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Developing high-performance electrocatalysts for oxygen evolution reaction (OER) is crucial in the pursuit of clean and sustainable hydrogen energy, yet still challenging. Herein, a spontaneous redox strategy is reported to achieve iridium single-atoms anchored on hierarchical nanosheet-based porous Fe doped ß-Ni(OH)2 pyramid array electrodes (SAs Ir/Fe-ß-Ni(OH)2), which exhibits high OER performance with a low overpotential of 175 mV at 10 mA cm-2 and a remarkable OER current density in alkaline electrolyte, surpassing Fe-ß-Ni(OH)2/NF and IrO2 by 31 and 38 times at 1.43 V versus RHE, respectively. OER catalytic mechanism demonstrates that the conversion of *OHâ*O and the active lattice O content can be significantly improved due to the modulation effect of the Ir single atoms on the local electronic structure and the redox behavior of FeNi (oxy) hydroxide true active species. This work provides a promising insight into understanding the OER enhancement mechanism for Ir single-atoms modified FeNi-hydroxide systems.
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OBJECTIVES: This study investigated the potential effects of perfluoroalkyl substance (PFAS) in serum on MAFLD, NAFLD, and liver fibrosis. METHODS: Our sample included 696 participants (≥ 18 years) from the 2017-2018 NHANES study with available serum PFASs, covariates, and outcomes. Using the first quartile of PFAS as the reference group, we used weighted binary logistic regression and multiple ordered logistic regression used to analyze the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and multiple ordinal logistic regression to investigate the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and calculated the odds ratio (OR) and 95% confidence interval for each chemical. Finally, stratified analysis and sensitivity analysis were performed according to gender, age, BMI, and serum cotinine concentration. RESULTS: A total of 696 study subjects were included, including 212 NAFLD patients (weighted 27.03%) and 253 MAFLD patients (weighted 32.65%). The quartile 2 of serum PFOA was positively correlated with MAFLD and NAFLD (MAFLD, OR 2.29, 95% CI 1.05-4.98; NAFLD, OR 2.37, 95% CI 1.03-5.47). PFAS were not significantly associated with liver fibrosis after adjusting for potential confounders in MAFLD and NAFLD. Stratified analysis showed that PFOA was strongly associated with MAFLD, NAFLD, and liver fibrosis in males and obese subjects. In women over 60 years old, PFHxS was also correlated with MAFLD, NAFLD, and liver fibrosis. CONCLUSION: The serum PFOA was positively associated with MAFLD and NAFLD in US adults. After stratified analysis, the serum PFHxS was correlated with MFALD, NAFLD, and liver fibrosis.
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The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.
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1-Naftilisotiocianato , Colestase , Diterpenos , Fenantrenos , Animais , Camundongos , 1-Naftilisotiocianato/toxicidade , 1-Naftilisotiocianato/metabolismo , Interleucina-17/toxicidade , Interleucina-17/metabolismo , Interleucina-17/uso terapêutico , Interleucina-4/toxicidade , Interleucina-4/metabolismo , Interleucina-4/uso terapêutico , Simulação de Acoplamento Molecular , Fígado/metabolismo , Colestase/induzido quimicamente , Ácidos e Sais Biliares , Compostos de EpóxiRESUMO
The Partial nitritation-Anammox (PN/A) process can be restricted when treating high ammonia nitrogen wastewater containing antibiotics. This study aims to explore the response mechanism of the PN/A process under antibiotic stress. Results showed the PN/A process achieved a nitrogen removal rate higher than 1.01 ± 0.03 kg N/m3/d under long-term sulfamethazine stress. The increase of extracellular polymers from 22.52 to 43.96 mg/g VSS was conducive to resisting antibiotic inhibitory. The increase of Denitratisoma and SM1A02 abundance as well as functional genes nirS and nirK indicated denitrifiers should play an important role in the stability of the PN/A system under sulfamethazine stress. In addition, antibiotic-resistant genes (ARGs) sul1 and intI1 significantly increased by 8.78 and 5.12 times of the initial values to maintain the resistance of PN/A process to sulfamethazine stress. This study uncovers the response mechanism of the PN/A process under antibiotic stress, offering a scientific basis and guidance for further application in the future.
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Antibacterianos , Antibacterianos/farmacologia , Microbiota/efeitos dos fármacos , Reatores Biológicos , Águas Residuárias/microbiologia , Eliminação de Resíduos Líquidos/métodos , Nitrogênio/metabolismoRESUMO
Previous studies have reported sex differences in altered brain function in patients with chronic insomnia (CI). However, sex-related alterations in brain morphology have rarely been investigated. This study aimed to investigate sex-specific grey matter (GM) alterations in patients with CI and to examine the relationship between GM alterations and neuropsychological assessments. Ninety-three (65 females and 28 males) patients and 78 healthy (50 females and 28 males) controls were recruited. Structural magnetic resonance imaging data were analysed using voxel-based morphometry to test for interactions between sex and diagnosis. Spearman's correlation was used to assess the associations among structure, disease duration, and sleep-, mood-, and cognition-related assessments. Males with CI showed reduced GM volume in the left inferior parietal lobe, left middle cingulate cortex, and right supramarginal gyrus. Females with CI showed increased GM volume in the right Rolandic operculum. Moreover, mood-related assessments were negatively correlated with GM volumes in the right supramarginal gyrus and left inferior parietal lobe in the male patients, and cognitive-related assessments were positively correlated with GM volumes in the Rolandic operculum in the female patients. Our findings indicate sex-specific alterations in brain morphology in CI, thereby broadening our understanding of sex differences in CI and potentially providing complementary evidence for the development of more effective therapies and individual treatments.
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Substância Cinzenta , Distúrbios do Início e da Manutenção do Sono , Humanos , Masculino , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Córtex Cerebral/patologia , Cognição/fisiologia , Lobo Parietal , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
Indirubin is the main component of the traditional Chinese medicine Indigo naturalis (IN), a potent agonist of aryl hydrocarbon receptors (AhRs). In China, IN is used to treat psoriasis and ulcerative colitis, and indirubin is used for the treatment of chronic myelogenous leukaemia. However, IN and indirubin have adverse reactions, such as abdominal pain, diarrhoea, and intussusception, and their specific mechanism is unclear.The purpose of our research was to determine the specific mechanism underlying the adverse effects of IN and indirubin. By tracking the modifications in guinea pigs after the intragastric administration of indirubin for 28 days.The results demonstrate that indirubin could accelerate bowel movements and decrease intestinal acetylcholinesterase (AchE) expression. Experiments with NCM460 cells revealed that indirubin significantly reduced the expression of AchE, and the AchE levels were increased after the silencing of AhR and re-exposure to indirubin.This study showed that the inhibition of AchE expression by indirubin plays a key role in the occurrence of adverse reactions to indirubin and that the underlying mechanism is related to AhR-mediated AchE downregulation.
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Acetilcolinesterase , Psoríase , Cobaias , Animais , Indóis/farmacologia , Indóis/metabolismo , Índigo Carmim , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
BACKGROUND: This study aimed to explore the potential associations between trans fatty acid (TFA) and α-klotho levels. METHODS: Datasets from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) were analysed for this study. Multivariable linear regression and restricted cubic spline (RCS) analyses were performed to examine the relationships between plasma TFA and serum α-klotho levels. RESULTS: A total of 1,205 participants were included, with a geometric mean (GM) of 803.60 (95% CI: 787.45, 820.00) pg/mL for serum α-klotho levels. RCS analysis revealed L-shaped relationships between TFA and α-klotho levels. The inflection points for palmitelaidic acid (PA), vaccinic acid (VA), elaidic acid (EA), and total TFA levels were 4.55, 20.50, 18.70, and 46.40 µmol/L, respectively. Before reaching the inflection point, serum α-klotho levels were negatively correlated with plasma PA, VA, EA and total TFA levels, with ß values (95% CI) of -0.15 (-0.24, -0.06), -0.16 (-0.23, -0.09), -0.14 (-0.22, -0.05) and - 0.19 (-0.27, -0.11), respectively. Linolelaidic acid (LA) levels exhibited an inverse and linear association with α-klotho levels ( Pnonlinearity=0.167, Poverall<0.001). L-shaped relationships between TFA and α-klotho levels were also observed in the subgroups of participants who were aged < 65 years, were male, did not exercise, were ex-smokers, and were overweight/obese. CONCLUSIONS: L-shaped correlations between plasma PA, VA, EA, and total TFA levels and serum α-klotho levels were observed among adults in the United States.
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Proteínas Klotho , Inquéritos Nutricionais , Ácidos Graxos trans , Humanos , Masculino , Feminino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Adulto , Ácidos Graxos trans/sangue , Glucuronidase/sangue , Idoso , Ácidos Oleicos/sangue , Ácido Oleico/sangue , Modelos LinearesRESUMO
INTRODUCTION: The occurrence of acute kidney injury (AKI) is associated with a higher risk of mortality in patients with traumatic brain injury (TBI). This study aimed to explore the relationship between serum magnesium levels and the risk of AKI in patients with TBI. METHODS: Patients with TBI were identified from the Medical Information Mart Intensive Care IV (MIMIC-IV) 2008-2019. The relationship between serum magnesium levels at admission and magnesium coefficient of variation (CV) during hospitalization and the risk of AKI was analyzed using multivariable logistic regression analysis and expressed as odds ratio (OR) and 95% confidence interval (CI). Subgroup analyses were performed according to Glasgow Coma Scale (GCS) score (<14, ≥14), sepsis (no, yes), and estimated glomerular filtration rate (eGFR; <60, ≥60). RESULTS: Of the 991 patients included, 140 (14.13%) developed AKI during hospitalization. Patients with magnesium levels ≤1.7 mg/dL (tertile 1) (OR = 1.68, 95% CI: 1.01-2.81) were associated with a higher risk of AKI compared to those with magnesium levels of 1.7-2.0 mg/dL (tertile 2), but no association was found in those with magnesium levels >2.0 mg/dL (tertile 3) (p = 0.479). For magnesium CV, patients with magnesium CV >10% (tertile 3) (OR = 2.26, 95% CI: 1.16-4.41) were linked to an increased risk of AKI compared to those with magnesium CV ≤4% (tertile 1), but there may be a slight association between magnesium CV of 4%-10% (tertile 2) and AKI risk (OR = 1.86, 95% CI: 0.99-3.48; p = 0.053). Subgroup analyses showed that lower magnesium levels (≤1.7 mg/dL) or greater magnesium CV (>10%) were associated with a higher risk of AKI only in patients with a GCS score ≥14, non-sepsis, or eGFR ≥60 mL/min/1.73 m2 (p < 0.05). CONCLUSION: Lower serum magnesium levels at admission or greater magnesium CV during hospitalization were associated with a higher risk of AKI in patients with TBI.
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Injúria Renal Aguda , Lesões Encefálicas Traumáticas , Magnésio , Humanos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Magnésio/sangue , Feminino , Masculino , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/complicações , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Idoso , Bases de Dados Factuais , Taxa de Filtração Glomerular , Hospitalização , Escala de Coma de GlasgowRESUMO
Pinctada martensii hydrolysate (PMH) has been proved to have the effect of ameliorating disorders of glucose and lipid metabolism in db/db mice, but the mechanism of its hyperglycemia effect is still unclear. Bacterial communities in fecal samples from a normal control group, a diabetic control group, and a PMH-treated diabetes mellitus type 2 (T2DM) group were analyzed by 16S gene sequencing. Nano LC-MS/MS was used to analyze mice neuropeptides and proteomes. The 16S rDNA sequencing results showed that PMH modulated the structure and composition of the gut microbiota and improved the structure and composition of Firmicutes and Bacteroidetes at the phylum level and Desulfovibrionaceae and Erysipelatoclostridiaceae at the family level. Furthermore, the expressions of functional proteins of the central nervous system, immune response-related protein, and proteins related to fatty acid oxidation in the brain disrupted by an abnormal diet were recovered by PMH. PMH regulates the brain neuropeptidome and proteome and further regulates blood glucose in diabetic mice through the gut-brain axis. PMH may be used as a prebiotic agent to attenuate T2DM, and target-specific microbial species may have unique therapeutic promise for metabolic diseases.
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Encéfalo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Proteoma , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Eixo Encéfalo-Intestino/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Prebióticos , Fezes/microbiologia , Fezes/químicaRESUMO
Strobilanthes sarcorrhiza (CTS) is a medicinal plant with various pharmacological effects such as tonifying kidney and anti-inflammatory. However, the chemical composition and difference of its four parts (leaves, stems, rhizomes, and root tubers) have been rarely reported. In this study, ultrafast flow liquid chromatography coupled with quadrupole-time-of-flight MS was applied to analyze the chemical profile of CTS and identify 55 compounds, including terpenoids, phenylethanol glycosides, fatty acid derivatives, chain glycosides, flavonoid glycosides, and others. Among these compounds, 34 compounds were first identified in CTS. They were mainly terpenoids, phenylethanol glycosides, fatty acid derivatives, and so forth. Multivariate statistical analysis, such as principal component analysis and orthogonal partial least squares-discriminant analysis were also used to evaluate the difference in chemical compounds from the four parts of CTS. The results showed that phenylethanol glycosides were the main compounds of the underground parts, while terpenoids were the main compounds of the aboveground parts. This study revealed the chemical diversity and similarity of CTS and suggested that the rhizomes could be used as an alternative medicinal part to improve the resource utilization of CTS.
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Espectrometria de Massas , Análise Multivariada , Espectrometria de Massas/métodos , Cromatografia Líquida/métodos , Extratos Vegetais/química , Terpenos/análise , Terpenos/química , Glicosídeos/análise , Glicosídeos/química , Cromatografia Líquida de Alta Pressão/métodosRESUMO
As a dominating air pollutant, atmospheric fine particulate matter within 2.5 µm in diameter (PM2.5) has attracted increasing attention from the researchers all over the world, which will lead to various adverse effects on the central nervous system (CNS), yet the potential mechanism is unclear. In this study, the microglia (BV2 cell line) were exposed to different concentrations of PM2.5 (5, 10 and 20⯵g/cm2) for 24â¯h. It was found that PM2.5 could result in adverse effects on microglia such as decreased cell viability, structural damage and even cell death. And it was reported that long non-coding RNAs (lncRNAs) could participate in multitudinous neurological diseases. Therefore, the microarray analysis was conducted in order to disclose the underlying neurotoxicity mechanism of PM2.5 by ascertaining the differentially expressed lncRNAs (DElncRNAs). The consequences indicated that the DElncRNAs were enriched in various biological pathways, including ferroptosis, IL-17 signaling pathway and NOD-like receptor signaling pathway. Moreover, the cis- and trans-regulated mRNAs by DElncRNAs as well as the corresponding transcriptional factors (TFs) were observed, such as CEBPA, MYC, MEIS1 and KLF4. In summary, our study supplies some candidate libraries and potential preventive target against PM2.5-induced toxicity through targeting lncRNAs. Furthermore, the post-transcriptional regulation will contribute to the future research on PM2.5-induced neurotoxicity.
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Poluentes Atmosféricos , RNA Longo não Codificante , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Microglia/metabolismo , Material Particulado/toxicidade , Material Particulado/metabolismo , Poluentes Atmosféricos/toxicidade , Análise em MicrossériesRESUMO
This study aims to explore the correlation between intestinal toxicity and composition changes of Euphorbia ebracteolata before and after Terminalia chebula soup(TCS) processing. Intragastric administration was performed on the whole animal model. By using fecal water content, inflammatory causes, and pathological damage of different parts of the intestinal tract of mice as indexes, the differences in intestinal toxicity of dichloromethane extraction of raw E. ebracteolata(REDE), dichloromethane extraction of TCS, and dichloromethane extraction of E. ebracteolata after simulated TCS processing(STREDE) were compared, so as to investigate the effect of TCS processing on the intestinal toxicity of E. ebracteolata. At the same time, the component databases of E. ebracteolata and T. chebula were constructed, and the composition changes of diterpenoids, tannins, and phenolic acids in the three extracted parts were analyzed by HPLC-TOF-MS. HPLC was used to compare the content of four diterpenoids including ent-11α-hydroxyabicta-8(14), 13(15)-dien-16, 12-olide(HAO), jolkinolide B(JNB), fischeria A(FA), and jolkinolide E(JNE) in the E. ebracteolata before and after processing and the residue of container wall after processing, so as to investigate the effect of TCS processing on the content and structure of the diterpenoids. The results showed that the REDE group could significantly increase the fecal water content and the release levels of TNF-α and IL-1ß from each intestinal segment, and intestinal tissue damage was accompanied by significant infiltration of inflammatory cells. However, compared with the REDE group, the intestinal tissue damage in the STREDE group was alleviated, and the infiltration of inflammatory cells decreased. The intestinal toxicity significantly decreased. Mass spectrometry analysis showed that there was no significant difference in the content of diterpenoids of REDE before and after simulated TCS processing, but a large number of tannins and phenolic acids were added. The results of HPLC showed that the content of four diterpenoids of E. ebracteo-lata decreased to varying degrees after TCS processing, ranging from-0.35% to-19.74%, and the decreased part mainly remained in the container wall, indicating that the structure of toxic diterpenoids of E. ebracteolata was not changed after TCS processing. The antagonistic effect of tannic and phenolic acids in the TCS may be the main reason for the reduced intestinal toxicity of E. ebracteolata after TCS processing. The TCS processing for E. ebracteolata is scientific.
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Medicamentos de Ervas Chinesas , Euphorbia , Terminalia , Euphorbia/química , Animais , Terminalia/química , Camundongos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Masculino , Intestinos/efeitos dos fármacos , Intestinos/química , Cromatografia Líquida de Alta Pressão , HumanosRESUMO
As a viable supplement to the fifth generation wireless communication, visible light communications (VLC) with affluent spectrum resources can cater to the ever-increasing high speed data transmission demand. However, the nonlinear characteristics of light emitting diode (LED) can distort the transmitted signal in the VLC link, which damages the communication quality. To mitigate the nonlinear impairments, a reproducing kernel Hilbert space post-distortion scheme is proposed in this paper, which is based on kernel recursive least squares (KRLS) with adaptive kernel width. In this kernel based method, the kernel width will affect the approximation ability of the model. Therefore, in the recursive process of KRLS, Gauss-Newton (GN) algorithm is adopted to update the kernel width. In addition, combined with the enhanced novelty criterion (ENC), the KRLS-GN post-distorter learns the sparse dictionary adaptively according to the input data, which is beneficial to complete the linearization under the limited memory budget constraints. The performance of the proposed KRLS-GN-ENC scheme is verified by simulations, and the results show that KRLS-GN-ENC can achieve a significant improvement over KRLS-ENC. Compared with the schemes based on classical polynomial filtering, KRLS-GN-ENC exhibits better nonlinear compensation performance and faster convergence speed.
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Patients with NPM1 gene mutation-associated acute myeloid leukemia (AML), particularly those over the age of 60, have no viable targeted therapeutic choices. In this study, we identified HEN-463, a sesquiterpene lactone derivative specific targets AML with this gene mutation. This compound inhibits the interaction of LAS1-NOL9 by covalently binding to the C264 site of the ribosomal biogenesis-related protein LAS1, which translocates the LAS1 to the cytoplasm, thereby inhibiting the maturation of 28 S rRNA. This has a profound effect on the NPM1-MDM2-p53 pathway and ultimately results in the stabilization of p53. Combining this treatment with the XPO1 inhibitor Selinexor (Sel) can ideally preserve the stabilized p53 in the nucleus, considerably enhancing the efficacy of HEN-463 and addressing Sel's drug resistance. Patients with AML over the age of 60 who possess the NPM1 mutation have an unusually elevated level of LAS1, which has a significant impact on their prognosis. In NPM1-mutant AML cells, decreased LAS1 expression promotes proliferation inhibition, apoptosis, cell differentiation, and cell cycle arrest. This suggests that it may be a therapeutic target for this kind of blood cancer, especially in patients over the age of 60.
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Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteína Supressora de Tumor p53/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Proteínas Ribossômicas/metabolismo , Polinucleotídeo 5'-Hidroxiquinase/genética , Polinucleotídeo 5'-Hidroxiquinase/metabolismoRESUMO
Selective N-methylation of amines with methanol is an important reaction in the synthesis of high-value-added fine chemicals, including dyes, surfactants, pharmaceuticals, agrochemicals, and materials. However, N-methylated amines possess higher reactivities and are prone to further transform into N,N-dimethylated amines. Therefore, it is still a challenge to controllably regulate the selectivity of N-methylation using heterogeneous catalysts without the use of base. Herein, we developed a series of Pd/Zn(Al)O catalysts with abundant basic sites, and the selectivity of N-methylation was controlled by a heterogeneous Pd/Zn(Al)O catalyst with a Zn/Al ratio of 10 and a Pd loading of 0.4 wt % in the pressure of H2. The experimental results showed that the appropriate basic properties of the catalyst were beneficial to form the desired N-methylated amine. The low loading of Pd in the catalyst was highly dispersed on the support, providing sufficient active sites. These were attributed to the Zn vacancies formed by Al-doped Zn, which were beneficial to form the highly active and stable Pd sites. Furthermore, a series of amines and nitrobenzenes with different functional groups were well tolerated for the selective synthesis of N-methylated amines in the absence of base.
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Triptolide (TP) exhibits therapeutic potential against multiple diseases. However, its application in clinics is limited by TP-induced hepatoxicity. TP can activate invariant natural killer T (iNKT) cells in the liver, shifting Th1 cytokine bias to Th2 cytokine bias. The damaging role of iNKT cells in TP-induced hepatoxicity has been established, and iNKT cell deficiency can mitigate hepatotoxicity. However, the activation of iNKT cells in vitro by TP requires the presence of antigen-presenting cells. Therefore, we hypothesized that TP could induce dendritic cells (DCs) to activate iNKT cells, thereby leading to hepatotoxicity. The hepatic conventional DCs (cDCs) exhibited immunogenic activities after TP administration, upregulating the expression of CD1d, co-stimulatory molecules, and IL-12. Neutralization with IL-12p40 antibody extenuated TP-induced hepatotoxicity and reduced iNKT cell activation, suggesting that IL-12 could cause liver injury by activating iNKT cells. TP triggered the activation and upregulation of STING signaling pathway and increased endoplasmic reticulum (ER) stress. Downregulation of STING reduced cDC immunogenicity, inhibiting the activation of iNKT cells and hepatic damage. These indicated the regulatory effects of STING pathway on cDCs and iNKT cells, and the important roles it plays in hepatoxicity. ER stress inhibitor, 4-phenylbutyrate (4-PBA), also suppressed iNKT cell activation and liver injury, which might be regulated by the STING signaling pathway. Our results demonstrated the possible mechanisms underlying TP-induced hepatoxicity, where the activation of cDCs and iNKT cells was stimulated by upregulated STING signaling and increased ER stress as a result of TP administration.
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Doença Hepática Induzida por Substâncias e Drogas , Células T Matadoras Naturais , Humanos , Células T Matadoras Naturais/metabolismo , Transdução de Sinais , Citocinas/metabolismo , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Estresse do Retículo Endoplasmático , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
V-domain immunoglobulin suppressor of T-cell activation (VISTA), an important negative checkpoint protein, participates in immunoregulation. Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients exhibit high levels of autoantibodies and multi-organ tissue injury, primarily involving the kidney and skin. In wild-type (WT) mice and Vsir-/- mice with pristane-induced lupus-like disease, we found that VISTA deficiency exacerbated the lupus-like disease in mice, possibly through aberrant activation of type I interferon (IFN-I) signaling, CD4+ T cell, and noncanonical nuclear factor-κB (NF-κB) pathway. Surface plasmon resonance results showed that imatinib, an FDA-approved tyrosine kinase inhibitor, may have a high affinity for human VISTA-ECD with a KD value of 0.2009 µM. The biological activities of imatinib and VISTA agonist M351-0056 were studied in monocytes and T cells and in lupus-like disease murine model of chronic graft-versus-host disease (cGVHD) and lupus-prone MRL/lpr mice. VISTA small-molecule agonist reduced the cytokine production of peripheral blood mononuclear cells (PBMCs) and Jurkat cells and inhibited PBMCs proliferation. Moreover, they attenuated the levels of autoantibodies, renal injury, inflammatory cytokines, chemokines, and immune cell expansion in the cGVHD mouse model and MRL/lpr mice. Our findings also demonstrated that VISTA small-molecule agonist ameliorated the development of SLE through improving aberrantly activated IFN-I signaling and noncanonical NF-κB pathway. In conclusion, VISTA has a protective effect on the development and progression of SLE. VISTA agonist M351-0056 and imatinib have been firstly demonstrated to attenuate SLE, suggesting interventions to enhance VISTA function may be effective in treating SLE. VISTA deficiency exacerbates pristane-induced lupus-like disease in mice by promoting activation of the IFN-I and noncanonical NF-κB pathway. Imatinib was screened as a small-molecule VISTA agonist by molecular docking, SPR, and cellular level experiments. VISTA agonists (M351-0056 and imatinib) alleviated lupus-like disease progression in the cGVHD mouse model and MRL/lpr mice by inhibiting activation of IFN-I and noncanonical NF-κB pathway.
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Lúpus Eritematoso Sistêmico , NF-kappa B , Humanos , Animais , Camundongos , NF-kappa B/metabolismo , Mesilato de Imatinib/farmacologia , Interferons , Leucócitos Mononucleares , Simulação de Acoplamento Molecular , Camundongos Endogâmicos MRL lpr , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Citocinas/metabolismo , Autoanticorpos , Modelos Animais de DoençasRESUMO
The overuse of thiamethoxam (THM) has threatened the survival of living organisms and it is necessary to find an environmentally friendly material to remove THM frequently detected in water. Biochar prepared from cow manure modified with ZnCl2 (Zn-CBC) was used to remove THM. Compared to the unmodified cow manure biochar (CBC), the removal ratio of THM by Zn-CBC was enhanced 35 times. In the mechanistic analysis, SEM and BET showed that Zn-CBC had a good pore structure and its specific surface area (166.502 m2 g-1) increased to 17 times that of CBC, indicating that Zn-CBC had good pore adsorption properties. The adsorption kinetic and isotherm implied that the main mechanism was chemisorption including π-π interaction and H-bonding. Furthermore, the stable graphitized structure of Zn-CBC allowed for efficient adsorption and reusability. In addition, this study constructed an intelligent prediction model using batch experiment data, and the high R2 (0.978) and low RMSE (0.057) implied that the model could accurately and quantitatively predict the adsorption efficiency. This paper provides a novel perspective to simultaneously remove the neonicotinoid insecticides and realize the resource utilization of cow manure.
RESUMO
IL-17 is closely associated with inflammation in intrahepatic cholestasis (IHC). Targeting IL-17 ameliorates IHC in mice. Invariant natural killer T (iNKT) cells are predominantly enriched in the liver and they mediate drug-induced liver injury through their secreted cytokines. However, whether iNKT17 cells are involved in ethinylestradiol (EE)-induced IHC remains unclear. In the present study, the administration of EE (10 mg/kg in vivo and 6.25 µM in vitro) promoted the activation and expansion of iNKT17 cells, which contributed to a novel hepatic iNKT17/Treg imbalance. iNKT cell-deficient Jα18-/- mice and the RORγt inhibitor digoxin (20 µg) alleviated EE-induced cholestatic hepatotoxicity and downregulated the IL-17 signalling pathway. In contrast, the co-administration of EE with recombinant IL-17 (1 µg) to Jα18-/- mice induced cholestatic hepatotoxicity and increased the infiltration of hepatic neutrophils and monocytes. Importantly, the administration of IL-17-/- iNKT cells (3.5 × 105) to Jα18-/- mice resulted in the attenuation of hepatotoxicity and the recruitment of fewer hepatic neutrophils and monocytes than the adoptive transfer of wild-type iNKT cells. These results indicated that iNKT17 cells could exert pathogenic effects. The recruitment and activation of iNKT17 cells could be attributed to the high level of CXCR3 expression on their surface. CXCL10 deficiency ameliorated EE-induced cholestatic liver damage, reduced hepatic CXCR3+ iNKT cells and inhibited RORγt expression. These findings suggest that iNKT17 cells play a key role in EE-induced cholestatic liver injury via CXCR3-mediated recruitment and activation. Our study provides new insights and therapeutic targets for cholestatic diseases.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Colestase , Células T Matadoras Naturais , Camundongos , Animais , Interleucina-17 , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Etinilestradiol/toxicidade , Colestase/induzido quimicamente , Colestase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células T Matadoras Naturais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Catalytic hydrogenation reduction based on sodium borohydride (NaBH4) has gained attention as an appealing "one-stone-two-birds" approach for the simultaneous elimination of nitroaromatic pollutants and the production of high-value aminoaromatics under mild conditions. However, the slow kinetics of NaBH4 dissociation on the surface of catalysts restrict the catalytic hydrogenation reduction efficiency. Herein, we report an intelligent localized sulfidation strategy for an in situ implantation of Bi2S3 nanorods within quasi-Bi-MOF architectures (Bi2S3@quasi-Bi-MOF) by fine-tuning the pyrolysis temperature. In this novel Bi2S3@quasi-Bi-MOF, the porous quasi-Bi-MOF enables efficient adsorption of BH4- and 4-nitrophenol (4-NP), while Bi2S3 facilitates the BH4- dissociation to form Hads* species adsorbed on the catalyst surface. Benefiting from the synergistic structure, Bi2S3@quasi-Bi-MOF exhibits excellent performance for the catalytic reduction of 4-NP, delivering a high turnover frequency (TOF) of 1.67 × 10-4 mmol mg-1 min-1 and an extremely high normalized rate constant (knor) of 435298 s-1 g-1. The kinetic analysis and electrochemical tests indicate that this catalytic hydrogenation reduction follows the Langmuir-Hinshelwood mechanism. This study enriches the synthetic strategy of MOF-based derivatives and offers a new catalytic platform for hydrogenation reduction reactions.