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Berberine (BBR) is a traditional Chinese herb with broad antimicrobial activity. Gut microbiota plays an important role in the metabolism of bile acids and cholesterol. Our study investigated the effects of BBR on alleviating cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Adult male C57BL/6J mice fed with high cholesterol diet (HC) containing 1.25 % cholesterol (HC group) or fed with chow diet containing 0.02 % cholesterol (Chow group) served as controls. BBR50 and BBR100 group mice were fed with HC, and oral BBR daily at doses of 50 or 100 mg/kg respectively for 8 weeks. The results showed that BBR could reshape the homeostasis and composition of gut microbiota. The abundance of Clostridium genera was significantly inhibited by BBR, which resulted in a significant reduction of secondary bile acids within the enterohepatic circulation and a significant lower hydrophobic index of bile acids. The absorption of cholesterol in intestine, the deposition of cholesterol in liver and the excretion of cholesterol in biliary tract were significantly inhibited by BBR, which promoted the unsaturation of cholesterol in bile. These findings suggest the potential utility of BBR as a functional food to alleviate the negative effects of high cholesterol diet.
Assuntos
Berberina , Ácidos e Sais Biliares , Colesterol na Dieta , Colesterol , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Animais , Berberina/farmacologia , Ácidos e Sais Biliares/metabolismo , Masculino , Colesterol/metabolismo , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Fígado/efeitos dos fármacosRESUMO
BACKGROUND: Cholesterol gallstone disease is a common disease. Reducing cholesterol burden is important to prevent/treat gallstone. In this study, we investigated the application of diosgenin (DG) to prevent the formation of gallstone in mice. METHODS: Adult male C57BL/6J mice were fed with the lithogenic diet (LD) only or LD supplemented with DG or ezetimibe for 8 weeks. Incidences of gallstone formation were documented. Intestine and liver tissues were collected to measure the lipid contents and expression of genes in cholesterol metabolism. Caco2 cells were treated with DG to monitor the regulation on cholesterol absorption and the transcriptional regulation of Npc1l1 gene. Changes of gut microbiota by DG was analyzed. Intraperitoneal injection of LPS on mice was performed to verify its effects on STAT3 activation and Npc1l1 expression in the small intestine. RESULTS: LD led to 100% formation of gallstones in mice. In comparison, dietary DG or ezetimibe supplementary completely prevents gallstones formation. DG inhibited intestinal cholesterol absorption in mice as well as in Caco2 cells by down-regulation of Npc1l1 expression. DG could directly inhibit phosphorylation of STAT3 and its transcriptional regulation of Npc1l1 expression. Furthermore, DG could modulate gut microbiota profiles and LPS mediated STAT3 activation and Npc1l1 expression. CONCLUSION: Our results demonstrated that dietary DG could inhibit intestinal cholesterol absorption through decreasing NPC1L1 expression to prevent cholesterol gallstone formation.
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Diosgenina , Cálculos Biliares , Humanos , Camundongos , Masculino , Animais , Cálculos Biliares/prevenção & controle , Cálculos Biliares/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Diosgenina/farmacologia , Diosgenina/metabolismo , Células CACO-2 , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Intestinos , Colesterol , Dieta , Ezetimiba/farmacologia , Ezetimiba/metabolismo , Fígado/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: The incidence of gallstone-related disease steadily increased in the last few years. Here, we aimed to investigate the effect of tauroursodeoxycholic acid1 (TUDCA) on preventing cholesterol gallstones formation in high-fat fed (HFD) mice. MATERIAL AND METHODS: Specific pathogen-free male C57Bl/6 mice were fed a lithogenic diet2 (LD group) alone or in combination with TUDCA (5g/kg diet) for 8 weeks. Upon sacrifice, serum, gallbladder, liver and small intestine were collected and the formation of gallstones or crystals in the gallbladder was analyzed. Additionally, the intestinal microbiota, and bile acid composition, serum lipids and hepatic lipids were studied. RESULTS: Cholesterol gallstones with cholesterol crystals formed in mice of the LD-fed group (15/15, 100%). However, only cholesterol crystals were found in three mice without the presence of any gallstone in the TUDCA-treated group. Both serum and hepatic total cholesterol levels in the TUDCA group were significantly decreased compared with the LD group. Concomitantly, mRNA expression of Abcg5 and Abcg8 was significantly lower in the liver of the TUDCA group whilst mRNA transcripts for Abcb11, Acat2, and Cyp27 were significantly increased compared with the LD group. Additionally, the gallbladder cholesterol saturation index (1.06±0.15) in the TUDCA group was significantly decreased compared with the LD group. Interestingly, the ratio of Firmicutes/Bacteroides in the TUDCA group was increased 3x fold. CONCLUSIONS: TUDCA can inhibit the absorption and synthesis of lipids in the small intestine by improving the intestinal microbiota in HFD-fed mice, thus reducing gallstone formation.
Assuntos
Colagogos e Coleréticos/uso terapêutico , Cálculos Biliares/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Modelos Animais de Doenças , Cálculos Biliares/metabolismo , Cálculos Biliares/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We present for the first time, to the best of our knowledge, the influence of spherical aberration on the beam quality of a single-stage laser amplifier. We set up an amplifier with a special structure to measure the spherical aberration distribution in the cavity. The output power of the oscillator was controlled, and the pump power of the amplifier was adjusted to improve the beam quality. The results show that there is an optimal amplifier pump power, which maximizes the output laser beam quality. In the presented experiment, an optimal laser beam was achieved with an output power of 10.54 W and beam quality of Mx2=1.54, My2=1.39 for a pump power of 9.33 W, oscillator output power of 9.2 W, and a beam quality of Mx2=2.10, My2=2.03.
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Hemophilia B (HB) is an X-linked disorder caused by defects of F9 encoded coagulation factor IX, which is an ideal model for gene therapy. Most existing HB gene therapies are based on viral mediated gene supplementation, which could increase immunoreaction. In this study, CRISPR/Cas9 system was used for gene correction in an F9 mutant HB mouse model in both adult mice (in vivo) and in germline cells (ex vivo). In vivo, naked Cas9-sgRNA plasmid and donor DNA were delivered to HB mice livers to recover the mutation via hydrodynamic tail vein (HTV) injection. 62.5% of the HTV-treated mice showed a detectable gene correction (>1%) in the F9 alleles of hepatocytes, which was sufficient to remit the coagulation deficiency. Ex vivo, three different forms of Cas9 were microinjected into germline cells of HB mice to investigate their efficiency and safety in gene correction. Cas9 protein showed higher gene recovery rates, less embryo toxicity, and lower mosaic repair percentage, making it more suitable for germline gene therapy. Our study strongly supports that CRISPR/Cas9-mediated genome editing is feasible in gene therapy of genetic disorders.
Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes , Hemofilia B/genética , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Modelos Animais de Doenças , Fator IX/genética , Fator IX/metabolismo , Feminino , Loci Gênicos , Terapia Genética , Células Germinativas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Plasmídeos , Alinhamento de SequênciaRESUMO
BACKGROUND: The gut microbiome exerts extensive roles in metabolism of nutrients, pharmaceuticals, organic chemicals. Little has been known for the role of gut microbiota in regulating cholesterol and bile acids in association with gallstone formation. This study investigated the changes in the composition of gut microbiota in mice fed with lithogenic diet (LD). METHODS: Adult male C57BL/6 J mice were fed with either lithogenic diet (1.25% cholesterol and 0.5% cholic acid) or chow diet as control for 56 days. The fecal microbiota were determined by 16S rRNA gene sequencing. RESULTS: LD led to formation of cholesterol gallstone in mice. The richness and alpha diversity of gut microbial reduced in mice fed with LD. Firmicutes was significantly decreased from 59.71% under chow diet to 31.45% under LD, P < 0.01, as well as the ratio of Firmicutes to Bacteroidetes. Differences in gut microbiota composition were also observed at phylum, family and genus levels between the two groups. CONCLUSION: Our results suggested that gut microbiota dysbiosis might play an important role in the pathogenesis of cholesterol gallstone formation in mice.
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Colesterol/metabolismo , Disbiose/microbiologia , Cálculos Biliares/microbiologia , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/análise , Animais , Bacteroidetes/genética , Dieta/efeitos adversos , Dieta/métodos , Firmicutes/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Hemophilia B, or the Christmas disease, is a common human disease caused by coagulation factor â ¨ (Fâ ¨) deficiency. It is an X-linked recessive hereditary disease. Here we obtained Fâ ¨-knockout mouse strains with phenotype of hemophilia B with the CRISPR/Cas system efficiently. We chose the 8th exon as the target locus, and co-injected codon-optimized Cas9 mRNA with sgRNA of Fâ ¨ into C57BL/6 mice zygotes. We obtained 60 mice in total and genotyped them by high resolution melting (HRM) and sequencing. The results showed the mutation rate was 85.0% in total, and 79.5% and 95.2% in males and females, respectively. No off-targets were detected in the similar locus by HRM. We future measured the Fâ ¨ activity of each mice. The Fâ ¨: C of mutant mice were significantly below the normal level and reduced to 6.82% of wild-type mice. The activity assay demonstrated that all the mutant mice were lack of Fâ ¨. In summary, we have generated hemophilia B model mice with extreme efficiency, using the RNA-guided Cas9 nuclease gene editing system.
Assuntos
Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Hemofilia B/genética , Animais , Sequência de Bases , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , RNA Guia de Cinetoplastídeos/genéticaRESUMO
The mainstream partial nitritation/anammox (PN/A) process represents a significant innovation in decarbonizing municipal wastewater treatment. However, its implementation is considerably hampered by the challenge of stable nitrite supply. In this study, a pilot-scale PN/A system receiving real sewage (20 m3) was operated at room temperature for nearly one year. Remarkable PN performance with relatively high nitrite accumulation ratio of 75.04 ± 10.05 % was obtained via in-situ free ammonia (FA) strategy. The ammonium concentration enriched in the zeolite increased significantly by 548.8 times compared to that in the aqueous phase by ion exchange. This substantial increase robustly inhibited nitrite-oxidizing bacteria (NOB), resulting in high relative abundance ratio of ammonia-oxidizing bacteria (AOB) to NOB of 37.93 ± 12.61 in the zeolite biofilm, compared to 10.22 ± 1.67 in suspended floc sludge. The significant differences in FA concentrations between zeolite biofilm and suspended floc sludge resulted in distinct spatial distribution disparities of AOB and NOB, which were central to achieving stable nitrite accumulation without complex multiple selective pressures. Consequently, compliant effluent with total nitrogen of 10.91 ± 4.23 mg N/L was achieved at 10.4-31.1 °C without external carbon source addition. The biocarriers in the anammox process played a key role in enhancing functional genes and electron flow, supporting anammox-dominated nitrogen removal. This study presents a flexible and adaptable strategy for mainstream nitrite shunting, highlighting its potential for large-scale implementation of mainstream anammox treatment.
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Recently, learning-based multi-exposure fusion (MEF) methods have made significant improvements. However, these methods mainly focus on static scenes and are prone to generate ghosting artifacts when tackling a more common scenario, i.e., the input images include motion, due to the lack of a benchmark dataset and solution for dynamic scenes. In this paper, we fill this gap by creating an MEF dataset of dynamic scenes, which contains multi-exposure image sequences and their corresponding high-quality reference images. To construct such a dataset, we propose a 'static-for-dynamic' strategy to obtain multi-exposure sequences with motions and their corresponding reference images. To the best of our knowledge, this is the first MEF dataset of dynamic scenes. Correspondingly, we propose a deep dynamic MEF (DDMEF) framework to reconstruct a ghost-free high-quality image from only two differently exposed images of a dynamic scene. DDMEF is achieved through two steps: pre-enhancement-based alignment and privilege-information-guided fusion. The former pre-enhances the input images before alignment, which helps to address the misalignments caused by the significant exposure difference. The latter introduces a privilege distillation scheme with an information attention transfer loss, which effectively improves the deghosting ability of the fusion network. Extensive qualitative and quantitative experimental results show that the proposed method outperforms state-of-the-art dynamic MEF methods. The source code and dataset are released at https://github.com/Tx000/Deep_dynamicMEF.
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Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol/biossíntese , Digestão/fisiologia , Cálculos Biliares/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Bile/metabolismo , Colelitíase , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Desulfovibrionales/fisiologia , Fezes/microbiologia , Absorção Intestinal , Metabolismo dos Lipídeos , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicrobiotaRESUMO
Increasing evidence suggests that cholecystectomy is an independent risk factor for non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to hepatic lipid deposition after cholecystectomy are unclear. In this study, adult male C57BL/6J mice that underwent a cholecystectomy or sham operation were fed either a high-fat diet (HFD) or a chow diet for 56 days. Significantly increased steatohepatitis, liver/body weight ratio, hepatic triglycerides, and glucose intolerance were observed in postcholecystectomy mice fed the HFD. Notable alterations in the composition of gut microbiota after cholecystectomy were observed in both HFD- and chow-diet-fed mice. Our results indicate that cholecystectomy alters the gut microbiota profile, which might contribute to the development of NAFLD in mice.
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Cholesterol gallstone disease is a common global condition. This study investigated the role of plant sterols (PS) in the prevention of gallstone formation and the underlying mechanisms. Adult male mice were fed a lithogenic diet (LD) alone or supplemented with PS (LD-ps), phospholipids (LD-pl) or both PS and phospholipids (LD-ps/pl) for 8 weeks. Incidences of gallstone formation were compared among the groups. Lipids in the bile, liver and serum were analyzed. The expression of genes involved in cholesterol absorption, transport and metabolism in the liver and small intestine was determined. The incidences of gallstone formation were 100% (10/10), 20% (2/10), 100% (10/10) and 40% (4/10) in the LD, LD-ps, LD-pl and LD-ps/pl groups, respectively. Serum cholesterol and intestinal cholesterol absorption were decreased in PS-supplemented mice. The expression of genes related to cholesterol transport and metabolism in the liver was down-regulated by dietary PS. PS supplementation decreased Niemann-Pick C1-like 1 expression in the small intestine and reduced intestinal cholesterol absorption. Our results demonstrated that PS could inhibit intestinal cholesterol absorption and thus prevent cholesterol gallstone formation.
Assuntos
Colesterol/metabolismo , Cálculos Biliares/prevenção & controle , Absorção Intestinal/efeitos dos fármacos , Fitosteróis/farmacologia , Animais , Colesterol/administração & dosagem , Colesterol/efeitos adversos , Dieta , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.
Assuntos
Transtornos Cronobiológicos/complicações , Cálculos Biliares/etiologia , Microbioma Gastrointestinal , Metabolismo dos Lipídeos , Fígado/metabolismo , Animais , Colesterol/metabolismo , Transtornos Cronobiológicos/etiologia , Transtornos Cronobiológicos/metabolismo , Transtornos Cronobiológicos/microbiologia , Ritmo Circadiano/fisiologia , Dieta/efeitos adversos , Cálculos Biliares/metabolismo , Cálculos Biliares/microbiologia , Microbioma Gastrointestinal/fisiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
We present a Minimal Event Distance Aneuploidy Lineage Tree (MEDALT) algorithm that infers the evolution history of a cell population based on single-cell copy number (SCCN) profiles, and a statistical routine named lineage speciation analysis (LSA), whichty facilitates discovery of fitness-associated alterations and genes from SCCN lineage trees. MEDALT appears more accurate than phylogenetics approaches in reconstructing copy number lineage. From data from 20 triple-negative breast cancer patients, our approaches effectively prioritize genes that are essential for breast cancer cell fitness and predict patient survival, including those implicating convergent evolution.The source code of our study is available at https://github.com/KChen-lab/MEDALT .
Assuntos
Aneuploidia , Biologia Computacional/métodos , Dosagem de Genes , RNA-Seq , Análise de Célula Única , Software , Algoritmos , Evolução Molecular , Estudos de Associação Genética , Aptidão Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA-Seq/métodos , Análise de Célula Única/métodosRESUMO
Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.
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Cálculos Biliares/metabolismo , Metilaminas/metabolismo , Oxigenases/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/metabolismo , Colesterol/metabolismo , Dieta , Modelos Animais de Doenças , Feminino , Cálculos Biliares/patologia , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica , Humanos , Lipoproteínas/metabolismo , Fígado/metabolismo , Masculino , Metilaminas/sangue , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Oxigenases/genética , RNA Mensageiro/metabolismoRESUMO
In this paper, we deal with the problem of finding the best possible bounds for the first Seiffert mean in terms of the geometric combination of logarithmic and the Neuman-Sándor means, and in terms of the geometric combination of logarithmic and the second Seiffert means.
RESUMO
Excessive cholesterol contributes to the development of cardiovascular diseases. Berberine (BBR) has been reported to regulate cholesterol homeostasis. Here, we found that BBR could ameliorate the hepatic autophagic flux blockade caused by cholesterol overloading. The underlying mechanism included lowering hepatic cholesterol level, modulating the cholesterol distribution targeting the plasma membrane by decreasing sterol carrier protein 2 expression and inhibiting cyclooxygenase 2-mediated production of prostaglandin metabolites, which decreased the phosphorylation of Akt/mTOR. Our study provides evidences that BBR could be a therapeutic agent for protecting liver under cholesterol overloading via the regulation of autophagic flux.
Assuntos
Autofagia/efeitos dos fármacos , Berberina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Fígado/metabolismo , Prostaglandinas/metabolismo , Animais , Colesterol/metabolismo , Colesterol/farmacologia , Ciclo-Oxigenase 2/química , Dieta Hiperlipídica , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Sequestossoma-1/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
p,p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and ß-hexachlorocyclohexane (ß-HCH) were two predominant organochlorine pesticides (OCPs) metabolites in human body associated with disorders of fatty acid metabolism. However, the underlying mechanisms have not been fully clarified. In this study, adult male C57BL/6 mice were exposed to low dose of p, p'-DDE and ß-HCH for 8 wk. OCPs accumulation in organs, hepatic fatty acid composition, tricarboxylic acid cycle (TCA) metabolites and other metabolite profiles were analyzed. Expression levels of genes involved in hepatic lipogenesis and ß-oxidation were measured. Mitochondrial function was evaluated in HepG2 cells exposed to OCPs. High accumulation of p, p'-DDE and ß-HCH was found in liver and damaged mitochondria was observed under electron microscopy. Expression of genes in fatty acid synthesis increased and that in mitochondrial fatty acid ß-oxidation decreased in OCPs treatment groups. OCPs changed metabolite profiles in liver tissues, varied hepatic fatty acid compositions and levels of several TCA cycle metabolites. Furthermore, MitoTracker Green fluorescence, ATP levels, mitochondrial membrane potential and OCR decreased in HepG2 cells exposed to OCPs. In conclusion, chronic exposure to OCPs at doses equivalent to internal exposures in humans impaired mitochondrial function, decreased fatty acid ß-oxidation and aggravated disorders of fatty acid metabolism.
Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hidrocarbonetos Clorados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Praguicidas/farmacologia , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Progressão da Doença , Ácidos Graxos/metabolismo , Hepatócitos/patologia , Hexaclorocicloexano/metabolismo , Hexaclorocicloexano/farmacologia , Humanos , Transtornos do Metabolismo dos Lipídeos/etiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Camundongos , OxirreduçãoRESUMO
Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and ß-hexachlorocyclohexane (ß-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and ß-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human.
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Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Hidrocarbonetos Clorados/toxicidade , Praguicidas/toxicidade , Animais , Diclorodifenil Dicloroetileno/análise , Hexaclorocicloexano/metabolismo , Hexaclorocicloexano/toxicidade , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/metabolismo , Intestinos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Praguicidas/análise , Praguicidas/metabolismo , RNA Ribossômico 16SRESUMO
BACKGROUND: EGF-containing fibulin-like extracellular matrix protein1 (EFEMP1) gene was relative with the formation and development of tumors and had an anti-angiogenic function. Recently, many studies investigating the function of EFEMP1 gene, including its roles in prostate cancer and glioma, have been reported. EFEMP1 suppressed glioma growth by modulating EGFR and AKT signaling pathway or promoted growth through the regulation of Notch pathway were identified. However, the susceptibility of EFEMP1and glioma has not been well studied to date. Here, the authors were aimed to investigate whether the single nucleotide polymorphisms (SNPs) of EFEMP1 were associated with glioma susceptibility. METHODS: The authors genotyped 14 common tagging SNPs of EFEMP1 gene via the Sequenom Mass ARRYiPLEX platform and assessed their association with glioma risk in a hospital-based case-control study in a Chinese Han population (979 cases and 1007 controls). RESULTS: Four SNPs were significant associated with glioma risk (rs1346787, P=0.004, adjusted OR=1.49; rs3791679, P=0.014, adjusted OR=1.27; rs1346786, P=0.002, adjusted OR=1.41; rs3791675, P=0.011, adjusted OR=1.27). In further stratified analysis, all the significant SNPs except rs1346787 were associated with both low-grade gliomas and glioblastoma (GBM). In haplotype analysis, 4 haplotype blocks were identified and 2 of them were revealed significant associated with glioma, the haplotype "AA" (adjusted OR=1.44, P=0.005) in block 1 and haplotype "GG" (adjusted OR=1.65, P=0.0004) in block 2 had a 44% and 65% increased glioma risk respectively, compared with corresponding non-carriers. The results of haplotype analysis were significantly consistent with the single-locus analysis. CONCLUSIONS: The authors' results suggested that common genetic variants in EFEMP1 gene were associated with glioma and contributed to glioma susceptibility, which might help to reveal the mechanism of gliomas and provide new insight for the diagnosis and treatment.