bioactive agents.
Asunto(s)
Alcaloides de Amaryllidaceae , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacología , Alcaloides de Amaryllidaceae/síntesis química , Humanos , Estereoisomerismo , Línea Celular Tumoral , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacosRESUMEN
Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.
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Antioxidantes , Peroxidación de Lípido , Animales , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Peroxidación de Lípido/efectos de los fármacos , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/metabolismo , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/metabolismo , Radicales Libres/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Lípidos/químicaRESUMEN
The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR.
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Diabetes Mellitus Experimental , Retinopatía Diabética , Microglía , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Retinopatía Diabética/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Retina/patología , Retina/efectos de los fármacos , Retina/metabolismo , Ratones Endogámicos C57BL , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Vasos Retinianos/metabolismo , Tiofenos/farmacología , Tiofenos/uso terapéutico , Angiopoyetina 2/metabolismo , Angiopoyetina 2/antagonistas & inhibidoresRESUMEN
Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
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Ferroptosis , Hepatopatías , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Ratones , Animales , Humanos , Diclorhidrato de trans-1,4-Bis(2-clorobenzaminometil)ciclohexano , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismoRESUMEN
Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid ß-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.
Asunto(s)
Degeneración Macular , Epitelio Pigmentado de la Retina , Humanos , Epitelio Pigmentado de la Retina/metabolismo , Lipoproteínas LDL/metabolismo , Estrés Oxidativo , Células Epiteliales , Pigmentos Retinianos/metabolismo , Pigmentos Retinianos/farmacologíaRESUMEN
Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that reduces phospholipid hydroperoxide. Studies have reported that the loss of GPx4 activity through anticancer drugs leads to ferroptosis, an iron-dependent lipid peroxidation-induced cell death. In this study, we established Tamoxifen-inducible GPx4-deficient Mouse embryonic fibroblast (MEF) cells (ETK1 cells) and found that Tamoxifen-inducible gene disruption of GPx4 induces slow cell death at ~72â h. In contrast, RSL3- or erastin-induced ferroptosis occurred quickly within 24â h. Therefore, we investigated the differences in these mechanisms between GPx4 gene disruption-induced cell death and RSL3- or erastin-induced ferroptosis. We found that GPx4-deficiency induced lipid peroxidation at 24â h in Tamoxifen-treated ETK1 cells, which was not suppressed by iron chelators, although lipid peroxidation in RSL3- or erastin-treated cells induced ferroptosis that was inhibited by iron chelators. We revealed that GPx4-deficient cell death was MEK1-dependent but RSL3- or erastin-induced ferroptosis was not, although MEK1/2 inhibitors suppressed both GPx4-deficient cell death and RSL3- or erastin-induced ferroptosis. In GPx4-deficient cell death, the phosphorylation of MEK1/2 and ERK2 was observed 39â h after lipid peroxidation, but ERK1 was not phosphorylated. Selective inhibitors of ERK2 inhibited GPx4-deficient cell death but not in RSL3- or erastin-induced cell death. These findings suggest that iron-independent lipid peroxidation due to GPx4 disruption induced cell death via the activation of MEK1/ERK2 as a downstream signal of lipid peroxidation in Tamoxifen-treated ETK1 cells. This indicates that GPx4 gene disruption induces slow cell death and involves a different pathway from RSL3- and erastin-induced ferroptosis in ETK1 cells.
RESUMEN
Bone marrow cells are the most sensitive to exposure to X-rays in the body and are selectively damaged even by doses that are generally considered permissive in other organs. Ascorbic acid (Asc) is a potent antioxidant that is reported to alleviate damages caused by X-ray exposure. However, rodents can synthesize Asc, which creates difficulties in rigorously assessing its effects in such laboratory animals. To address this issue, we employed mice with defects in their ability to synthesize Asc due to a genetic ablation of aldehyde reductase (Akr1a-KO). In this study, concentrations of white blood cells (WBCs) were decreased 3 days after exposure to X-rays at 2 Gy and then gradually recovered. At approximately one month, the recovery rate of WBCs was delayed in the Akr1a-KO mouse group, which was reversed via supplementation with Asc. Following exposure to X-rays, Asc levels decreased in plasma, bone marrow cells, and the liver during an early period, and then started to increase. X-ray exposure stimulated the pituitary gland to release adrenocorticotropic hormone (ACTH), which stimulated corticosterone secretion. Asc released from the liver, which was also stimulated by ACTH, appeared to be recruited to the bone marrow. Since corticosterone in high doses is injurious, these collective results imply that Asc protects bone marrow via its antioxidant capacity against ROS produced via exposure to X-rays and the cytotoxic action of transiently elevated corticosterone.
RESUMEN
White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood-brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.
Asunto(s)
Isquemia Encefálica , Estenosis Carotídea , Trastornos Cerebrovasculares , Demencia Vascular , Sustancia Blanca , Animales , Ratones , Demencia Vascular/complicaciones , Etoxiquina/metabolismo , Etoxiquina/farmacología , Etoxiquina/uso terapéutico , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Isquemia Encefálica/patología , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/metabolismo , Modelos Animales de Enfermedad , Estenosis Carotídea/complicaciones , Estenosis Carotídea/metabolismo , Estenosis Carotídea/patología , Ratones Endogámicos C57BLRESUMEN
We developed a novel thiourea Lewis-base catalyst with phenol moieties for the enantioselective 5-exo-bromolactonization of stilbenecarboxylic acids to afford chiral 3-substituted phthalides. The phenol moieties are crucial for the enantio- and regio-selectivity.
RESUMEN
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury. METHODS AND RESULTS: The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R. CONCLUSIONS: Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.
Asunto(s)
Ferroptosis , Sobrecarga de Hierro , Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Daño por Reperfusión , Ratones , Animales , Ciclosporina/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Deferasirox/farmacología , Deferasirox/metabolismo , Deferasirox/uso terapéutico , Remodelación Ventricular , Miocitos Cardíacos/metabolismo , Infarto del Miocardio/metabolismo , Daño por Reperfusión/metabolismo , Hierro/metabolismo , Hipoxia/metabolismo , Sobrecarga de Hierro/metabolismo , Isquemia Miocárdica/metabolismoRESUMEN
A-values of 20 substituents were estimated by quantum chemistry calculations of different theoretical levels. Comparison with the reported experimental values provided a good benchmark to evaluate the theoretical levels for the conformational analysis of organic molecules.
RESUMEN
BACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.
Asunto(s)
Ferroptosis , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/metabolismo , Reperfusión , Isquemia/metabolismo , Glutatión/metabolismo , Fosfolípidos/metabolismo , FosfatidilcolinasRESUMEN
The presence of hydrogen peroxide along with ferrous iron produces hydroxyl radicals that preferably oxidize polyunsaturated fatty acids (PUFA) to alkyl radicals (Lâ¢). The reaction of L⢠with an oxygen molecule produces lipid peroxyl radical (LOOâ¢) that collectively trigger chain reactions, which results in the accumulation of lipid peroxidation products (LOOH). Oxygenase enzymes, such as lipoxygenase, also stimulate the peroxidation of PUFA. The production of phospholipid hydroperoxides (P-LOOH) can result in the destruction of the architecture of cell membranes and ultimate cell death. This iron-dependent regulated cell death is generally referred to as ferroptosis. Radical scavengers, which include tocopherol and nitric oxide (â¢NO), react with lipid radicals and terminate the chain reaction. When tocopherol reductively detoxifies lipid radicals, the resultant tocopherol radicals are recycled via reduction by coenzyme Q or ascorbate. CoQ radicals are reduced back by the anti-ferroptotic enzyme FSP1. â¢NO reacts with lipid radicals and produces less reactive nitroso compounds. The resulting P-LOOH is reductively detoxified by the action of glutathione peroxidase 4 (GPX4) or peroxiredoxin 6 (PRDX6). The hydrolytic removal of LOOH from P-LOOH by calcium-independent phospholipase A2 leads the preservation of membrane structure. While the expression of such protective genes or the presence of these anti-oxidant compounds serve to maintain a healthy condition, tumor cells employ them to make themselves resistant to anti-tumor treatments. Thus, these defense mechanisms against ferroptosis are protective in ordinary cells but are also potential targets for cancer treatment.
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Ferroptosis , Peroxidación de Lípido , Ferroptosis/genética , Vitamina E , Hierro/metabolismo , Óxido Nítrico , Lípidos , TocoferolesRESUMEN
BACKGROUND: Although the loading dose (LD) of vancomycin (VCM) contributes to its efficacy, it may not be conducted adequately. Herein, the objective was to evaluate the effect of LD on patient prognosis using therapeutic drug monitoring by pharmacists and elucidate the impact of an antimicrobial stewardship program (ASP)-driven educational intervention on the LD implementation rate and patient prognosis. MATERIALS AND METHODS: First, a retrospective cohort study was conducted involving 121 adult patients administered with VCM and compared with 28-day mortality in LD and non-LD groups. To avoid confounding, the propensity score method was employed. Second, post-training with ASP-driven lectures, a questionnaire survey was conducted for healthcare workers, including physicians, nurses, and pharmacists. The rates of VCM LD implementation and 28-day mortality were compared during a period of one year and 9 months between the pre-ASP (n = 38) and post-ASP (n = 33) groups. RESULTS: After propensity score matching, the 28-day mortality in the LD group was significantly improved, suggesting that the early increase in blood levels of VCM due to an LD is an important factor influencing patient prognosis. After the lecture, a questionnaire survey revealed that the understanding rates of "well" and "slightly well" for educational lectures exceeded 80% of all healthcare workers. The rate of LD implementation significantly increased to 63.6% (21/33) in the post-ASP group compared with 31.6% (12/38) in the pre-ASP group (p = 0.007), and the 28-day mortality declined from 23.7% (9/38) to 6.1% (2/33) (p = 0.041). CONCLUSION: This method of ASP-driven educational intervention would facilitate LD implementation, improving patient prognosis.
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Programas de Optimización del Uso de los Antimicrobianos , Vancomicina , Adulto , Humanos , Vancomicina/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/métodos , Estudios Retrospectivos , Farmacéuticos , Personal de Salud , Antibacterianos/uso terapéuticoRESUMEN
Our recent efforts to develop novel N-Heterocyclic carbene (NHC)-catalyzed asymmetric reactions are described. During our investigation for development of the acylation reactions via acylazoliums generated by the reactions of NHCs and α-oxidized aldehydes, we have observed significant effects of substitution at a remote site of the carbene carbon of NHCs. In addition, we also observed a significant enhancement of the enantioselectivity by the addition of carboxylate anions. From this observation, we proposed a novel working hypothesis involving a formation of a complex of the substrate and additive to reinforce the recognition of the catalyst for enhancement of the catalytic performance of the asymmetric N-heterocyclic carbene system. By applying this concept, we achieved the kinetic resolutions of both cyclic and acyclic alcohols in excellent enantioselectivities. The effects of the remote substitution were also observed in intramolecular Stetter reaction and intermolecular benzoin reaction. In these reactions, the comparison of the catalytic performance of the NHCs bearing variable remote substitutions provided insights into the reaction mechanism because the remote substitution tuned the electronic nature of NHCs without affecting the steric and electrostatic factors around the reaction site. We also developed an intramolecular benzoin condensation involving two aldehydes, which is challenging to realize. Using the substrates bearing proper protecting groups, we succeeded in the stereo divergent synthesis of a variety of inososes, which are important intermediates for the synthesis of biologically active cyclitols.
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Aldehídos , Benzoína , Estereoisomerismo , Aldehídos/química , Alcoholes/químicaRESUMEN
A remote electronic effect of chiral aminoindanol-derived N-heterocyclic carbene catalyst on an asymmetric benzoin reaction was investigated. The catalyst bearing remote electron-withdrawing substituents increased enantioselectivity of the reaction at the cost of the reaction rate. DFT calculations rationalized the increased enantioselectivity.
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Benzoína , Metano , Estereoisomerismo , CatálisisAsunto(s)
Cardiotoxicidad , Ferroptosis , Humanos , Cardiotoxicidad/etiología , Doxorrubicina/efectos adversos , MitocondriasRESUMEN
The impact of radiation-induced hydrogen peroxide (H2O2) on the biological effects of X-rays and carbon-ion beams was investigated using a selenium-deficient (SeD) mouse model. Selenium is the active center of glutathione peroxidase (GSH-Px), and SeD mice lack the ability to degrade H2O2. Male and female SeD mice were prepared by feeding a torula yeast-based SeD diet and ultrapure water. Thirty-day survival rates after whole-body irradiation, radiation-induced leg contracture, and MRI-based redox imaging of the brain were assessed and compared between SeD and normal mice. Thirty-day lethality after whole-body 5.6â Gy irradiation with X-rays or carbon-ion beams was higher in the SeD mice than in the normal mice, while SeD did not give the notable difference between X-rays and carbon-ion beams. SeD also did not affect the maximum leg contracture level after irradiation with carbon-ion beams, but delayed the leg contraction rate. In addition, no marked effects of SeD were observed on variations in the redox status of the brain after irradiation. Collectively, the present results indicate that SeD slightly altered the biological effects of X-rays and/or carbon-ion beams. GSH-Px processes endogenous H2O2 generated through mitochondrial respiration, but does not have the capacity to degrade H2O2 produced by irradiation.
RESUMEN
The remote electronic effects of chiral N-heterocyclic carbene catalysts on the asymmetric intramolecular Stetter reaction are investigated. The reaction rate and enantioselectivity were markedly influenced by a substituent at a remote position of the catalyst. The absolute configurations of the products are revised on the basis of X-ray diffraction. Density-functional theory calculations rationalize the improvement of the enantioselectivity using an electron-deficient catalyst.