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BACKGROUND: Ribosomal RNA processing protein 15 (RRP15) has been found to regulate the progression of hepatocellular carcinoma (HCC). Nevertheless, the extent to which it contributes to the spread of HCC cells remains uncertain. Thus, the objective of this research was to assess the biological function of RRP15 in the migration of HCC. METHODS: The expression of RRP15 in HCC tissue microarray (TMA), tumor tissues and cell lines were determined. In vitro, the effects of RRP15 knockdown on the migration, invasion and adhesion ability of HCC cells were assessed by wound healing assay, transwell and adhesion assay, respectively. The effect of RRP15 knockdown on HCC migration was also evaluated in vivo in a mouse model. RESULTS: Bioinformatics analysis showed that high expression of RRP15 was significantly associated with low survival rate of HCC. The expression level of RRP15 was strikingly upregulated in HCC tissues and cell lines compared with the corresponding controls, and TMA data also indicated that RRP15 was a pivotal prognostic factor for HCC. RRP15 knockdown in HCC cells reduced epithelial-to-mesenchymal transition (EMT) and inhibited migration in vitro and in vivo, independent of P53 expression. Mechanistically, blockade of RRP15 reduced the protein level of the transcription factor POZ/BTB and AT hook containing zinc finger 1 (PATZ1), resulting in decreased expression of the downstream genes encoding laminin 5 subunits, LAMC2 and LAMB3, eventually suppressing the integrin ß4 (ITGB4)/focal adhesion kinase (FAK)/nuclear factor κB kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. CONCLUSIONS: RRP15 promotes HCC migration by activating the LAMC2/ITGB4/FAK pathway, providing a new target for future HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Processamento Pós-Transcricional do RNA , Proteínas Ribossômicas , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Ribossomos/metabolismo , Ribossomos/patologia , Fatores de Transcrição/genética , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismoRESUMO
INTRODUCTION: Smoking is a cause of nonalcoholic fatty liver disease (NAFLD), but the dose-response relationship between secondhand smoke exposure (SHS) and NAFLD is unclear. This study sought to determine the relationship between SHS and NAFLD risk among adult nonsmokers in the United States. AIMS AND METHODS: Data from 7412 adult nonsmokers aged ≥20 years who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016 were used in this study. SHS was defined as a nonsmoker with a serum cotinine concentration of 0.05-10.00 ng/mL. NAFLD was identified using the U.S. fatty liver index (USFLI), hepatic steatosis index (HSI), and fatty liver index (FLI). Weighted multivariable logistic regression and restricted cubic spline models were applied to evaluate the relationship between SHS and NAFLD risk. RESULTS: The participants had a weighted mean age of 49.2 years, and 55.5% were female. SHS was associated with NAFLD (odds ratio [OR] 1.22; 95% confidence interval CI: 1.05 to 1.42), showing a linear dose-response relationship (natural log of cotinine level: OR 1.10, 95% CI: 1.05 to 1.17). Sensitivity analyses using different NAFLD definitions (HSI: OR 1.21, 95% CI: 1.01 to 1.46; FLI: OR 1.26, 95% CI: 1.06 to 1.49), excluding participants taking hepatotoxic drugs, and propensity score-adjusted analysis yielded similar results. The association between SHS and NAFLD was consistent in analyses stratified by age, sex, and race/ethnicity. CONCLUSIONS: Among this nationally representative sample of U.S. adults, SHS had a linear dose-response relationship with the risk of NAFLD, suggesting that measures to lower SHS might lower NAFLD risk. IMPLICATIONS: This study assessed the association between secondhand smoke exposure and the risk of nonalcoholic fatty liver disease (NAFLD) using data from 7412 adult nonsmokers aged 20 years or older who participated in the United States NHANES between 2007 and 2016. Secondhand smoke exposure was measured using serum cotinine levels. Three different noninvasive indexes were used to measure NAFLD. Secondhand smoke exposure was associated with an increased risk of NAFLD, with a linear dose-response relationship. The results of sensitivity analyses and subgroup analyses were consistent.
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Cotinina , Hepatopatia Gordurosa não Alcoólica , Inquéritos Nutricionais , Poluição por Fumaça de Tabaco , Humanos , Feminino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Masculino , Pessoa de Meia-Idade , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Estados Unidos/epidemiologia , Adulto , Cotinina/sangue , Fatores de Risco , não Fumantes/estatística & dados numéricos , Adulto JovemRESUMO
Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.
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Injúria Renal Aguda , Exercício Físico , Erros Inatos do Transporte Tubular Renal , Humanos , Injúria Renal Aguda/etiologia , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/complicações , Adolescente , Masculino , Recidiva , Proteínas Facilitadoras de Transporte de Glucose/genética , Xantina Oxidase , Cálculos Urinários/genética , Cálculos Urinários/etiologia , Cálculos Urinários/complicações , China , Mutação , População do Leste AsiáticoRESUMO
BACKGROUND AND AIMS: NAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver. APPROACH AND RESULTS: Expression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepatic Fgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high-fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+ -Ca2+ /calmodulin-dependent protein kinase kinase beta-dependent AMP-activated protein kinase (AMPK)-Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage. CONCLUSIONS: Our study identifies FGF4 as a stress-responsive regulator of liver pathophysiology that acts through an FGFR4-AMPK-Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.
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Hepatopatia Gordurosa não Alcoólica , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Caspase 6/metabolismo , Caspase 6/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Fator 4 de Crescimento de Fibroblastos/metabolismo , Fator 4 de Crescimento de Fibroblastos/farmacologia , Fator 4 de Crescimento de Fibroblastos/uso terapêutico , Humanos , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/uso terapêuticoRESUMO
BACKGROUND: Scarce evidence exists on pediatric colorectal polyp risk factors. This study explored the clinical manifestations, morphological and pathological characteristics of, and risk factors for pediatric colorectal polyps. METHODS: This retrospective case-control study included children who received colonoscopy, divided into a colorectal polyp group and a normal control group based on colonoscopy results. The risk factors for colorectal polyps in children were analyzed through logistic regression analysis. RESULTS: The mean age of children with polyps was 6.77 ± 3.44 years. Polyps were detected predominantly in males (72.9%); hematochezia was the primary clinical manifestation (80.25%). Most polyps were juvenile (88.9%) and solitary (87.7%); 50.6% were located in the rectosigmoid area. Univariate analysis showed that gender (P = 0.037), age (P < 0.001), family aggregation (P < 0.001), specific immunoglobulin E (sIgE) (P < 0.001), platelet count (P = 0.001), aspartate aminotransferase (AST) (P = 0.016), meat intake (P = 0.010), and vegetable intake (P < 0.001) were significantly associated with colorectal polyps. Age ≤ 6 years (3-6 years: OR: 26.601, 95% CI: 3.761-160.910; < 3 years: OR: 22.678, 95% CI: 1.873-274.535), positive family aggregation (OR: 3.540, 95% CI: 1.177-10.643), positive sIgE (OR:2.263, 95% CI: 1.076-4.761), and higher meat intake (OR:1.046, 95% CI: 1.029-1.063) were risk factors for pediatric colorectal polyps in logistic regression analysis. Higher vegetable intake (OR: 0.993, 95% CI: 0.986-1.000) was a protective factor against pediatric colorectal polyps. The area under the curve (AUC) of meat intake in the receiver operating characteristic (ROC) curve analysis for predicting colorectal polyps was 0.607; the best cut-off value was 92.14 g/d (P = 0.010, 95% CI: 0.527-0.687). The meat and vegetable intake combination AUC in predicting pediatric colorectal polyps was 0.781 (P < 0.001, 95% CI: 0.718-0.845). CONCLUSIONS: Juvenile, solitary, and located in the rectosigmoid region polyps are most common in children. Hematochezia is the main clinical manifestation. Most polyps were, but multiple and proximally located polyps were also detected. Age ≤ 6 years, especially 3-6 years, positive family aggregation, positive sIgE, and higher meat intake are risk factors for pediatric colorectal polyps. A higher vegetable intake is a protective factor.
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Pólipos do Colo , Masculino , Criança , Humanos , Pré-Escolar , Estudos de Casos e Controles , Estudos Retrospectivos , Pólipos do Colo/diagnóstico , Pólipos do Colo/epidemiologia , Pólipos do Colo/etiologia , China/epidemiologia , Imunoglobulina E , Fatores de RiscoRESUMO
BACKGROUND: Intestinal epithelial barrier disruption and bacterial translocation exacerbates the progression of alcoholic liver disease. Lactobacillus rhamnosus GG (LGG), a probiotic, has been shown benefits in chronic liver disease and in regulating gut dysbiosis. Previous studies showed the protective roles of LGG in ethanol-disrupted gut barrier functions and liver injury. Inosine, a metabolite produced by intestinal bacteria, has the anti-inflammatory and immunregulatory functions. In this study, the synergistic effect of LGG and inosine was investigated in a mouse model of alcohol-induced liver disease (ALD). METHODS: Male C57BL/6 mice were fed with a Lieber-DeCarli diet containing 5% alcohol for four weeks to establish a model of alcohol-induced liver injury. LGG or a combination of LGG and inosine were administrated orally to explore a new therapeutic method for alcohol-induced liver disease and to investigate the underlying mechanisms. Liver damage was evaluated by transaminases and pathological changes. Tight junction proteins, composition of the gut microbiome, cytokines, lipopolysaccharides (LPS), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), F4/80+ macrophages, as well as p38, Jun N-terminal kinase (JNK), were determined by qRT-PCR, RNAseq, ELISA, IHC and western blot. Regulatory T (Treg) cells were characterized by positive staining of CD4, CD25 and Foxp3 using flow cytometry. IFN-γ-producing CD4+ T (Th1) cells were examined by intracellular cytokine staining. RESULTS: Alcohol consumption induced elevated liver enzymes, steatosis and inflammation, while LGG combined with inosine treatment was more significant to ameliorate these symptoms compared with LGG alone. When LGG combined with inosine were administered to ALD mice, intestinal microecology significantly improved reflected by intestinal villi and tight junction proteins recovery and the restoration of intestinal flora. Combined therapy inhibited phosphorylation of p38 and JNK to alleviate hepatic inflammation. Moreover, flow cytometry analysis showed that long-term excessive alcohol consumption reduced Tregs population while increased Th1 population, which was restored by a combination of LGG and inosine treatment. CONCLUSIONS: The findings from the study indicate that the combined LGG and inosine treatment ameliorates ALD by improving the gut ecosystem, intestinal barrier function, immune homeostasis and liver injury.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Lacticaseibacillus rhamnosus , Hepatopatias Alcoólicas , Animais , Ecossistema , Etanol/toxicidade , Inflamação , Inosina , Lacticaseibacillus rhamnosus/fisiologia , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Células Th1 , Proteínas de Junções ÍntimasRESUMO
The remediation of environmental boron contamination has received extensive research attention. The adsorbent ECH@NGM aerogel with high hydrophilic and mechanical properties was synthesized to remove boron. The ECH@NGM aerogel had a high adsorption capacity of 81.11 mg/g, which was 14.50% higher than that of commercial boron-selective resin Amberlite IRA743. The Freundlich model and pseudo-second-order model described the adsorption behavior well. In addition, the response surface methodology (RSM) could predict the experimental outcomes and optimize the reaction conditions, and X-ray photoelectron spectroscopy (XPS) and control tests were utilized to investigate probable adsorption mechanisms. These data showed that the B â N coordination bond was the primary adsorption force. The adsorbent had good resistance to interference from coexisting salts, high reusability, good adsorption performance even after five reuse cycles, and a high desorption rate in a relatively short time. The adsorption performance in real brines could be maintained at 80%. Therefore, this work not only provided ECH@NGM aerogels for the removal of boron from brine but also elucidated the main adsorption processes between N-containing adsorbents and boron, facilitating the design of future adsorbents for boron removal.
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BACKGROUND AND AIM: Acute liver failure (ALF) poses a serious public health issue. The menstrual blood-derived mesenchymal stem cells (MenSCs) have been applied to cure various liver-related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF. METHODS: We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d-galactosamine (d-GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin-eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells. RESULTS: The MenSCs can decrease the lipid polysaccharide-induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated-NF-kBp65 (p-NF-kBp65), PI3K, and p-AKT, p-mTOR and p-IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes. CONCLUSIONS: The MenSCs can attenuate the ALF-induced liver injury via inhibition of TLR4-mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p-NF-κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above-mentioned effects.
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Agonistas do Receptor A2 de Adenosina , Falência Hepática Aguda , Menstruação , Células-Tronco Mesenquimais , Agonistas do Receptor A2 de Adenosina/imunologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/terapia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/terapia , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA-143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir-143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1-mediated miRNA-143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA-143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA-143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.
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Hepatite Autoimune/complicações , Hepatócitos/patologia , Inflamação/prevenção & controle , Cirrose Hepática/prevenção & controle , MAP Quinase Quinase Quinases/metabolismo , MicroRNAs/administração & dosagem , Animais , Hepatite Autoimune/patologia , Hepatócitos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , MicroRNAs/genéticaRESUMO
BACKGROUND AND AIMS: Helicobacter pylori (H. pylori) infection can occur in early childhood, without eradication therapies such infection can persist throughout life and cause many different diseases. This study investigated the metabolic characteristics and explored the underlying mechanism of children with H. pylori infection, and identified potential biomarkers for evaluating the efficacy of H. pylori eradication therapies. METHODS: We performed 1H NMR-based metabonomics coupled with multivariate analysis to investigate the metabolic profiling of serum samples between Children with and without H. pylori infection. In the same manner, we compared the alternations of metabolites in H. pylori-infected children before and after H. pylori eradication therapies. RESULTS: 21 metabolites from serum in H. pylori-infected and H. pylori-uninfected children were identified, which were mainly involved in energy, amino acid, lipid and microbial metabolism. We found that the serum levels of trimethylamine N-oxide and alanine were significantly higher in H. pylori-infected children compared to uninfected sera, whereas lactate was significantly lower. We also found that the levels of trimethylamine N-oxide and creatine in H. pylori-infected children was significantly decreased after H. pylori eradication therapies, whereas lactate and low-density lipoprotein/very low-density lipoprotein was significantly increased. CONCLUSIONS: This is the first study using 1H NMR-based metabolomics approach to explore the effects of H. pylori infection in children. Our results demonstrated that the disturbances of metabolism in energy, amino acids, lipids and microbiota could play an important role in the pathogenesis of gastrointestinal and extragastric diseases caused by H. pylori infection. Trimethylamine N-oxide and lactate might serve as potential serum biomarkers for evaluating the efficacy of H. pylori eradication therapies.
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Infecções por Helicobacter , Helicobacter pylori , Microbiota , Criança , Pré-Escolar , Humanos , Metabolômica , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Sodium alginate (SA) is a marine polysaccharide biomass material that is environmentally friendly and exhibits color-changing properties under certain conditions. In this study, we have discovered sodium alginate solution to be chromogenic under four conditions, namely alkali-chromogenic, thermo-chromogenic, force-chromogenic and photo-chromogenic. Under simple strong alkaline conditions, sodium alginate forms clusters of blue light-absorbing chromogenic aggregates, which exhibit a bright yellow color at a certain size. Under different temperature conditions, SA shows varying shades of yellow, and the color tends to stabilize after 48 h of resting. The aggregates can be dispersed by stirring, which changes SA from yellow to colorless. The yellow color can then be recovered after resting. Additionally, exposure to sunlight can cause the yellow SA to fade, but the color can be restored by reheating. Therefore, the force-chromogenic and photo-chromogenic properties are reversible. This makes it a promising material for use in color-developing and indicating materials. It is expected to become a sodium alginate cluster pigment with broad application prospects in the future.
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Vast and complex intestinal communities are regulated and balanced through interactions with their host organisms, and disruption of gut microbial balance can cause a variety of diseases. Studying the mechanisms of pathogenic intestinal flora in the host and early detection of bacterial translocation and colonization can guide clinical diagnosis, provide targeted treatments, and improve patient prognosis. The use of in vivo imaging techniques to track microorganisms in the intestine, and study structural and functional changes of both cells and proteins, may clarify the governing equilibrium between the flora and host. Despite the recent rapid development of in vivo imaging of intestinal microecology, determining the ideal methodology for clinical use remains a challenge. Advances in optics, computer technology, and molecular biology promise to expand the horizons of research and development, thereby providing exciting opportunities to study the spatio-temporal dynamics of gut microbiota and the origins of disease. Here, this study reviews the characteristics and problems associated with optical imaging techniques, including bioluminescence, conventional fluorescence, novel metabolic labeling methods, nanomaterials, intelligently activated imaging agents, and photoacoustic (PA) imaging. It hopes to provide a valuable theoretical basis for future bio-intelligent imaging of intestinal bacteria.
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Microbioma Gastrointestinal , Humanos , Imagem Óptica , BactériasRESUMO
AIMS: Alcoholic liver disease (ALD) can develop into cirrhosis and hepatocellular carcinoma but no specific drugs are available. Fenofibrate is therapeutically effective in ALD, however, the exact mechanism remains unknown. We explored the hub genes of ALD and the role of fenofibrate in ALD. MAIN METHODS: The hub genes of ALD were screened by bioinformatics method, and their functional enrichment, signalling pathways, target genes and their correlation with immune microenvironment and pathogenic genes were analysed. We also analysed the binding affinity of fenofibrate to proteins of hub genes using molecular docking techniques, and the effects on hub gene expression, lipid deposition, oxidative stress and inflammation in the liver of National Institute on Alcohol Abuse and Alcoholism (NIAAA) model mice. The regulatory effects of fenofibrate on MOXD1 and PDZK1P1 were investigated after gene silencing of peroxisome proliferator-activated receptor-α (Ppar-α). KEY FINDINGS: Hub genes identified, including monooxygenase DBH-like 1 (MOXD1), PDZK1-interacting protein 1 (PDZK1IP1) and solute carrier 51 ß (SLC51B), are highly predictive for ALD. Hepatic MOXD1 and PDZK1IP1 expression was elevated in patients with ALD and NIAAA model mice, with no significant difference in SLC51B expression between the groups. Fenofibrate binds tightly to MOXD1 and PDZK1IP1, inhibits their hepatic expression independently of PPAR-α signalling, and ameliorates lipid deposition, oxidative stress and inflammatory responses in NIAAA model mice. SIGNIFICANCE: MOXD1 and PDZK1IP1 are key genes in ALD progression; fenofibrate improves liver damage in NIAAA model mice by downregulating their expression. Our findings provide insight for improving diagnostic and therapeutic strategies for ALD.
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Fígado Gorduroso Alcoólico , Fenofibrato , Hipercolesterolemia , Hepatopatias Alcoólicas , Camundongos , Humanos , Animais , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Simulação de Acoplamento Molecular , Fígado/metabolismo , Inflamação/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Hipercolesterolemia/metabolismo , Hepatopatias Alcoólicas/patologia , Lipídeos/farmacologia , Proteínas de Membrana/metabolismoRESUMO
BACKGROUND AND AIMS: Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. METHODS: Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1-/-) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. RESULTS: CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1-/- mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. CONCLUSIONS: Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH.
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Hepatopatia Gordurosa não Alcoólica , Compostos de Fenilureia , Piperidinas , Animais , Humanos , Camundongos , Colina/metabolismo , Colina/farmacologia , Modelos Animais de Doenças , Fígado/metabolismo , Cirrose Hepática/patologia , Ativação de Macrófagos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metionina/metabolismo , Metionina/farmacologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores CCR1/genética , Receptores CCR1/metabolismo , Receptores de Quimiocinas/metabolismoRESUMO
[This corrects the article DOI: 10.1016/j.apsb.2023.12.012.].
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Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.
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A composite aerogel with good mechanical properties and adjustable physical properties was synthesized by a sol-gel technique on the base of gelatin for the boron adsorption from water solution. The adsorption key variables, for instance, initial boron concentration (C0) (900-1100 mg/L), the contact time (t) (8-9 h), and pH (9-11), were optimized using central composite design to obtain improved boron adsorption performance of epichlorohydrin-modified gelatin (EMG)/N-methyl-d-glutamine (NMDG) aerogel loaded with hydroxylated carbon nanotubes (EMG@NMDG). The adsorption followed the pseudo-second-order and Freundlich model. At pH of 10, C0 of 1000 mg/L and t of 10 h, the largest adsorbed amount of EMG@NMDG was 85.79 mg/g. Regeneration experiments were carried out by eluting the adsorbent using HCl. The analysis showed that the adsorption in actual brine was 62.65 mg/g. Therefore, the developed EMG@NMDG aerogel has potential value for the boron extraction from brine and wastewater.
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The poor processing and rheological properties of highly filled composites caused by the high loading of fillers can be improved with the use of maleic anhydride grafted polyethylene wax (PEWM) as compatibilizer and lubricant. In this study, two PEWMs with different molecular weights were synthesized by melt grafting, and their compositions and grafting degrees were characterized by Fourier transform infrared (FTIR) spectroscopy and acid-base titration. Subsequently, magnesium hydroxide (MH)/linear low-density polyethylene (LLDPE) composites with 60 wt% of MH were prepared using polyethylene wax (PEW) and PEWM, respectively. The equilibrium torque and melt flow index tests indicate that the processability and fluidity of MH/MAPP/LLDPE composites are significantly improved with the addition of PEWM. The addition of PEWM with a lower molecular weight leads to a substantial reduction in viscosity. The mechanical properties are also increased. The limiting oxygen index (LOI) test and cone calorimeter test (CCT) show that both PEW and PEWM have adverse effects on flame retardancy. This study provides a strategy to simultaneously improve the processability and mechanical properties of highly filled composites.
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Introduction: Enteric dysbacteriosis is strongly associated with nonalcoholic fatty liver disease (NAFLD). However, the underlying causal relationship remains unknown. Thus, the present study aimed to investigate the relationship between gut microbiota and NAFLD using Mendelian randomization (MR) and analyze the target genes potentially regulated by specific microbiota. Methods: Bidirectional two-sample MR analysis was performed using inverse variance weighted (IVW) supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Data were pooled from gut microbiota and NAFLD association studies. The least absolute shrinkage, selection operator regression, and the Support Vector Machine algorithm were used to identify genes regulated by these intestinal flora in NAFLD. The liver expression of these genes was verified in methionine choline-deficient (MCD) diet-fed mice. Results: IVW results confirmed a causal relationship between eight specific gut microbes and NAFLD. Notably, the order Actinomycetales, NB1n, the family Actinomycetaceae, Oxalobacteraceae and the genus Ruminococcaceae UCG005 were positively correlated, whereas Lactobacillaceae, the Christensenellaceae R7 group, and Intestinibacter were negatively correlated with NAFLD onset. In NAFLD, these eight bacteria regulated four genes: colony-stimulating factor 2 receptor ß, fucosyltransferase 2, 17-beta-hydroxysteroid dehydrogenase 14, and microtubule affinity regulatory kinase 3 (MAPK3). All genes, except MARK3, were differentially expressed in the liver tissues of MCD diet-fed mice. Discussion: The abundance of eight gut microbiota species and NAFLD progression displayed a causal relationship based on the expression of the four target genes. Our findings contributed to the advancement of intestinal microecology-based diagnostic technologies and targeted therapies for NAFLD.
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OBJECTIVE: Cryptococcal meningitis (CM) is a not rare condition in HIV-negative patients. Here, we describe the clinical characteristics, possible risk factors, and outcomes of HIV-negative patients with CM. METHODS: Medical records from 99 HIV-negative patients with CM admitted to our hospital from 2010 to 2021 were reviewed systematically. We compared the clinical features and outcomes between patients with underlying diseases and otherwise healthy hosts. RESULTS: The 99 HIV-negative CM patients had a mean age at presentation of 56.2 ± 16.2 years, and the female-to-male ratio was 77:22. A total of 52 (52.5%) CM patients had underlying conditions, and 47 patients (47.5%) had no underlying conditions. Kidney transplant represented the most frequent underlying condition (11.1%), followed by rheumatic disease (10.1%) and hematological diseases (9.1%). Compared to patients without underlying conditions, those with underlying conditions had significantly more fever, more steroid therapy, higher serum creatinine, and lower albumin, IgG, hemoglobin, and platelets (p < 0.05 for each). CM patients without underlying conditions had significantly more alcohol abuse than those with underlying conditions (31.9% vs. 9.6%, p = 0.011). By logistic regression analysis, male gender (OR = 3.16, p = 0.001), higher CSF WBC (OR = 2.88, p = 0.005), and protein (OR = 2.82, p = 0.002) were significantly associated with mortality. CONCLUSION: Patients with underlying conditions had a similar mortality to patients without underlying conditions. Alcohol abuse was a probable risk factor for CM for previously healthy patients. Male gender, higher CSF WBC, and protein were significantly associated with mortality.