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Ammonia borane (AB) with 19.6â wt % H2 content is widely considered a safe and efficient medium for H2 storage and release. Co-based nanocatalysts present strong contenders for replacing precious metal-based catalysts in AB hydrolysis due to their high activity and cost-effectiveness. However, precisely adjusting the active centers and surface properties of Co-based nanomaterials to enhance their activity, as well as suppressing the migration and loss of metal atoms to improve their stability, presents many challenges. In this study, mesoporous-silica-confined bimetallic Co-Cu nanoparticles embedded in nitrogen-doped carbon (CoxCu1-x@NC@mSiO2) were synthesized using a facile mSiO2-confined thermal pyrolysis strategy. The obtained product, an optimized Co0.8Cu0.2@NC@mSiO2 catalyst, exhibits enhanced performance with a turnover frequency of 240.9â molH2 â molmetal â min-1 for AB hydrolysis at 298â K, surpassing most noble-metal-free catalysts. Moreover, Co0.8Cu0.2@NC@mSiO2 demonstrates magnetic recyclability and extraordinary stability, with a negligible decline of only 0.8 % over 30â cycles of use. This enhanced performance was attributed to the synergistic effect between Co and Cu, as well as silica confinement. This work proposes a promising method for constructing noble-metal-free catalysts for AB hydrolysis.
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Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.
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Epigénesis Genética , Histonas , Acetilación , Carcinogénesis/genética , Células Hep G2 , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Histonas/genética , Histonas/metabolismo , HumanosRESUMEN
OBJECTIVES: The aim of this study was to examine the clinical significance of oxidative stress (OS)-related indices, including inflammatory markers and lipid and platelet (PLT) parameter, in coronary artery lesions (CALs) in Kawasaki disease (KD). METHODS: Clinical data of 952 KD patients diagnosed between January 2019 and March 2022 were collected and divided into CAL and NCAL groups. All the KD patients were randomly divided into training set and verification set. The univariate analysis and multivariate logistic regression analysis of training set were used to identify the OS-related independent risk factors of CALs, which were then used to construct a predictive nomogram. Calibration curve and receiver operating characteristic curve were used to evaluate the performance of the model. The predictive nomogram was further validated on verification set. RESULTS: In the training set, 137 KD patients (18.0%) showed CALs. C-reactive protein, serum amyloid A, PLT count, monocyte-to-high-density lipoprotein (HDL) ratio, and PLT-to-lymphocyte ratio were significantly higher, whereas HDL was lower in the CAL group than the NCAL group. Increased C-reactive protein, serum amyloid A, PLT, and decreased HDL were identified as independent risk factors. The nomogram constructed using these factors showed satisfactory calibration degree and discriminatory power (the area under the curve, 0.887). In the verification set, the area under the curve was 0.795. CONCLUSION: The predictive nomogram constructed using 4 OS-related risk factors associated with CALs in patients with KD could be a useful tool for early diagnosis of CALs in KD.
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Síndrome Mucocutáneo Linfonodular , Humanos , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Proteína C-Reactiva , Vasos Coronarios/patología , Proteína Amiloide A Sérica , Factores de RiesgoRESUMEN
Ammonia borane (AB) is a promising material for chemical H2 storage owing to its high H2 density (up to 19.6â wt %). However, the development of an efficient catalyst for driving H2 evolution through AB hydrolysis remains challenging. Therefore, a visible-light-driven strategy for generating H2 through AB hydrolysis was implemented in this study using Ni-Pt nanoparticles supported on phosphorus-doped TiO2 (Ni-Pt/P-TiO2 ) as photocatalysts. Through surface engineering, P-TiO2 was prepared by phytic-acid-assisted phosphorization and then employed as an ideal support for immobilizing Ni-Pt nanoparticles via a facile co-reduction strategy. Under visible-light irradiation at 283â K, Ni40 Pt60 /P-TiO2 exhibited improved recyclability and a high turnover frequency of 967.8â mol H 2 ${{_{{\rm H}{_{2}}}}}$ molPt -1 min-1 . Characterization experiments and density functional theory calculations indicated that the enhanced performance of Ni40 Pt60 /P-TiO2 originated from a combination of the Ni-Pt alloying effect, the Mott-Schottky junction at the metal-semiconductor interface, and strong metal-support interactions. These findings not only underscore the benefits of utilizing multipronged effects to construct highly active AB-hydrolyzing catalysts, but also pave a path toward designing high-performance catalysts by surface engineering to modulate the electronic metal-support interactions for other visible-light-induced reactions.
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For conventional polycrystalline Ni-rich cathode material consisting of numerous primary particles in disordered orientation, the crystal anisotropy in charge/discharge process results in the poor rate capability and rapid capacity degradation. In this work, highly-dispersed submicron single-crystal LiNi0.8 Co0.15 Al0.05 O2 (SC-NCA) cathode is efficiently prepared by spray pyrolysis (SP) technique followed by a simple solid-state lithiation reaction. Porous Ni0.8 Co0.15 Al0.05 Ox precursor prepared via SP exhibits high chemical activity for lithiation reaction, enabling the fabrication of single-crystal cathode at a relatively low temperature. In this way, the contradiction between high crystallinity and cation disordering is well balanced. The resulted optimized SC-NCA shows polyhedral single-crystal morphology with moderate grain size (≈1 µm), which are beneficial to shortening the Li+ diffusion path and improving the structural stability. As cathode for lithium ion batteries, SC-NCA delivers a high discharge capacity of 202 and 140 mAh g-1 at 0.1 and 10 C, respectively, and maintains superior capacity retention of 161 mAh g-1 after 200 cycles at 1C. No micro-crack is observed in the cycled SC-NCA particles, indicating such single-crystal morphology can greatly relieve the anisotropic micro-strain. This effective, continuous and adaptable strategy for preparing single-crystal Ni-rich cathode without any additive may accelerate their practical application.
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The Barkam-Jiuzhaigou-Wuqi gravity profile extends across the Jiuzhaigou Ms7.0 earthquake (in 2017) zone and passes through several historical big earthquakes' zones. We have obtained Bouguer gravity anomalies along the profile composed of 365 gravity observation stations with Global Positioning System (GPS) coordinates, analyzed the observed data and inverted subsurface density structure. The results show that the Moho depth has a big lateral variation from southwest to northeast, which shallows from 57 km to 43 km with maximum variation up to 14 km within 800 km. The most acute depth change of the Moho is in the boundary region between the Bayan Har block and West Qinling-Qilian block. According to our analysis, it is related to the eastward movement of the Bayan Har block. There are three main pieces of evidence that support it: (1) Density is higher in the east of the Bayan Har block and smaller in the west, which is the same as seismic activity; (2) Two thin low-density layers exist in the upper and middle crust of the Bayan Har block, which may promote inter-layer slip and the Jiuzhaigou Ms7.0 earthquake occurred in the boundary area of the two low-density layers, where the crustal density and Moho surface fluctuate sharply; (3) the GPS velocity field in the southwestern part gravity profile is significantly larger than that of the northeastern part, which is consistent with the density structure. Our studies also suggest that the large undulation of the Moho prevents the movement of the Bayan Har block, and strain is prone to accumulate here. The dynamic background analysis of the crust in this area indicates that the Moho surface uplifts in the West Qinling-Qilian block, which decelerates the eastern migration of material on the Qinghai-Tibet Plateau, and leads to the weak tectonic activity of the north part of the Bayan Har block.
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Hepatitis B virus (HBV) is a major risk factor for liver diseases, in which HBV covalently closed circular DNA (cccDNA), as the genomic form that templates viral transcription, plays crucial roles in sustaining viral persistence. Clinically, the excessive ethanol intake accelerates the progression of liver diseases with HBV infection. Here, we supposed that ethanol might trigger HBV cccDNA in the liver. Interestingly, we observed that the ethanol remarkably elevated the levels of HBeAg, HBsAg, HBV DNA and cccDNA in HBV-expressing hepatoma cells. Mechanically, the ethanol increased the levels of HBx and MSL2 in vivo and in HBV-expressing HepG2 cells, but not in HBV-free HepG2 cells. Moreover, the down-regulation of MSL2 by small interference RNA could block the ethanol-promoted HBV cccDNA in HepG2.2.15 cells. As a commonly administered treatment for HBV, the effect of IFNα on ethanol-triggered HBV cccDNA remains poorly understood. Strikingly, we showed that the treatment with IFN-α2b inhibited the ethanol-promoted cccDNA through depressing MSL2 in the cells. Thus, we conclude that IFN-α2b inhibits the ethanol-enriched HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx. Our finding provides new insights into the mechanism by which IFN-α2b inhibits ethanol-enhanced HBV cccDNA. Therapeutically, IFNα may contribute to the cccDNA induced by ethanol in liver.
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ADN Circular/genética , Etanol/farmacología , Virus de la Hepatitis B/genética , Hepatitis B/complicaciones , Interferón-alfa/farmacología , Hígado/efectos de los fármacos , Adyuvantes Inmunológicos/farmacología , Consumo de Bebidas Alcohólicas/epidemiología , ADN Viral/genética , Células Hep G2 , Hepatitis B/tratamiento farmacológico , Hepatitis B/genética , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/genética , Antígenos e de la Hepatitis B/análisis , Antígenos e de la Hepatitis B/genética , Virus de la Hepatitis B/fisiología , Humanos , Interferón alfa-2 , Hígado/metabolismo , Hígado/virología , Ubiquitina-Proteína Ligasas/análisis , Ubiquitina-Proteína Ligasas/genética , Replicación Viral/efectos de los fármacosRESUMEN
PURPOSES: The aim of this study was to investigate the serum levels and clinical significance of interleukin 1ß (IL-1ß) and IL-6 in children with hyperuricemia (HUA). METHODS: We included 71 children with HUA and 71 children with no HUA as control subjects. Children with HUA were divided into groups I and II according to whether they had a history of acute gout-like attacks (including sudden monoarthritis of rapid onset with intense pain and swelling). Group I was examined twice (A, in the acute phase; B, in the remission phase). Serum IL-1ß and IL-6 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-1ß and IL-6 levels were increased in children with HUA and were overall statistically different from the control group (P < 0.05, respectively). Serum IL-1ß and IL-6 were significantly higher in group IA in comparison with group IB, group II, and control subjects (P < 0.05, respectively), as well as in groups IB and II compared with control subjects (P < 0.05, respectively). In group IB, the serum IL-1ß and IL-6 concentrations were higher than those in group II, but there were no statistical differences (P > 0.05). In addition, in children with HUA, serum IL-1ß and IL-6 levels were positively associated with white blood cell count, neutrophil count, monocyte count, uric acid levels, erythrocyte sedimentation rate, C-reactive protein, blood urea nitrogen, and serum creatinine levels (all P < 0.05), but were not associated with triglycerides, total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol levels (all P > 0.05). CONCLUSION: IL-1ß and IL-6 levels are increased in children with hyperuricemia, even if they have not had acute gout. Further studies are necessary to fully characterize the significance of IL-1ß and IL-6 found in HUA children, and whether they could be correlated with long-term prognosis.
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Hiperuricemia/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Recuento de Leucocitos , MasculinoRESUMEN
PURPOSES: The aims of this study were to investigate urinary macrophage migration inhibitory factor (MIF) levels and their clinical significance in Henoch-Schönlein purpura (HSP) children with or without nephritis (N) and to assess the influence of steroid treatment on the urine MIF levels of HSPN patients. METHODS: Group I comprised 35 children with HSPN who were examined twice (A before treatment and B after steroid treatment). Group II comprised 41 children with HSP. The control group included 32 healthy children. Urinary MIF levels were measured via enzyme linked immunosorbent assay. The levels of serum creatinine, blood urea nitrogen, urinary microalbumin (mAlb), and 24-hour proteinuria were performed to determine their associations with MIF levels. RESULTS: Urinary MIF levels were significantly higher in group I compared with group II and the control group (P < 0.01); however, no significant difference was found between group II and the control group (P > 0.05). Upon examination, albeit urinary MIF concentration was significantly lower in group IB compared with group IA (P < 0.05), these concentrations were statistically higher than that of group II (P < 0.05). In addition, in the HSPN patients, the urinary MIF was positively associated with urinary microalbumin and 24-hour proteinuria but no association with serum creatinine and blood urea nitrogen. CONCLUSIONS: Elevated urinary MIF levels were found to be correlated with proteinuria in pediatric HSPN. An obvious decrease in urinary MIF concentrations among the children with HSPN was associated with steroid treatment. Urinary MIF can be used as a noninvasive biomarker in pediatric HSPN.
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Vasculitis por IgA , Oxidorreductasas Intramoleculares/orina , Factores Inhibidores de la Migración de Macrófagos/orina , Nefritis , Biomarcadores/orina , Niño , Preescolar , Monitoreo de Drogas/métodos , Femenino , Glucocorticoides/administración & dosificación , Humanos , Vasculitis por IgA/complicaciones , Vasculitis por IgA/diagnóstico , Pruebas de Función Renal/métodos , Masculino , Nefritis/diagnóstico , Nefritis/etiología , Nefritis/orina , Estadística como AsuntoRESUMEN
OBJECTIVE: To explore the values of fat saturation sequence in MRI for juvenile arthritis.â© Methods: A total of 1 131 cases with juvenile arthritis and 1 601 with symptomatic arthritis were examined by MRI normal T1 weighted imaging (T1WI) and T2 weighted imaging (T2WI) sequence and spectral presaturation attenuatedinversion recovery (SPAIR) T2 fat saturation sequence. All the images were independently evaluated by two senior doctors from the Department of Radiology and the Department of Pediatric Rheumatology and Immunology respectively to confirm the types and degree of pathological changes of joint tissues.â© Results: Among the subjects, 847 patients demonstrated positive in MRI, accounting for 52.9%; 409 patients showed positive in normal sequence, accounting for 48.3%; 816 patients showed positive in fat saturation sequence, accounting for 96.3%. Joint hydrops accounted for 59.5%. Bone marrow edema accounted for 39.7%. The relevant ratio of bone marrow edema, joint hydrops, thickening of synovium and cartilage injuries in fat saturation sequence were higher than that in normal sequence (P<0.05). The relevant ratio of bone erosion in normal sequence was higher than that in fat saturation sequence (P<0.05). However, no significant difference of joint cysts was found between the fat saturation sequence and normal sequence (P<0.05).â© Conclusion: Application of fat saturation sequence by MRI to check juvenile arthritis could obviously improve the positive MRI relevant ratio. In addition, the relevant ratio of the early pathological changes of juvenile arthritis (such as bone marrow edema and joint hydrops) was high, which might provide references for the early diagnosis of juvenile arthritis.
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Tejido Adiposo/diagnóstico por imagen , Artritis Juvenil/diagnóstico por imagen , Enfermedades de la Médula Ósea/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Niño , Diagnóstico Precoz , Edema/diagnóstico por imagen , Humanos , Articulaciones/diagnóstico por imagen , Membrana Sinovial/diagnóstico por imagenRESUMEN
The biothiols sensing mechanism of (E)-7-(diethylamino)-3-(2-nitrovinyl)-2H-chromen-2-one (DCO) has been investigated using the density functional theory (DFT) and time-dependent DFT methods. The theoretical results indicate that the excited-state intermolecular hydrogen bonding (H-B) plays an important role for the biothiols sensing mechanism of the fluorescence sensor DCO. Multiple H-B interaction sites exist in DCO and in its Michael addition product DCOT, which then induce the formation of the H-B complexes with water molecules, DCOH2 and DCOTH4. In the first excited state, the intermolecular H-Bs between water molecule and DCO in DCOH2 are cooperatively and generally strengthened and thus induced the weak fluorescence emission of DCO, while the cooperative H-Bs between water molecule and DCOT in DCOTH4 are overall weakened and thus responsible for the enhanced fluorescence emission of DCOT. Moreover, the theoretical results suggest that the blue shift of the UV-Vis absorption spectrum of DCOT can be attributed to the relatively weak excited-state intramolecular charge transfer in DCOT compared to DCO.
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Colorantes Fluorescentes/química , Compuestos de Sulfhidrilo/química , Fluorescencia , Enlace de Hidrógeno , Modelos Químicos , Estructura Molecular , Análisis Espectral , Agua/químicaRESUMEN
Improving saccharification of barley malt is beneficial to promoting economic benefits of beer brewers, but there are few detailed reports on the application of cellulase and laccase in barley malt. So, barley malt was pretreated by cellulase and laccase, and the malt wort and brewer's spent grains were analyzed by HPLC, FTIR and SEM in this study. The concentration of malt wort was increased significantly to 8.1 (° Bx), which increased by 28.6% after barley malt was pretreated by cellulase, but laccase could not improve saccharification of barley malt. Through analysis of sugar in malt wort and cellulose and lignin components as well as physical and chemical structures of brewer's spent grains, the increase in sugar content in malt wort was mainly due to the increase in glucose because of hydrolysis of cellulose in barley malt by cellulase. Furtherly, laccase and cellulase should have a mutual inhibition when they are pretreated simultaneously.
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Objective: N6-methyladenosine (m6A) modification may modulate various biological processes. Nonetheless, clinical implications of m6A modification in pancreatic cancer are undefined. Herein, this study comprehensively characterized the m6A modification patterns in pancreatic cancer based on m6A regulators. Methods: Genetic mutation and expression pattern of 21 m6A regulators and their correlations were assessed in pancreatic cancer from TCGA dataset. m6A modification patterns were clustered using unsupervised clustering analysis in TCGA and ICGC datasets. Differences in survival, biological functions and immune cell infiltrations were assessed between modification patterns. A m6A scoring system was developed by principal component analysis. Genetic mutations and TIDE scores were compared between high and low m6A score groups. Results: ZC3H13 (11%), RBM15B (9%), YTHDF1 (8%), and YTHDC1 (6%) frequently occurred mutations among m6A regulators. Also, most of regulators were distinctly dysregulated in pancreatic cancer. There were tight crosslinks between regulators. Two m6A modification patterns were constructed, with distinct prognoses, immune cell infiltration and biological functions. Furthermore, we quantified m6A score in each sample. High m6A scores indicated undesirable clinical outcomes. There were more frequent mutations in high m6A score samples. Lower TIDE score was found in high m6A score group, with AUC = 0.61, indicating that m6A scores might be used for predicting the response to immunotherapy. Conclusion: Collectively, these data demonstrated that m6A modification participates pancreatic cancer progress and ornaments immune microenvironment, providing an insight into pancreatic cancer pathogenesis and facilitating precision medicine development.
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INTRODUCTION: The incidence of hyperuricemia (HUA) at younger ages is increasing along the coastal regions of China. This study aimed to compare the frequency of dual energy CT (DECT) urate crystal deposition between symptomatic hyperuricemic children and asymptomatic hyperuricemic children. MATERIAL AND METHODS: Fifty-six hyperuricemic children were divided into a Joint Group (n = 33) and an Asymptomatic Group (n = 23) according to whether they had a history of arthritis symptoms, which includes rapid onset monoarthritis with intense pain and swelling. We analyzed DECT scans of their feet from the Joint Group and the Asymptomatic Group and compared their clinical features. RESULTS: DECT urate deposits were observed in 28/33 (84.8%) children with symptomatic HUA and 14/23 (60.9%) with asymptomatic HUA. We found 60 areas of urate deposition in the Joint Group; DECT urate crystal deposition was most frequently observed in the first metatarsophalangeal (MTP) joint (30.0%), ankle joint (15.0%), and calcaneus (13.3%). 39 urate deposits were found in the Asymptomatic Group; DECT urate crystal deposition was most frequently observed in the calcaneus (25.6%), the first MTP joint (17.9%), and the first phalanx (15.4%). CONCLUSIONS: Urate deposition can occur in children with HUA, and these deposits occur more frequently in hyperuricemic children with a history of arthritis symptoms. Also, the urate deposition in the first MTP joint and calcaneus was more prevalent than in other joints. It is important to give more attention to hyperuricemic children.
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Ovomucin, accounting for â¼3.5% of total egg white protein, is responsible for the thick gel characteristics of liquid egg white. Besides its excellent foaming and emulsion capacities, it possesses anti-viral, anti-bacterial, anti-tumor and other bioactivities. This paper reviews compositional, structural, physicochemical, functional and biological properties of ovomucin, as well as development of methods of extraction. As one of the least defined proteins in egg white, further study is required to characterize the structure and to explore its full potential in new applications as functional foods and nutraceuticals.
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Abnormal lipid metabolism plays crucial roles in the development of cancer. Spindlin 1 (SPIN1) involving the process of spindle organization and chromosomal stability serves as an important player in the carcinogenesis. In this study, we try to identify the new function of SPIN1 in lipid metabolism of liver cancer. Tissue microarray showed that 75% (60/80) of hepatocellular carcinoma (HCC) tissues were positive for SPIN1, which was highly expressed in clinical HCC samples and positively associated with malignancy of HCC. Strikingly, SPIN1 could modulate abnormal lipid metabolism by increasing intracellular triglycerides, cholesterols, and lipid droplets in hepatoma cells, which could remarkably enhance the proliferation of hepatoma cells. Mechanistically, SPIN1 up-regulated FASN in hepatoma cells. SPIN1 co-activated transcriptional factor SREBP1c in the promoter of FASN through interaction with SREBP1c. Moreover, SPIN1 promoted the growth of liver cancer in vitro and in vivo and the levels of intracellular triglycerides, cholesterols and lipid droplets were increased in the tumor tissues from mice. In conclusion, SPIN1 modulates abnormal lipid metabolism and enhances growth of liver cancer through SREBP1c-triggered FASN signaling. Therapeutically, SPIN1 may serve as a novel target for HCC.
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Carcinoma Hepatocelular/patología , Proteínas de Ciclo Celular/metabolismo , Acido Graso Sintasa Tipo I/genética , Neoplasias Hepáticas/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Proteínas de Ciclo Celular/genética , Proliferación Celular/genética , Acido Graso Sintasa Tipo I/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Hep G2 , Hepatectomía , Humanos , Lipogénesis/genética , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Masculino , Ratones , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Fosfoproteínas/genética , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas/metabolismo , Transducción de Señal/genética , Análisis de Matrices Tisulares , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is assembled by histones and non-histones into a chromatin-like cccDNA minichromosome in the nucleus. The cellular histone acetyltransferase GCN5, displaying succinyltransferase activity, is recruited onto cccDNA to modulate HBV transcription in cells. Clinically, IFN-α is able to repress cccDNA. However, the underlying mechanism of IFN-α in the depression of cccDNA mediated by GCN5 is poorly understood. Here, we explored the effect of IFN-α on GCN5-mediated succinylation in the epigenetic regulation of HBV cccDNA minichromosome. RESULTS: Succinylation modification of the cccDNA minichromosome has been observed in HBV-infected human liver-chimeric mice and HBV-expressing cell lines. Moreover, histone H3K79 succinylation by GCN5 was identified in the system. Interestingly, the mutant of histone H3K79 efficiently blocked the replication of HBV, and interference with GCN5 resulted in decreased levels of HBV DNA, HBsAg, and HBeAg in the supernatant from de novo HBV-infected HepaRG cells. Consistently, the levels of histone H3K79 succinylation were significantly elevated in the livers of HBV-infected human liver-chimeric mice. The knockdown or overexpression of GCN5 or the mutant of GCN5 could affect the binding of GCN5 to cccDNA or H3K79 succinylation, leading to a change in cccDNA transcription activity. In addition, Southern blot analysis validated that siGCN5 decreased the levels of cccDNA in the cells, suggesting that GCN5-mediated succinylation of histone H3K79 contributes to the epigenetic regulation of cccDNA minichromosome. Strikingly, IFN-α effectively depressed histone H3K79 succinylation in HBV cccDNA minichromosome in de novo HepG2-NTCP and HBV-infected HepaRG cells. CONCLUSIONS: IFN-α epigenetically regulates the HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Our findings provide new insights into the mechanism by which IFN-α modulate the epigenetic regulation of HBV cccDNA minichromosome.
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Epigénesis Genética/genética , Virus de la Hepatitis B/genética , Histonas/química , Interferón-alfa/farmacología , Animales , Southern Blotting/métodos , Línea Celular/efectos de los fármacos , Línea Celular/metabolismo , Femenino , Antígenos de Superficie de la Hepatitis B/efectos de los fármacos , Antígenos de Superficie de la Hepatitis B/metabolismo , Antígenos e de la Hepatitis B/efectos de los fármacos , Antígenos e de la Hepatitis B/metabolismo , Histona Acetiltransferasas/metabolismo , Histonas/metabolismo , Humanos , Interferón-alfa/metabolismo , Masculino , Ratones , Modelos AnimalesRESUMEN
Rationale: Chronic ethanol consumption as a public health problem worldwide boosts the development of chronic liver diseases in hepatitis B virus (HBV)-infected patients. Arachidonic acid metabolite prostaglandin E2 (PGE2) activates regulatory T cells (Tregs) function. Here, we aim to investigate the underlying mechanism by which chronic ethanol consumption enriches the HBV-induced abnormal lipid metabolism and Tregs. Methods: The si-RNAs were used to weaken the expression of SWELL1 in HepG2, HepG2.2.15 and K180 cancer cell lines, followed by RNA sequencing from HepG2 cells. Arachidonic acid metabolite PGE2 and LTD4 were measured by ELISA assay in vivo and in vitro. Western blot analysis and RT-qPCR were used to examine HBx and SWELL1 and transcriptional factor Sp1 in clinical HCC samples and cell lines. The effect of chronic ethanol consumption on Tregs was tested by flow cytometry in HBV-Tg mice. The splenic Tregs were collected and analyzed by RNA sequencing. Results: The cooperative effect of ethanol and HBV in abnormal lipid metabolism was observed in vivo and in vitro. The depression of SWELL1 (or HBx) resulted in the reduction of lipid content and arachidonic acid metabolite, correlating with suppression of relative gene atlas. Ethanol and SWELL1 elevated the levels of PGE2 or LTD4 in the liver of mice and cell lines. Interestingly, the ethanol modulated abnormal lipid metabolism through activating HBx/Sp1/SWELL1/arachidonic acid signaling. Chronic ethanol consumption remarkably increased the population of PBL Tregs and splenic Tregs in HBV-Tg mice, consistently with the enhanced expression of PD-L1 in vivo and in vitro. Mechanically, RNA-seq data showed that multiple genes were altered in the transcriptomic atlas of Tregs sorting from ethanol-fed mice or HBV-Tg mice. Conclusion: The chronic ethanol intake enriches the HBV-enhanced abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activates Tregs in mice.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Ácido Araquidónico/genética , Hepatitis B/genética , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Proteínas de la Membrana/genética , Linfocitos T Reguladores/efectos de los fármacos , Consumo de Bebidas Alcohólicas/genética , Animales , Línea Celular Tumoral , Dinoprostona/genética , Modelos Animales de Enfermedad , Etanol/efectos adversos , Células Hep G2 , Hepatitis B/virología , Virus de la Hepatitis B/patogenicidad , Humanos , Hígado/efectos de los fármacos , Hígado/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Transcripción Sp1/genética , Bazo/efectos de los fármacos , Bazo/virología , Transactivadores/genéticaRESUMEN
Egg proteins are recognized as excellent sources of bioactive peptides, such as angiotensin-converting enzyme inhibitory (ACEi) peptides. Oral administration of a thermolysin-digested egg white hydrolysate (T-EWH) caused a significant blood pressure reduction in spontaneously hypertensive rats; a further ACEi assay implied that its ACEi activity was enhanced after in vitro gastrointestinal (GI) digestion. These results indicated that T-EWH contained ACEi peptides resisting GI digestion and/or being further released during GI digestion. Therefore, the objective of this study was to identify these responsible ACEi peptides from T-EWH. The conventionally activity-guided fractionation was applied, coupled with a synchronized GI digestion throughout, during which both peptide yield and ACEi activity before and after the GI digestion were measured. Finally, six ACEi peptides (LAPYK, LKISQ, LKYAT, INKVVR, LFLIKH, and LGHWVY) with good GI resistance were identified with IC50 values <20 µM, especially LKYAT (0.09 µM). The structure-activity relationship of these peptides was discussed. The discovery of GI-resistant ACEi peptides could further support the application of egg white proteins as functional food ingredients.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Proteínas del Huevo/química , Tracto Gastrointestinal/metabolismo , Hipertensión/metabolismo , Péptidos/química , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Pollos , Digestión , Clara de Huevo/química , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Péptidos/administración & dosificación , Péptidos/metabolismo , Peptidil-Dipeptidasa A/química , Hidrolisados de Proteína/química , Ratas , Ratas Endogámicas SHRRESUMEN
Geophysical processes of the pre-earthquake activities are difficult to be determined since less pre-seismic signal is observed directly. Crustal density changes derived from the periodical terrestrial gravimetry may provide meaningful deep information for the pre-earthquake cue. In this study, the crustal density changes following the 2016 MS6.4 Menyuan earthquake are estimated using ground-based gravity-change data from 2011 to 2015 in the northeastern Tibetan Plateau. The results show that negative density changes dominate the region between the South Longshou Mountain fault and the Daban Mountain fault except the southeast of this region (the seismic region) during 2011-2012. Positive density changes appeared in the middle crust near the epicenter during 2012-2013 and in the upper and middle crust east of the epicenter approximately 1.5 years before the earthquake (2013-2014), and then negative density changes appeared under and northeast of the epicenter approximately four months before the earthquake (2014-2015). The state of the crustal materials near the seismic region changed from convergence to expansion, in turn, indicating that the characteristics of the deep seismogenic process was corresponding to Amos Nur's 1974 dilatancy-fluid diffusion model.