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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and Pxr-null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFα (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor α target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.
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Hígado Graso Alcohólico/genética , Receptores de Esteroides/genética , Regulación hacia Arriba , Animales , Etanol/efectos adversos , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/patología , Eliminación de Gen , Lipogénesis , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor X de Pregnano , ARN Mensajero/genética , Receptores de Esteroides/metabolismoRESUMEN
The development of new electrocatalysts for electrochemical oxygen reduction to replace expensive and rare platinum-based catalysts is an important issue in energy storage and conversion research. In this context, conductive and porous metal-organic frameworks (MOFs) are considered promising materials for the oxygen reduction reaction (ORR) due to not only their high surface area and well-developed pores but also versatile structural features and chemical compositions. Herein, the preparation of bimetallic conductive 2D MOFs (Cox Niy -CATs) are reported for use as catalysts in the ORR. The ratio of the two metal ions (Co2+ and Ni2+ ) in the bimetallic Cox Niy -CATs is rationally controlled to determine the optimal composition of Cox Niy -CAT for efficient performance in the ORR. Indeed, bimetallic MOFs display enhanced ORR activity compared to their monometallic counterparts (Co-CAT or Ni-CAT). During the ORR, bimetallic Cox Niy -CATs retain an advantageous characteristic of Co-CAT in relation to its high diffusion-limiting current density, as well as a key advantage of Ni-CAT in relation to its high onset potential. Moreover, the ORR-active bimetallic Cox Niy -CAT with excellent ORR activity is prepared at a large scale via a convenient method using a ball-mill reactor.
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A convenient method for the confined incorporation of highly active bimetallic PdCo nanocatalysts within a hollow and porous metal-organic framework (MOF) support is presented. Several chemical conversions occur simultaneously during the one-step low temperature pyrolysis of well-designed polystyrene@ZIF-67/Pd2+ core-shell microspheres, where ZIF (zeolitic imidazolate framework) is a subclass of MOF: the polystyrene core is removed, resulting in a beneficial hollow and porous ZIF support; the ZIF-67 shell acts as a well-defined porous support and as a felicitous Co2+ supplier for metal nanoparticle formation; and Pd2+ and Co2+ are reduced to form catalytically active bimetallic PdCo nanoparticles in the well-defined micropores, inducing the confined growth of PdCo nanoparticles with excellent dispersity.
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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid ß-oxidation and upregulation of Srebp-1c- regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene, implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. Also, PXR-dependent was the binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase (ALDH) 1A1 and anti-apoptotic Bcl-2, but increased pro-apoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia following binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism, but protects against alcoholic hyperlipidemia.
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Porous metal-organic frameworks (MOFs) are interesting materials owing to their interesting structural features and their many useful properties and applications. In particular, the structural features are greatly important to optimize the MOFs' porosities and so properties. Indeed, the MOFs' well-developed micropore and high surface area are the most important structural features, and as such, many practical applications of MOFs originate from these structural features. We herein demonstrate a strategy for improving the crystallinity of MOFs, and so increasing the porosity and surface area of poorly crystalline MOFs by making them in core-shell-type hybrids through the induced growth on the well-crystalline template. Although poorly crystalline versions of MOFs generate naturally in the absence of the well-crystalline template, well-crystalline versions of MOFs produce inductively in the presence of the well-crystalline template. In addition, the crystallinity enhancement of MOFs brings together the improvement in their porosities and surface areas. The surface areas and pore volumes of the well-crystalline versions of MOFs produced through the induced growth on the template are calculated based on this study, indicating that MOF surface areas increase by up to 7 times compared to the poorly crystalline versions.
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ABSTRACTBackground:A growing number of studies are emphasizing the importance of positive and negative appraisals of caregiving and the utilization of social resources to buffer the negative effects of caring for persons with dementia. By assessing the roles of unmet needs and formal support, this study tested a hypothesized model for Korean family caregivers' satisfaction and burden in providing care for persons with dementia. METHODS: The stress process model and a two-factor model were used as the conceptual framework for this study. Data for 320 family caregivers from a large cross-sectional survey, the Seoul Dementia Management study, were analyzed using structural equation modeling. In the hypothesized model, the exogenous variables were patient symptoms, including cognitive impairment, behavioral problems, and dependency on others to help with activities of daily living and with instrumental activities of daily living. The endogenous variables were the caregiver's perception of the unmet needs of the patient, formal support, caregiving satisfaction, and caregiving burden. RESULTS: The adjusted model explained the mediating effect of unmet needs on the relationship between patient symptoms or formal support and caregiving satisfaction. Formal support also had a mediating effect on the relationship between patient symptoms and unmet needs. Patient symptoms and caregiving satisfaction had a significant direct effect on caregiving burden. CONCLUSION: The level of unmet needs of persons with dementia and their family caregivers must be considered in the development of support programs focused on improving caregiving satisfaction.
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Cuidadores/psicología , Costo de Enfermedad , Demencia , Familia/psicología , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Satisfacción Personal , Apoyo Social , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Demencia/psicología , Fatiga/epidemiología , Fatiga/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , República de Corea , Estrés Psicológico/epidemiología , Estrés Psicológico/psicología , Encuestas y CuestionariosRESUMEN
The growth of one metal-organic framework (MOF) on another MOF for constructing a heterocompositional hybrid MOF is an interesting research topic because of the curiosity regarding the occurrence of this phenomenon and the value of hybrid MOFs as multifunctional materials or routes for fine-tuning MOF properties. In particular, the anisotropic growth of MOF on MOF is fascinating for the development of MOFs possessing atypical shapes and heterostructures or abnormal properties. Herein, we clarify the understanding of growth behavior of a secondary MOF on an initial MOF template, such as isotropic or anisotropic ways associated with their cell parameters. The isotropic growth of MIL-68-Br on the MIL-68 template results in the formation of core-shell-type MIL-68@MIL-68-Br. However, the unique anisotropic growth of a secondary MOF (MOF-NDC) on the MIL-68 template results in semitubular particles, and structural features of this unknown secondary MOF are successfully speculated for the first time on the basis of its unique growth behavior and morphological characteristics. Finally, the validation of this structural speculation is verified by the powder X-ray diffraction and the selected area electron diffraction studies. The results suggests that the growth behavior and morphological features of MOFs should be considered to be important factors for understanding the MOFs' structures.
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Au or Ag nanoparticles-embedded hollow carbon spheres, which display outstanding catalytic activity and excellent recyclability, are prepared by a one-step pyrolysis of metal-organic framework (MOF) hybrids consisting of polystyrene cores and MOF shells loaded with noble metal ions (polystyrene@ZIF-8/M(n+) ; M(n+) = Au(3+) or Ag(+) ).
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Microsized chemosensor particle (CPP-16, CPP means coordination polymer particle), which is made from a metal-organic framework (MOF), is synthesized using pyrene-functionalized organic building block. This building block contains three important parts, a framework construction part, a Cu(2+) detection part, and a fluorophore part. PXRD studies have revealed that CPP-16 has a 3D cubic structure of MOF-5. During both MOF formation and sensing event, fluorophores within CPP-16 undergo dual changes in conformation and optical properties. After MOF construction, pyrene moieties experience an unusual complete conversion from monomer to excimer form. This conversion takes place due to a confinement effect induced by space limitations within the MOF structure. The selective sensing ability of CPP-16 on Cu(2+) over many other metal ions is verified by emission spectra and is also visually identified by fluorescence microscopy images. Specific interaction of Cu(2+) with binding sites within CPP-16 causes a second conformational change of the fluorophores, where they change from stacked excimer (CPP-16) to quenched excimer states (CPP-16·Cu(2+)).
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A precise fabrication of nanobamboo structures made from hybrid coordination polymers of the type {Fex In1-x }-MIL-88B is demonstrated. The compositions of the hybrid coordination polymer nanobamboos of {Fex In1-x }-MIL-88B (x=0.06, 0.19, or 0.75) are regulated by altering the amount of metal ions used in the reactions. Interestingly, the formation of a virtual In-MIL-88B (precise structure, {Fe0.06 In0.94 }-MIL-88B), which cannot be created in a typical reaction, is induced by the assistance of a Fe-MIL-88B structure. The a and c cell parameters of {Fe0.06 In0.94 }-MIL-88B are calculated at 10.95 and 19.86â Å, respectively. These values of {Fe0.06 In0.94 }-MIL-88B are larger than those of pure Fe-MIL-88B owing to the large ionic size of In(3+) within the framework.
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Tumor cell contamination (TCC) of peripheral blood stem cells (PBSCs) is a major risk in the autologous PBSC transplant setting. However, the effect of different mobilization regimens (cytokines only versus cytokines + chemotherapy) on TCC of PBSCs and its impact on treatment outcomes have not been systematically reviewed. In the present meta-analysis, we aimed to investigate this effect in breast cancer patients since multiple studies have been conducted in this setting. We systematically searched MEDLINE and Cochrane Library up to May 2012. Seventeen studies (1,819 patients) were assessed. There was no significant difference in the incidence of TCC of PBSCs between the two mobilization regimens. When the analysis was restricted to granulocyte colony-stimulating factor as a cytokine, this difference was again not significant. We also found that TCC of PBSCs was associated with a higher annual recurrence rate in these patients. This suggests that there may be a significant risk for reinfusion of tumor cell-positive PBSCs, and whether it can increase the risk of disease recurrence needs to be determined. This study also raises important questions regarding the causes of TCC of PBSCs. These issues should be investigated systematically in PBSC transplant patients.
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Neoplasias de la Mama/terapia , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre de Sangre Periférica/métodos , Antineoplásicos/administración & dosificación , Eliminación de Componentes Sanguíneos/efectos adversos , Eliminación de Componentes Sanguíneos/métodos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Citocinas/administración & dosificación , Femenino , Movilización de Célula Madre Hematopoyética/efectos adversos , Humanos , Células Neoplásicas Circulantes/patología , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Recurrencia , Factores de Riesgo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor signaling potentiates ethanol (EtOH)-induced hepatotoxicity in male mice, however, how PXR signaling modulates EtOH-induced hepatotoxicity in female mice is unknown. Wild type (WT) and Pxr-null mice received 5 % EtOH-containing diets or paired-fed control diets for 8 weeks followed by assessment of liver injury, EtOH elimination rates, histology, and changes in gene and protein expression; microarray and bioinformatic analyses were also employed to identify PXR targets in chronic EtOH-induced hepatotoxicity. In WT females, EtOH ingestion significantly increased serum ethanol and alanine aminotransferase (ALT) levels, hepatic Pxr mRNA, constitutive androstane receptor activation, Cyp2b10 mRNA and protein, oxidative stress, endoplasmic stress (phospho-elF2α) and pro-apoptotic (Bax) protein expression. Unexpectedly, EtOH-fed female Pxr-null mice displayed increased EtOH elimination and elevated levels of hepatic acetaldehyde detoxifying aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA and protein, EtOH-metabolizing alcohol dehydrogenase 1 (ADH1), and lipid suppressing microsomal triglyceride transport protein (MTP) protein, aldo-keto reductase 1b7 (Akr1b7) and Cyp2a5 mRNA, but suppressed CYP2B10 protein levels, with evidence of protection against chronic EtOH-induced oxidative stress and hepatotoxicity. While liver injury was not different between the two WT sexes, female sex may suppress EtOH-induced macrovesicular steatosis in the liver. Several genes and pathways important in retinol and steroid hormone biosynthesis, chemical carcinogenesis, and arachidonic acid metabolism were upregulated by EtOH in a PXR-dependent manner in both sexes. Together, these data establish that female Pxr-null mice are resistant to chronic EtOH-induced hepatotoxicity and unravel the PXR-dependent and -independent mechanisms that contribute to EtOH-induced hepatotoxicity.
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Although obesity and subsequent liver injury are increasingly prevalent in women, female mouse models have generally shown resistance to high-fat diet (HFD)-induced obesity. We evaluated control and HFD-fed male and female FVB/N mice, a strain well-suited to transgenic analyses, for phenotypic, histological, and molecular markers related to control of glucose, lipids, and inflammation in serum, liver, and perigonadal white adipose tissues. Unlike many mouse models, HFD-fed FVB/N females gained more perigonadal and mesenteric fat mass and overall body weight than their male counterparts, with increased hepatic expression of lipogenic PPARγ target genes (Cd36, Fsp27, and Fsp27ß), oxidative stress genes and protein (Nqo1 and CYP2E1), inflammatory gene (Mip-2), and the pro-fibrotic gene Pai-1, along with increases in malondialdehyde and serum ALT levels. Further, inherent to females (independently of HFD), hepatic antioxidant heme oxygenase-1 (HMOX1, HO-1) protein levels were reduced compared to their male counterparts. In contrast, males may have been relatively protected from HFD-induced oxidative stress and liver injury by elevated mRNA and protein levels of hepatic antioxidants BHMT and Gpx2, increased fatty acid oxidation genes in liver and adipocytes (Pparδ), despite disorganized and inflamed adipocytes. Thus, female FVB/N mice offer a valuable preclinical, genetically malleable model that recapitulates many of the features of diet-induced obesity and liver damage observed in human females.
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Dieta Alta en Grasa , Hemo-Oxigenasa 1 , Inflamación , Hígado , Obesidad , Estrés Oxidativo , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Obesidad/metabolismo , Obesidad/patología , Obesidad/genética , Ratones , Masculino , Hígado/metabolismo , Hígado/patología , Inflamación/metabolismo , Inflamación/patología , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , PPAR gamma/metabolismo , PPAR gamma/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/genética , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/genética , Antígenos CD36/metabolismo , Antígenos CD36/genética , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de la Membrana , ProteínasRESUMEN
Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.
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Dieta Alta en Grasa , Hígado , Masculino , Femenino , Ratones , Animales , Receptor X de Pregnano/genética , Receptor X de Pregnano/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Aumento de Peso , Obesidad/metabolismo , Inflamación/metabolismo , Ratones NoqueadosRESUMEN
The conjugation of Eu(3+)-doped coordination polymers constructed from Gd(3+) and isophthalic acid (H(2)IPA) with silica particles is investigated for the production of luminescent microspheres. A series of doping ratio-controlled silica@coordination polymer core-shell spheres is easily synthesized by altering the amounts of metal nodes used in the reactions, where the ratios of Gd(3+) and Eu(3+) are 10:0 (1a), 9:1 (1b), 8:2 (1c), 7:3 (1d), 5:5 (1e), and 0:10 (1f). The formation of monodisperse uniform core-shell structures is achieved throughout the entirety of a series. Investigations of the photoluminescence property of the resulting series of silica@coordination polymer core-shell spheres reveal that 20% Eu(3+)-doped product (1c) has the strongest emission intensity. The subsequent calcination process on the silica@coordination polymer core-shell structures (1a-f) results in the formation of a series of doping ratio-controlled silica@Gd(2)O(3):Eu core-shell microspheres (2a-f) with uniform shell thickness. During the calcination step, the coordination polymers within silica@coordination polymer core-shells are transformed into metal oxides, resulting in silica@Gd(2)O(3):Eu core-shell structures. The final etching process on the silica@Gd(2)O(3):Eu core-shell microspheres (2a-f) produces a series of hollow Gd(2)O(3):Eu microspheres (3a-f) as a result of the elimination of silica cores. The luminescence intensities of silica@Gd(2)O(3):Eu core-shell (2a-f) and hollow Gd(2) O(3):Eu microspheres (3a-f) also vary depending upon the doping ratio of Eu(3+) ions.
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Europio/química , Luminiscencia , Microesferas , Polímeros/química , Dióxido de Silicio/químicaRESUMEN
BACKGROUND: The aim of this study was to investigate the association between obesity and prehypertension (preHT) after adjustment for socioeconomic position and health behavior factors. METHODS: The study sample included 1973 Korean men and women, 45-64 years of age. Subjects were classified into three groups based on their baseline blood pressure: prehypertensive, hypertensive and normotensive. Men with a waist circumference ≥90 cm or women ≥80 cm were considered abdominally obese. Body mass index (BMI) obesity was defined as having a BMI ≥25. The prevalence of abdominal obesity and BMI obesity was calculated with age adjustment using a direct method. Multinomial logistic regression analysis was applied. RESULTS: The prevalence of preHT in our study was 52.8%. We found that subjects with abdominal obesity were 2.06 times as likely to be prehypertensive as those without it and people with BMI obesity were 1.89 times as likely to be prehypertensive as those without it. Interestingly, men with BMI obesity had a higher preHT risk, while women with abdominal obesity had a higher preHT risk. CONCLUSIONS: Statistical analyses of a community-based random sample of the Korean population indicate that obesity is associated with preHT in Korean middle-aged subjects.
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Obesidad/epidemiología , Prehipertensión/epidemiología , Índice de Masa Corporal , Comorbilidad , Femenino , Conductas Relacionadas con la Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Obesidad Abdominal/epidemiología , Prevalencia , República de Corea/epidemiología , Distribución por Sexo , Factores Socioeconómicos , Circunferencia de la CinturaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease due to the current epidemics of obesity and diabetes. The pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor known for trans-activating liver genes involved in drug metabolism and transport, and more recently implicated in energy metabolism. The gut microbiota can modulate the host xenobiotic biotransformation and contribute to the development of obesity. While the male sex confers a higher risk for NAFLD than women before menopause, the mechanism remains unknown. We hypothesized that the presence of PXR promotes obesity by modifying the gut-liver axis in a sex-specific manner. Male and female C57BL/6 (wild-type/WT) and PXR-knockout (PXR-KO) mice were fed control or high-fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in males, accompanied by PXR-dependent up-regulation in hepatic genes involved in microbial response, inflammation, oxidative stress, and cancer; PXR-dependent increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, as well as a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum, with a PXR-dependent reduction of beneficial BAs in liver. The resistance to NAFLD in females may be explained by PXR-dependent decrease in pro-inflammatory bacteria (Ruminococcus gnavus and Peptococcaceae). In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammation-prone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.
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Microbioma Gastrointestinal/fisiología , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/metabolismo , Receptor X de Pregnano/metabolismo , Animales , Biomarcadores , Dieta Alta en Grasa/efectos adversos , Femenino , Redes Reguladoras de Genes , Prueba de Tolerancia a la Glucosa , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor X de Pregnano/genética , ARN Bacteriano/genética , ARN Ribosómico 16S , Factores SexualesRESUMEN
Data regarding the safety of anti-vascular endothelial growth factor (anti-VEGF) treatment is limited.To compare the adverse events (AEs) induced by aflibercept and ranibizumab using a spontaneous reporting system and determine the signals.We used data from the Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System Database (KIDS-KD), collected between 2007 and 2016. Differences in patient demographics, report type, reporter, causality, and serious-AEs between aflibercept and ranibizumab were compared. Metrics including proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were used to compare signals with the AEs on the drug labels in the United States of America and Korea. Logistic regression analysis was performed to identify AEs that are more likely to occur with drug use.A total of 32 aflibercept and 103 ranibizumab cases of AEs were identified. The proportion of AEs that were reported voluntarily was higher with aflibercept (50.5%) use than ranibizumab (4.9%), whereas the AEs reported by post-marketing surveillance were higher with ranibizumab (46.6%) use than aflibercept (31.3%). The percentage of AEs in patients >60 years old, reports by consumers, and the ratio of SAEs to AEs associated with aflibercept (84. %, 9.4%, and 75.0%, respectively) were higher than those of ranibizumab (77.7%, 1.9%, and 19.4%, respectively). The number of newly detected AEs after aflibercept and ranibizumab treatment was 3 and 8, respectively. Among these, conjunctivitis and medicine ineffective were not included on the aflibercept and ranibizumab labels, respectively. Endophthalmitis (OR 6.96, 95% CI 2.74-17.73) was more likely to be reported in patients with aflibercept than in patients without aflibercept, whereas medicine ineffective (OR 18.49, 95% CI 2.39-143.29) and retinal disorder (OR 7.03, 95% CI 1.60-30.96) were more likely to be reported in patients with ranibizumab than in patients without ranibizumab.New signals have been identified for aflibercept and ranibizumab. Further research is necessary to evaluate the causality of AEs that were detected as signals in this study.
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Inhibidores de la Angiogénesis/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Ranibizumab/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Endotelial Vascular , República de Corea/epidemiología , Adulto JovenRESUMEN
The endoplasmic reticulum (ER) is an organelle in which important cellular events such as protein synthesis and lipid production occur. Although many lipid molecules are produced in the ER, the effect of ER-organizing proteins on lipid synthesis in sebocytes has not been completely elucidated. Tropomyosin-receptor kinase fused gene (TFG) is located in ER exit sites and participates in COPII-coated vesicle formation along with many scaffold proteins, such as Sec. 13 and Sec. 16. In this study, we investigated the putative role of TFG in lipid production in sebocytes using an immortalized human sebocyte line. During IGF-1-induced lipogenesis, the level of the TFG protein was increased in a time- and dose-dependent manner. When TFG was over-expressed using recombinant adenovirus, lipid production in sebocytes was increased along with an up-regulation of the expression of lipogenic regulators, such as PPAR-γ, SREBP-1 and SCD. Conversely, down-regulation of TFG using a microRNA (miR) decreased lipid production and the expression of lipogenic regulators. Based on these data, TFG is a novel regulator of lipid synthesis in sebocytes.
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Vesículas Cubiertas por Proteínas de Revestimiento/genética , Lípidos/biosíntesis , Lipogénesis/genética , Proteínas/genética , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Línea Celular , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Lípidos/genética , PPAR gamma/genética , Estearoil-CoA Desaturasa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
We consider the problem of fusing probability scores from a set of classifiers to estimate a final fused probability score. Our interest is in scenarios where the classifiers are statistically dependent. To that end, we propose a new classifier fusion approach that is data driven and founded on the statistical theory of copulas. Numerical results with both simulated and real data show that our copula based classifier fusion approach produces better probability scores than individual classifiers and outperforms existing probability score fusion approaches.