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Multi-enzyme cascade catalysis has become an important technique for chemical reactions used in manufacturing and scientific study. In this research, we designed a four-enzyme integrated catalyst and used it to catalyse the deracemization reaction of cyclic chiral amines, where monoamine oxidase (MAO) catalyses the enantioselective oxidation of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MTQ), imine reductase (IRED) catalyses the stereo selective reduction of 1-methyl-3,4-dihydroisoquinoline (MDQ), formate dehydrogenase (FDH) is used for the cyclic regeneration of cofactors, and catalase (CAT) is used for decomposition of oxidative reactions. The four enzymes were immobilized via polydopamine (PDA)-encapsulated dendritic organosilica nanoparticles (DONs) as carriers, resulting in the amphiphilic core-shell catalysts. The hydrophilic PDA shell ensures the dispersion of the catalyst in water, and the hydrophobic DON core creates a microenvironment with the spatial confinement effect of the organic substrate and the preconcentration effect to enhance the stability of the enzymes and the catalytic efficiency. The core-shell structure improves the stability and reusability of the catalyst and rationally arranges the position of different enzymes according to the reaction sequence to improve the cascade catalytic performance and cofactor recovery efficiency.
Assuntos
Aminas , Monoaminoxidase , Polímeros , Aminas/química , Aminas/metabolismo , Monoaminoxidase/metabolismo , Monoaminoxidase/química , Polímeros/química , Polímeros/metabolismo , Formiato Desidrogenases/metabolismo , Formiato Desidrogenases/química , Catalase/química , Catalase/metabolismo , Indóis/química , Indóis/metabolismo , Estereoisomerismo , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Oxirredução , Nanopartículas/química , Biocatálise , Compostos de Organossilício/química , Oxirredutases/metabolismo , Oxirredutases/química , CatáliseRESUMO
The enantioselective synthesis of chiral diarylmethanols is highly desirable in synthetic chemistry and the pharmaceutical industry, but it remains challenging, especially in terms of green and sustainable production. Herein, a resin-immobilized palladium acetate catalyst was fabricated with high activity, stability, and reusability in Suzuki cross-coupling reaction of acyl halides with boronic acids, and the coimmobilization of alcohol dehydrogenase and glucose dehydrogenase on resin supports was also conducted for asymmetric bioreduction of diaryl ketones. Experimental results revealed that the physicochemical properties of the resins and the immobilization modes played important roles in affecting their catalytic performances. These two catalysts enabled the construction of a chemoenzymatic cascade for the enantioselective synthesis of a series of chiral diarylmethanols in high yields (83-90%) and enantioselectivities (87-98% ee). In addition, the asymmetric synthesis of the antihistaminic and anticholinergic drugs (S)-neobenodine and (S)-carbinoxamine was also achieved from the chiral diarylmethanol precursors, demonstrating the synthetic utility of the chemoenzymatic cascade.
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Álcool Desidrogenase , Paládio , Paládio/química , Estereoisomerismo , Estrutura Molecular , CatáliseRESUMO
A novel process for the synthesis of hydrated silica derived from ferronickel slag (FNS)-leaching residue was proposed in this study. The products of the purification of hydrated silica with 99.68% grade and 95.11% recovery can be obtained through ammonium fluoride (NH4F) roasting, followed by the process of water leaching, ammonia precipitating, and acid cleaning under the optimized conditions. The effects of NH4F mass ratio, roasting temperature, and roasting time on the water-leaching efficiency were investigated in detail. The thermodynamic and X-ray diffraction analyses indicated that the amorphous silica in FNS-leaching residue was converted to water-soluble fluoride salts ((NH4)2SiF6) during the roasting process, which are also supported by the scanning electron microscopy and thermogravimetry analyses. The Si-O bonds in amorphous silica could be effectively broken through the ammonium fluoride activation during a low-temperature roasting process. This work provides a meaningful reference for further studies on the facile synthesis of hydrated silica with similar mineral compositions.
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Multienzyme cascades (MECs) have gained much attention in synthetic chemistry but remain far from being a reliable synthetic tool. Here we report a four-enzyme cascade comprising a cofactor-independent and a cofactor self-sustaining bienzymatic modules for the enantioselective benzylic C-H amination of arylalkanes, a challenging transformation from bulk chemicals to high value-added chiral amines. The two modules were subsequently optimized by enzyme co-immobilization with microenvironmental tuning, and finally integrated in a gas-liquid segmented flow system, resulting in simultaneous improvements in enzyme performance, mass transfer, system compatibility, and productivity. The flow system enabled continuous C-H amination of arylalkanes (up to 100â mM) utilizing the sole cofactor NADH (0.5â mM) in >90 % conversion, achieving a high space-time yield (STY) of 3.6â g â L-1 â h-1, which is a 90-fold increase over the highest value previously reported.
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BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood-brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. METHODS: In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients' peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2-/-Il2rg-/-SirpαNODFlk2-/- mice. RESULTS: We found that engraftment of patients' PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1ß as a hub gene implicated in pathological changes. We further demonstrated that Il-1ß was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. CONCLUSIONS: Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient's lymphocytes.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Animais , Camundongos , Barreira Hematoencefálica , Leucócitos Mononucleares , Células Endoteliais , Camundongos Endogâmicos NOD , Autoanticorpos , Modelos Animais de Doenças , Receptores de N-Metil-D-AspartatoRESUMO
Autophagy is a fundamental recycling pathway that enhances cellular resilience, promoting survival. However, this survival mechanism can impede anti-cancer treatment strategies designed to induce cell death. In this study, we identified a novel autophagy inhibitor, Fangchinoline (Fan) isolated from the traditional Chinese medicine Stephania tetrandra. We speculated that when Fan blocks autophagy, cancer cells lose substantial self-preservation abilities during treatment. Firstly, we examined in detail the mechanism through which Fan inhibits autophagy. Specifically, Fan induced a significant increase in autophagosomes, as indicated by GFP-LC3 labeling, confirmed by the up-regulation of LC3-II. The autophagy receptor protein p62 was also up-regulated, suggesting a potential inhibition of autophagy flux. We further ruled out the possibility of fusion barriers between lysosomes and autophagosomes, as confirmed by their co-localization in double fluorescence staining. However, the lysosomal acid environment might be compromised, as suggested by the diminished fluorescence of acidity-sensitive dyes in the lysosomes and the corresponding decrease in mature forms of lysosomal cathepsin. To test the anti-cancer potential of Fan, we combined it with Cisplatin (Cis) or Paclitaxel (PTX) for lung cancer cell treatment. This combined treatment demonstrated a synergistically enhanced killing effect. These promising anti-tumor results were also replicated in a xenografted tumor model. The significance of this research lies in the identification of Fan as a potent autophagy inhibitor and its potential to enhance the efficacy of existing anti-cancer drugs. By unraveling the mechanisms of Fan's action on autophagy and demonstrating its synergistic effect in combination therapies, our study provides valuable insights for developing novel strategies to overcome autophagy-mediated resistance in cancer treatment.
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Autophagy is typically activated in cancer cells as a rescue strategy in response to cellular stress (e.g., chemotherapy). Herein, we found that Berbamine Hydrochloride (Ber) can act as an effective inhibitor of the late stage of autophagic flux, thereby potentiating the killing effect of chemotherapy agents. Lung carcinoma cells exposed to Ber exhibited increased autophagosomes, marked by LC3-II upregulation. The increased level of p62 after Ber treatment indicated that the autophagic flux was blocked at the late stage. The lysosome staining assay and cathepsin maturation detection indicated impaired lysosomal acidification. We found that Nox2 exhibited intensified co-localization with lysosomes in Ber-treated cells. Nox2 is a key enzyme for superoxide anion production capable of transferring electrons into the lysosomal lumen, thereby neutralizing the inner protons; this might explain the aberrant acidification. This hypothesis is further supported by the observed reversal of lysosomal cathepsin maturation by Nox2 inhibitors. Finally, Ber combined with cisplatin exhibited a synergistic killing effect on lung carcinoma cells. Further data suggested that lung carcinoma cells co-treated with Ber and cisplatin accumulated excessive reactive oxygen species (ROS), which typically activated MAPK-mediated mitochondria-dependent apoptosis. The enhanced anti-cancer effect of Ber combined with cisplatin was also confirmed in an in vivo xenograft mouse model. These findings indicate that Ber might be a promising adjuvant for enhancing the cancer cell killing effect of chemotherapy via the inhibition of autophagy. In this process, Nox2 might be a significant mediator of Ber-induced aberrant lysosomal acidification.
Assuntos
Antineoplásicos , Carcinoma , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Apoptose , Lisossomos/metabolismo , Pulmão/metabolismo , Concentração de Íons de Hidrogênio , Catepsinas/metabolismo , Catepsinas/farmacologia , Catepsinas/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/metabolismoRESUMO
Celery seeds have been used as an effective dietary supplement to manage hyperuricemia and diminish gout recurrence. Xanthine oxidase (XOD), the critical enzyme responsible for uric acid production, represents the most promising target for anti-hyperuricemia in clinical practice. In this study, we aimed to establish a method based on affinity ultrafiltration-liquid chromatography-mass spectrometry (UF-LC-MS) to directly and rapidly identify the bioactive compounds contributing to the XOD-inhibitory effects of celery seed crude extracts. Chemical profiling of celery seed extracts was performed using UPLC-TOF/MS. The structure was elucidated by matching the multistage fragment ion data to the database and publications of high-resolution natural product mass spectrometry. Thirty-two compounds, including fourteen flavonoids and six phenylpeptides, were identified from celery seed extracts. UF-LC-MS showed that luteolin-7-O-apinosyl glucoside, luteolin-7-O-glucoside, luteolin-7-O-malonyl apinoside, luteolin-7-O-6'-malonyl glucoside, luteolin, apigenin, and chrysoeriol were potential binding compounds of XOD. A further enzyme activity assay demonstrated that celery seed extract (IC50 = 1.98 mg/mL), luteolin-7-O-apinosyl glucoside (IC50 = 3140.51 µmol/L), luteolin-7-O-glucoside (IC50 = 975.83 µmol/L), luteolin-7-O-6'-malonyl glucoside (IC50 = 2018.37 µmol/L), luteolin (IC50 = 69.23 µmol/L), apigenin (IC50 = 92.56 µmol/L), and chrysoeriol (IC50 = 40.52 µmol/L) could dose-dependently inhibit XOD activities. This study highlighted UF-LC-MS as a useful platform for screening novel XOD inhibitors and revealed the chemical basis of celery seed as an anti-gout dietary supplement.
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Apium , Cromatografia Líquida de Alta Pressão , Apium/química , Sementes/química , Xantina Oxidase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espectrometria de Massas em Tandem , Modelos Moleculares , Estrutura Terciária de ProteínaRESUMO
The direct asymmetric reductive amination of heteroaryl ketones has been a long-standing synthetic challenge. Here we report the engineering of an amine dehydrogenase (AmDH) from Jeotgalicoccus aerolatus for the asymmetric synthesis of chiral α-(hetero)aryl primary amines in excellent conversions (up to 99 %) and enantioselectivities (up to 99 % ee). The best AmDH variant (Ja-AmDH-M33 ) exhibited high activity and specificity toward alkyl (hetero)aryl ketones, even for those bearing a bulky alkyl chain. An efficient directed evolution approach based on molecular docking was implemented to enlarge the active pocket with a more hydrophobic entrance, which is responsible for the high activity. The Ja-AmDH-M33 was also used for preparative-scale synthesis of pharmaceutically relevant amines and a key intermediate of chiral pincer ligands, which highlighted its practical application in synthetic chemistry.
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Cetonas , Oxirredutases , Aminação , Aminas/química , Cetonas/química , Simulação de Acoplamento Molecular , Oxirredutases/metabolismo , EstereoisomerismoRESUMO
TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Adulto , Aminoácidos/genética , Criança , Pré-Escolar , Exoma/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Sistema de Sinalização das MAP Quinases/genética , Masculino , Anormalidades Musculoesqueléticas/genética , FenótipoRESUMO
Although loose nanofiltration membranes have been extensively studied for dye desalination, high-throughput membranes with antifouling and antibacterial properties are still highly needed. In this study, a zwitterion-modified molybdenum disulfide (MoS2) dual-layer loose nanofiltration membrane was prepared with the integration of antibacterial, antifouling, and high-flux properties. To be specific, MoS2 nanosheets were loaded on a polyacrylonitrile ultrafiltration membrane through pressure-assisted self-assembly. Then, poly (sulfobetaine methacrylate) (PSBMA) was coated on the surface of the MoS2 membrane via a simple polydopamine (PDA)-assisted one-step codeposition to prepare PSBMA/PDA/MoS2 nanofiltration membranes. Elemental and morphological analyses confirmed the formation of the MoS2 layer and PSBMA/PDA coating. In addition, the effect of the PSBMA amount and codeposition time on surface properties and membrane performances was investigated. Under optimum conditions, the as-prepared membrane showed excellent water permeance of 262 LMH/bar with good dye rejection (99.8% for methylene blue) and salt permeability, as well as excellent antifouling and antibacterial properties benefiting from the synergy of PSBMA/PDA coating layers and MoS2 layers.
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Corynebacterium glutamicum has a long and successful history in the biotechnological production of L-lysine. Besides the adjustment of metabolic pathways, intracellular and extracellular transport systems are critical for the cellular metabolism of L-lysine or its by-products. Here, three amino acid transmembrane transporters, namely, GluE, BrnE/BrnF, and LysP, which are widely present in C. glutamicum strains, were each investigated by gene knockout. In comparison with that in the wild-type strain, the yield of L-lysine increased by 9.0%, 12.3%, and 10.0% after the deletion of the gluE, brnE/brnF, and lysP genes, respectively, in C. glutamicum 23,604. Moreover, the amount of by-product amino acids decreased significantly when the gluE and brnE/brnF genes were deleted. It was also demonstrated that there was no effect on the growth of the strain when the gluE or lysP gene was deleted, whereas the biomass of C. glutamicum WL1702 (ΔbrnE/ΔbrnF) in the fermentation medium was significantly reduced in comparison with that of the wild type. These results also provide useful information for enhancing the production of L-lysine or other amino acids by C. glutamicum.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos/genética , Corynebacterium glutamicum/metabolismo , Lisina/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/crescimento & desenvolvimento , Fermentação , Deleção de Genes , Engenharia Metabólica , Redes e Vias Metabólicas , MetabolômicaRESUMO
OBJECTIVES: Bile acid (BA) homeostasis is regulated by intestinal cellular signaling involving the farnesoid X receptor (FXR) and fibroblast growth factor 19 (FGF19) secretion. Using preterm and term pigs as a model, we examined postnatal changes in expression of the FXR-FGF19 axis that is poorly characterized in human infants. METHODS: Pigs delivered by caesarean section at 10-day preterm and near full term (115-day gestation) were fitted with orogastric and umbilical arterial catheters. Pigs were fed combined parenteral nutrition and minimal enteral nutrition for 5 days, followed by milk formula until 26 d days. Plasma and tissue samples were collected at days 0, 5, 11, and 26. Plasma FGF19 concentration and liver and distal intestinal gene expression of FGF19 and other FXR target genes were quantified. RESULTS: Plasma FGF19 levels were lower in preterm versus term newborn pigs (Pâ<â0.05), increased markedly by 5 days, especially in preterm pigs, and decreased in both groups until day 26. Likewise, intestinal FXR and FGF19 expression was lower (P ≤ 0.05) in premature versus term newborn pigs and decreased (P ≤ 0.05) between days 5 and 26. Hepatic expression of cholesterol 7α-hydroxylase (CYP7A1) was inversely correlated with plasma FGF19 in both groups. CONCLUSIONS: We conclude that the activity of FXR-FGF19 axis is lower in preterm than in term newborn pigs but increases transiently and then declines by the first month of age. We also provide supportive evidence of negative feedback between plasma FGF19 and hepatic CYP7A1 expression.
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Cesárea , Receptores Citoplasmáticos e Nucleares , Animais , Ácidos e Sais Biliares , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Gravidez , Receptores Citoplasmáticos e Nucleares/genética , Suínos , Regulação para CimaRESUMO
Cadmium (Cd) is a highly toxic element and non-essential to human. Herein, the source and fate of Cd were examined in a typical sediment profile from the North River, South China, which was affected by the massive Pb-Zn smelting activities for decades. An exceptionally high enrichment of Cd, 107-441 mg/kg, was observed across the whole profile. Approximately 50-75% of Cd was retained in the weak acid soluble fraction. Risk assessment based on geoaccumulation index (Igeo), potential ecological risk index (Eri), bioavailable metal index (BMI) and toxic risk index (TRI) further indicated an extremely strong degree of potential ecological pollution and high toxic risks. The mineralogical composition of particles from the sediment profile exhibited the presence of pyrite, magnetite, wurtzite and greenockite. This further confirmed that Cd was migrated from smelting slags to the North River basin and enriched in sediment profile. Sediment Cd speciation analysis also implied a possible transformation of Cd from metal oxides in smelting slags to adsorbed phases and carbonates, which enhances the bioavailability of Cd. The findings indicate proper countermeasures or remediation approaches should be promptly taken towards high ecological risks of Cd arising from the depth profile extending nearly 1 m, due to lead-zinc smelting related activities.
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Cádmio/análise , Monitoramento Ambiental/métodos , Sedimentos Geológicos/química , Chumbo/análise , Rios/química , Poluentes Químicos da Água/análise , Zinco/análise , Carbonatos/análise , China , Ecologia , Humanos , Medição de RiscoRESUMO
The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins. We next analyzed FXR-Gank-Tumor suppressor pathways in a large cohort of HBL patients which include 6 controls and 53 HBL samples. Systemic analysis of these samples and RNA-Seq approach revealed that the FXR-Gank axis is activated; markers of hepatic stem cells are dramatically elevated and hepatocyte markers are reduced in HBL samples. In the course of these studies, we found that RNA binding protein CUGBP1 is a new tumor suppressor protein which is reduced in all HBL samples. Therefore, we generated CUGBP1 KO mice and examined HBL signatures in the liver of these mice. Micro-array studies revealed that the HBL-specific molecular signature is developed in livers of CUGBP1 KO mice at very early ages. Thus, we conclude that FXR-Gank-TSPs-Stem cells pathway is a key determinant of liver cancer in animal models and in pediatric liver cancer. Our data provide a strong basis for development of FXR-Gank-based therapy for treatment of patients with hepatoblastoma.
Assuntos
Proteínas CELF1/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas/genética , Receptores Citoplasmáticos e Nucleares/genética , Animais , Proteínas CELF1/biossíntese , Diferenciação Celular/genética , Linhagem Celular Tumoral , Dietilnitrosamina/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatoblastoma/induzido quimicamente , Hepatoblastoma/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Pediatria , Receptores Citoplasmáticos e Nucleares/biossínteseRESUMO
Tannic acid-templated mesoporous silica (TAMS) was synthesized using a simple nonsurfactant template method and dopamine-functionalized TAMS (Dop-TAMS), which was prepared via a biomimetic coating, was developed as a new support for immobilization of NHase (NHase@Dop-TAMS). The Dop-TAMS was thoroughly characterized by the transmission electron microscopy (TEM), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), and Fourier transform infrared (FT-IR) and the results showed that the Dop-TAMS possessed sufficiently large pore size and volume for the accommodation of NHase. Studying the thermal stability, storage, shaking stability, and pH stability of the free and immobilized NHase indicated that the catalytic properties of NHase@Dop-TAMS were significantly enhanced. Moreover, the NHase@Dop-TAMS exhibited good reusability. All the results demonstrated that Dop-TAMS could be used as an excellent matrix for the immobilization of NHase.
Assuntos
Biomimética/métodos , Enzimas Imobilizadas/metabolismo , Hidroliases/metabolismo , Dióxido de Silício/química , Taninos/química , Enzimas Imobilizadas/química , Hidroliases/química , PorosidadeRESUMO
UNLABELLED: Liver cancer is the fifth most common cancer. A highly invasive surgical resection of the liver tumor is the main approach used to eliminate the tumor. Mechanisms that terminate liver regeneration when the liver reaches the original size are not known. The aims of this work were to generate an animal model that fails to stop liver regeneration after surgical resections and elucidate mechanisms that are involved in termination of liver regeneration. Because epigenetic control of liver function has been previously implicated in the regulation of liver proliferation, we generated C/EBPα-S193A knockin mice, which have alterations in formation of complexes of C/EBP family proteins with chromatin remodeling proteins. The C/EBPα-S193A mice have altered liver morphology and altered liver function leading to changes of glucose metabolism and blood parameters. Examination of the proliferative capacity of C/EBPα-S193A livers showed that livers of S193A mice have a higher rate of proliferation after birth, but stop proliferation at the age of 2 months. These animals have increased liver proliferation in response to liver surgery as well as carbon tetrachloride (CCl4 )-mediated injury. Importantly, livers of C/EBPα-S193A mice fail to stop liver regeneration after surgery when livers reach the original, preresection, size. The failure of S193A livers to stop regeneration correlates with the epigenetic repression of key regulators of liver proliferation C/EBPα, p53, FXR, SIRT1, PGC1α, and TERT by C/EBPß-HDAC1 complexes. The C/EBPß-HDAC1 complexes also repress promoters of enzymes of glucose synthesis PEPCK and G6Pase. CONCLUSION: Proper cooperation of C/EBP and chromatin remodeling proteins is essential for the termination of liver regeneration after surgery and for maintenance of liver functions.
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Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Hepatócitos/fisiologia , Histona Desacetilase 1/metabolismo , Regeneração Hepática , Animais , Ciclo Celular , Doença Hepática Induzida por Substâncias e Drogas , Glucose-6-Fosfatase/metabolismo , Hepatectomia , Fígado/fisiologia , Masculino , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Sirtuína 1/metabolismo , Telomerase/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
With the continuous increase in fossil fuels consumption and the rapid growth of atmospheric CO2 concentration, the harmonious state between human and nature faces severe challenges. Exploring green and sustainable energy resources and devising efficient methods for CO2 capture, sequestration and utilization are urgently required. Converting CO2 into fuels/chemicals/materials as an indispensable element for CO2 capture, sequestration and utilization may offer a win-win strategy to both decrease the CO2 concentration and achieve the efficient exploitation of carbon resources. Among the current major methods (including chemical, photochemical, electrochemical and enzymatic methods), the enzymatic method, which is inspired by the CO2 metabolic process in cells, offers a green and potent alternative for efficient CO2 conversion due to its superior stereo-specificity and region/chemo-selectivity. Thus, in this tutorial review, we firstly provide a brief background about enzymatic conversion for CO2 capture, sequestration and utilization. Next, we depict six major routes of the CO2 metabolic process in cells, which are taken as the inspiration source for the construction of enzymatic systems in vitro. Next, we focus on the state-of-the-art routes for the catalytic conversion of CO2 by a single enzyme system and by a multienzyme system. Some emerging approaches and materials utilized for constructing single-enzyme/multienzyme systems to enhance the catalytic activity/stability will be highlighted. Finally, a summary about the current advances and the future perspectives of the enzymatic conversion of CO2 will be presented.
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Dióxido de Carbono/metabolismo , Enzimas/química , Biocombustíveis , Dióxido de Carbono/química , Sequestro de Carbono , Catálise , Enzimas/metabolismo , Metano/metabolismo , Metanol/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo , FotossínteseRESUMO
This study investigated the impacts of buffer ions, natural organic matter (NOM), and particulate Fe(III) on ferrate(VI) decomposition and characterized Fe(VI) decomposition kinetics and exposure in various waters. Homogeneous and heterogeneous Fe(VI) decomposition can be described as a second- and first-order reaction with respect to Fe(VI), respectively. Fe(VI) decay was catalyzed by Fe(VI) decomposition products. Solutes capable of forming complexes with iron hydroxides retarded Fe(VI) decay. Fractionation of the resulting solutions from Fe(VI) self-decay and ferric chloride addition in borate- and phosphate-buffered waters showed that phosphate could sequester Fe(III). The nature of the iron precipitate from Fe(VI) decomposition was different from that of freshly precipitated ferric hydroxide from ferric chloride solutions. The stabilizing effects of different solutes on Fe(VI) are in the following order: phosphate > bicarbonate > borate. The constituents of colored and alkaline waters (NOM and bicarbonate) inhibited the catalytic effects of Fe(VI) decomposition products and stabilized Fe(VI) in natural waters. Because of the stabilizing effects of solutes, moderate doses of Fe(VI) added to natural waters at pH 7.5 resulted in exposures that have been shown to be effective for inactivation of target pathogens. Preformed ferric hydroxide was less effective than freshly dosed ferric chloride in accelerating Fe(VI) decomposition.
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Compostos Férricos/química , Ferro/metabolismo , Água/químicaRESUMO
Studies were conducted evaluating the nature of particles that result from ferrate reduction in a laboratory water matrix and in a natural surface water with a moderate amount of dissolved organic carbon. Particle characterization included size, surface charge, morphology, X-ray photoelectron spectroscopy, and transmission Fourier transform infrared spectroscopy. Characteristics of ferrate resultant particles were compared to particles formed from dosing ferric chloride, a common water treatment coagulant. In natural water, ferrate addition produced significantly more nanoparticles than ferric addition. These particles had a negative surface charge, resulting in a stable colloidal suspension. In natural and laboratory matrix waters, the ferrate resultant particles had a similar charge versus pH relationship as particles resulting from ferric addition. Particles resulting from ferrate had morphology that differed from particles resulting from ferric iron, with ferrate resultant particles appearing smoother and more granular. X-ray photoelectron spectroscopy results show ferrate resultant particles contained Fe2O3, while ferric resultant particles did not. Results also indicate potential differences in the mechanisms leading to particle formation between ferrate reduction and ferric hydrolysis.