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1.
Immunity ; 52(1): 4-6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31951549

RESUMO

Type I interferons (IFNs) can reprogram the cholesterol biosynthetic pathway to facilitate innate immune responses. In this issue of Immunity, Xiao et al. (2020) reveal that type I IFN signaling and 7-dehydrocholesterol (7-DHC) accumulation form a positive feedback loop to amplify innate immune responses to control viral infections by activating AKT3.


Assuntos
Imunidade Inata , Fosfatidilinositol 3-Quinases , Colesterol , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Esteróis
2.
J Zoo Wildl Med ; 50(4): 927-936, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926525

RESUMO

Seabirds have been widely used for monitoring the health of the oceans in diverse marine regions. Among low-cost survey strategies, systematic surveys of seabirds beached on coasts have been developed since the 20th century. However, these studies do not always address blood aspects. The assessment of the health status of birds based on the analysis of hematological and plasma chemistry is crucial to evaluate the overall health status profile of live organisms. Here, the authors study the variability of blood parameters by sex, age class, and year of beached Magellanic Penguin during the nonreproductive period in northern Argentina. Of 44 penguins, 77% were categorized as younger juveniles and the rest as older juveniles, and were captured and studied in coastal areas of Buenos Aires Province during the summers of 2017 and 2018. The mean body weight of beached penguins was affected by the age class of the individuals; most of the younger juveniles showed poor condition in terms of body mass (1,761 ± 235 g). No significant differences were observed in body weight between years and sex. Still, there were significant differences between years for alkaline phosphatase (ALP) and creatine phosphokinase (CPK) values. Twelve of the 20 blood parameters analyzed differ significantly with the age class of the beached penguins; younger juveniles were in a state of inanition. Our results may serve as a necessary first step in improving the conservation status of the Magellanic Penguin in nonbreeding grounds of Argentina, and call for a better knowledge of the health status of the species along its annual cycle.


Assuntos
Contagem de Eritrócitos/veterinária , Hematócrito , Contagem de Leucócitos/veterinária , Estações do Ano , Spheniscidae/sangue , Envelhecimento , Fosfatase Alcalina/sangue , Animais , Animais Selvagens , Anticorpos Heterófilos , Argentina , Glicemia , Proteínas Sanguíneas , Colesterol/sangue , Creatina Quinase/sangue , Feminino , Hemoglobinas , Contagem de Linfócitos/veterinária , Masculino , Fósforo/sangue , Transaminases/sangue , Ureia/sangue , Ácido Úrico/sangue
3.
Cell Physiol Biochem ; 54(1): 110-125, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31999897

RESUMO

BACKGROUND/AIMS: Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells. METHODS: The effect of Myriocin treatment, on F508-CFTR bronchial epithelial cell line IB3-1 cells, was studied by evaluating the expression of key proteins and genes involved in autophagy and lipid metabolism, by western blotting and real time PCR. Moreover, the amount of glycerol-phospholipids, triglycerides, and cholesterols, sphingomyelins and ceramides were measured in treated and untreated cells by LC-MS. Finally, Sptlc1 was transiently silenced and the effect on ceramide content, autophagy and transcriptional activities was evaluated as above mentioned. RESULTS: We demonstrate that Myriocin tightly regulates metabolic function and cell resilience to stress. Myriocin moves a transcriptional program that activates TFEB, major lipid metabolism and autophagy regulator, and FOXOs, central lipid metabolism and anti-inflammatory/anti-oxidant regulators. The activity of these transcriptional factors is associated with the induction of PPARs nuclear receptors activity, whose targets are genes involved in lipid transport compartmentalization and oxidation. Transient silencing of SPTCL1 recapitulates the effects induced by Myriocin. CONCLUSION: Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. We speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.


Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Esfingolipídeos/metabolismo , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular , Colesterol/análise , Cromatografia Líquida de Alta Pressão , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Espectrometria de Massas , PPAR gama/genética , PPAR gama/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Serina C-Palmitoiltransferase/antagonistas & inibidores , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Esfingolipídeos/análise , Esfingomielinas/análise
4.
N Engl J Med ; 382(3): 244-255, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31893580

RESUMO

BACKGROUND: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Lipoproteína(a)/sangue , Oligonucleotídeos/administração & dosagem , Adulto , Idoso , Doenças Cardiovasculares/sangue , Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Fatores de Risco
5.
Clin Sci (Lond) ; 134(2): 273-287, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31957803

RESUMO

The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-ß levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-ß in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.


Assuntos
Colesterol/metabolismo , Interferon gama/metabolismo , Linfócitos/metabolismo , Sulfotransferases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transporte Biológico , Colesterol/sangue , LDL-Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Metilação de DNA , Humanos , Mediadores da Inflamação/metabolismo , Interferon gama/genética , Células Jurkat , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Regiões Promotoras Genéticas/genética , Sulfotransferases/genética , Fator de Necrose Tumoral alfa/genética
6.
Biophys Chem ; 257: 106275, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31790909

RESUMO

We performed molecular dynamics simulations of a lipid bilayer consisting of POPC and cholesterol at temperatures from 283 to 308K and cholesterol concentrations from 0 to 50% mol/mol. The purpose of this study was to look for the existence of structural differences in the region delimited by these parameters and, in particular, in a region where coexistence of liquid disordered and liquid ordered phases has been proposed. Our interest in this range of concentration and temperature responds to the fact that polyene ionophore activity varies considerably along it. Two force fields, CHARMM36 and Slipids, were compared in order to determine the most suitable. Both force fields predict non-monotonic behaviors consistent with the existence of phase transitions. We found the presence of lateral structural heterogeneity, statistical in nature, in some of the bilayers occurring in this range of temperatures and sterol concentrations. This heterogeneity was produced by correlated ordering of the POPC tails and not due to cholesterol enrichment, and lasts for tens of nanoseconds. We relate these observations to the action of polyenes in these membranes.


Assuntos
Colesterol/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Fosfatidilcolinas/química , Microscopia de Força Atômica , Transição de Fase , Temperatura Ambiente
7.
J Agric Food Chem ; 68(2): 642-651, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830780

RESUMO

Cholesterol was usually used to stabilize liposome, although there have been controversies on the relationship between dietary cholesterol and health. The present study aimed to prepare a novel multifunctional nanoliposomes stabilized by sea cucumber-derived saponins using ultrasound-assisted film dispersion method. A novel uniform liposome with a mass ratio of egg yolk lecithin/sea cucumber saponins at 75:25 was successfully prepared to encapsulate saponin, and the particle size was 164.8 ± 1.70 nm with a PDI value of 0.214 ± 0.022 and zeta potential of -15.97 ± 1.23 mV. The digestion and absorption results in vivo showed that the dietary saponins in liposome form could delay the peak time of saponins and prolong their residence time in the serum. Moreover, saponins were more easily converted into their corresponding metabolites after administration with saponins in the liposome form. The novel liposome as an efficient carrier with multiple functions had great potential in the development of functional food and biomedical applications.


Assuntos
Colesterol/química , Lipossomos/química , Saponinas/química , Pepinos-do-Mar/química , Adsorção , Animais , Cinética , Nanopartículas/química , Tamanho da Partícula
8.
Food Chem ; 308: 125661, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669948

RESUMO

A high level of serum cholesterol is a major cause of atherosclerosis. Fenugreek is a well-known hypocholesterolaemic agent with amazing phytochemical composition. Due to its impact on plant metabolism, CO2 enrichment was tested as a strategy to support functional values in fenugreek seeds. Phytochemical composition and biological activities of three fenugreek cultivars (G2, G6 and G30) grown under ambient (aCO2, 400 µmol mol-1) and elevated CO2 (eCO2, 620 µmol mol-1) were assessed. Applying eCO2 improved physical parameters of fenugreek seeds, and enhanced their biological activities. A significant increase in hypocholesterolaemic potential, as indicated by inhibition of cholesterol micellar solubility and pancreatic lipase activity, was recorded. In addition, antioxidant, anti-lipid peroxidation and antibacterial activities were improved. These enhanced biological activities were accompanied by improved seed chemical composition at the primary and secondary metabolic levels. Therefore, eCO2 treatment represents an efficient strategy to increase the hypocholesterolaemic, antioxidant and antibacterial activities of fenugreek seeds.


Assuntos
Antioxidantes/farmacologia , Dióxido de Carbono/farmacologia , Colesterol/metabolismo , Extratos Vegetais/metabolismo , Trigonella/metabolismo , Animais , Peroxidação de Lipídeos , Pâncreas/enzimologia , Extratos Vegetais/química , Sementes/química , Sementes/metabolismo , Trigonella/química , Trigonella/efeitos dos fármacos
9.
Einstein (Sao Paulo) ; 18: eAO4876, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31576909

RESUMO

OBJECTIVE: To investigate the effects of sericin extracted from silkworm Bombyx mori cocoon on morphophysiological parameters in mice with obesity induced by high-fat diet. METHODS: Male C57Bl6 mice aged 9 weeks were allocated to one of two groups - Control and Obese, and fed a standard or high-fat diet for 10 weeks, respectively. Mice were then further subdivided into four groups with seven mice each, as follows: Control, Control-Sericin, Obese, and Obese-Sericin. The standard or high fat diet was given for 4 more weeks; sericin (1,000mg/kg body weight) was given orally to mice in the Control-Sericin and Obese-Sericin Groups during this period. Weight gain, food intake, fecal weight, fecal lipid content, gut motility and glucose tolerance were monitored. At the end of experimental period, plasma was collected for biochemical analysis. Samples of white adipose tissue, liver and jejunum were collected and processed for light microscopy analysis; liver fragments were used for lipid content determination. RESULTS: Obese mice experienced significantly greater weight gain and fat accumulation and had higher total cholesterol and glucose levels compared to controls. Retroperitoneal and periepididymal adipocyte hypertrophy, development of hepatic steatosis, increased cholesterol and triglyceride levels and morphometric changes in the jejunal wall were observed. CONCLUSION: Physiological changes induced by obesity were not fully reverted by sericin; however, sericin treatment restored jejunal morphometry and increased lipid excretion in feces in obese mice, suggesting potential anti-obesity effects.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Obesidade/tratamento farmacológico , Sericinas/uso terapêutico , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Colesterol/análise , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/patologia , Trânsito Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/fisiopatologia , Reprodutibilidade dos Testes , Sericinas/farmacologia , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/análise , Ganho de Peso/efeitos dos fármacos
10.
Gene ; 7242020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898706

RESUMO

AIM: The long noncoding RNAs (lncRNAs) have gradually been reported to be an important class of RNAs with pivotal roles in the development and progression of myocardial infarction (MI). In this study, we hypothesized that genetic variant of cyclin-dependent kinase inhibitor 2B antisense RNA (ANRIL) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may affect the prognosis of MI patients. METHODS: The study included 401 Han Chinese MI patients and 409 controls. Four lncRNA tag single nucleotide polymorphisms (SNPs)-ANRIL rs9632884 and rs1537373, MALAT1 rs619586 and rs3200401-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. RESULTS: rs9632884 and rs3200401 SNPs were significantly associated with lipid levels in both controls and MI patients (P < 0.003-0.046). Several SNPs interacted with sex and age to modify total cholesterol, low-density lipoprotein cholesterol, and creatinine levels to modify the risk of MI. No association between the lncRNAs SNPs and susceptibility to MI was found (P > 0.05 for all). CONCLUSIONS: Taken together, this study provides additional evidence that genetic variation of the ANRIL rs9632884 and MALAT1 rs3200401 can mediate lipid levels in MI patients.


Assuntos
Colesterol/sangue , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , Triglicerídeos/sangue , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Colesterol/genética , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Polimorfismo de Nucleotídeo Único , Fumar/genética , Triglicerídeos/genética
11.
Chemosphere ; 239: 124747, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514003

RESUMO

BACKGROUNDS: Polychlorinated biphenyls are persistent environmental pollutants associated with the onset of non-alcoholic fatty liver disease in humans, but there is limited information on the underlying mechanism. In the present study, we investigated the alterations in gene expression profiles in normal human liver cells L-02 following exposure to 2, 3, 3', 4, 4', 5 - hexachlorobiphenyl (PCB 156), a potent compound that may induce non-alcoholic fatty liver disease. METHODS: The L-02 cells were exposed to PCB 156 for 72 h and the contents of intracellular triacylglyceride and total cholesterol were subsequently measured. Microarray analysis of mRNAs and long non-coding RNAs (lncRNAs) in the cells was also performed after 3.4 µM PCB 156 treatment. RESULTS: Exposure to PCB 156 (3.4 µM, 72 h) resulted in significant increases of triacylglyceride and total cholesterol concentrations in L-02 cells. Microarray analysis identified 222 differentially expressed mRNAs and 628 differentially expressed lncRNAs. Gene Ontology and pathway analyses associated the differentially expressed mRNAs with metabolic and inflammatory processes. Moreover, lncRNA-mRNA co-expression network revealed 36 network pairs comprising 10 differentially expressed mRNAs and 34 dysregulated lncRNAs. The results of bioinformatics analysis further indicated that dysregulated lncRNA NONHSAT174696, lncRNA NONHSAT179219, and lncRNA NONHSAT161887, as the regulators of EDAR, CYP1B1, and ALDH3A1 respectively, played an important role in the PCB 156-induced lipid metabolism disorder. CONCLUSION: Our findings provide an overview of differentially expressed mRNAs and lncRNAs in L-02 cells exposed to PCB 156, and contribute to the field of polychlorinated biphenyl-induced non-alcoholic fatty liver disease.


Assuntos
Fígado/efeitos dos fármacos , Bifenilos Policlorados/toxicidade , Transcriptoma/efeitos dos fármacos , Aldeído Desidrogenase/genética , Linhagem Celular , Colesterol/metabolismo , Citocromo P-450 CYP1B1/genética , Receptor Edar/genética , Perfilação da Expressão Gênica , Humanos , Fígado/citologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante , RNA Mensageiro/metabolismo , Testes de Toxicidade , Triglicerídeos/metabolismo
12.
J Sci Food Agric ; 100(2): 705-713, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31599967

RESUMO

BACKGROUND: Despite the growing importance of probiotics apparent health benefits, an impediment to the use of new probiotic cultures is their safety. Hence there is a need to strictly examine the biosafety as well as health benefits of probiotics in in vivo model systems. RESULTS: In this study, two lactic acid bacterial (LAB) cultures Lactobacillus fermentum NCMR 2826 and FIX proven for their in vitro probiotic properties were investigated for their in vivo safety in Wistar rats. An acute toxicity study (14 days) with a high dose of biomass (1016 colony-forming units (CFU) mL-1 ) followed by a subchronic test for 13 weeks with oral feeding of the probiotic cultures in three different doses (107 , 108 and 1010 CFU mL-1 ) on a daily basis revealed the safety of the L. fermentum cultures. The probiotic feeding had no toxic effects on survival, body weight and food consumption with any of the dosages used throughout the treatment period. No statistically significant changes in relative organ weights and serum biochemical and hematological indices were found between the control and the probiotic fed animals. In addition to the safety attributes, the L. fermentum culture fed rats showed reduced serum cholesterol levels, macrovesicular steatosis and hepatocyte ballooning compared with control animals. Further, quantification of intestinal microbiota using real-time polymerase chain reaction (PCR) analysis from animal feces indicated a significant increase and stability of Lactobacillus and Bifidobacterium counts but a decrease of Escherichia coli numbers. CONCLUSION: This study of safety and beneficial features highlights the use of the two native L. fermentum isolates as potential probiotic food supplements. © 2019 Society of Chemical Industry.


Assuntos
Anticolesterolemiantes/administração & dosagem , Colesterol/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus fermentum/metabolismo , Probióticos/administração & dosagem , Animais , Anticolesterolemiantes/metabolismo , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Colesterol/sangue , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Lactobacillus fermentum/crescimento & desenvolvimento , Masculino , Probióticos/metabolismo , Ratos , Ratos Wistar
13.
Immunity ; 52(1): 109-122.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882361

RESUMO

Recent work suggests that cholesterol metabolism impacts innate immune responses against infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we have shown that upon DNA and RNA viral infection, macrophages reduced 7-dehydrocholesterol reductase (DHCR7) expression. DHCR7 deficiency or treatment with the natural product 7-dehydrocholesterol (7-DHC) could specifically promote phosphorylation of IRF3 (not TBK1) and enhance type I interferon (IFN-I) production in macrophages. We further elucidated that viral infection or 7-DHC treatment enhanced AKT3 expression and activation. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization. Deletion of DHCR7 and the DHCR7 inhibitors including AY9944 and the chemotherapy drug tamoxifen promoted clearance of Zika virus and multiple viruses in vitro or in vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeutics against emerging or highly pathogenic viruses.


Assuntos
Desidrocolesteróis/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/biossíntese , Macrófagos/imunologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Estomatite Vesicular/imunologia , Células A549 , Animais , Linhagem Celular , Colesterol/metabolismo , Ativação Enzimática/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/genética , Vírus da Estomatite Vesicular Indiana/imunologia
14.
Food Chem ; 309: 125762, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31670123

RESUMO

To provide the scientific evidences for a possible new hypocholesterolemic mechanism of apple condensed tannins (ACT), the direct interaction of ACT with cholesterol (CH) was investigated in the present study. Our results suggested that the quenching of ACT fluorescence by CH was carried out according to a static mechanism, while the interaction between ACT and CH in vitro was a spontaneous process. ACT were capable of binding with CH directly, and the CH-binding capacity (35.9-43.9%) of ACT remarkably enhanced with the increase of ACT concentration (0.5-2.0 mg proanthocyanidin B2 equivalent/mL). Besides, spectroscopic methods and morphological analysis were used to characterize the ACT-CH coprecipitates, the findings indicated that ACT were able to precipitate CH via ionic interactions, hydrophobic interactions and intermolecular hydrogen bonds rather than covalent bonds. In conclusion, the direct interaction of ACT with CH might play a role in their CH-lowering effects in humans and animals.


Assuntos
Colesterol/química , Malus/química , Taninos/química , Colesterol/metabolismo , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Malus/metabolismo , Tamanho da Partícula , Espectrometria de Fluorescência , Taninos/metabolismo
15.
Int J Cancer ; 146(1): 58-67, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30815851

RESUMO

Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age-course. We created two random 50-50% cohorts from six European cohorts comprising 813,927 individuals. In the "discovery cohort", we used Cox regression with attained age as time-scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p-value below 0.05 were additionally tested in the "replication cohort" where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age-plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age-interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age-interactions in breast cancer may suggest an influence by other age-related factors than menopause; however, further investigation of age-related effect modifiers in both breast and liver cancer is needed.


Assuntos
Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Neoplasias Hepáticas/epidemiologia , Triglicerídeos/sangue , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Neoplasias da Mama/sangue , Colesterol/sangue , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/sangue , Masculino , Reprodutibilidade dos Testes , Fatores de Risco
16.
Biosci Biotechnol Biochem ; 84(1): 126-133, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31538545

RESUMO

Insects must intake sterol compounds because of their inability to synthesize cholesterol de novo. In phytophagous insects, enzymatic conversion of phytosterols to cholesterol involving 24-dehydrocholesterol reductase (DHCR24) exerts to acquire cholesterol. Here, we reported the presence of two DHCR24 homologs in the silkworm Bombyx mori, BmDHCR24-1 and -2, with several transcript variants. Consistent with the data of spatial expression analyses by RT-PCR, predominant enzymatic activity of DHCR24 was observed in B. mori larval midgut whereas weak activity was observed in the other tissues examined. In addition, BmDHCR24-1 expression in HEK293 cells showed an enzymatic activity, but BmDHCR24-2 did not, although both BmDHCR24s were localized in the endoplasmic reticulum, where the mammalian DHCR24s are located to exert their enzymatic activities. The present data indicated that BmDHCR24-1 but not BmDHCR24-2 contributes to conversion of phytosterols to cholesterol mainly in the midgut of the phytophagous lepidopteran larvae.


Assuntos
Bombyx/enzimologia , Colesterol/biossíntese , Proteínas de Insetos/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Animais , Células HEK293 , Humanos , Proteínas de Insetos/genética , Larva/enzimologia , Túbulos de Malpighi/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Fitosteróis/metabolismo , Plantas/química , Plasmídeos/genética , Homologia de Sequência do Ácido Nucleico , Distribuição Tecidual , Transcrição Genética , Transfecção
17.
Zhonghua Nei Ke Za Zhi ; 59(1): 18-22, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887831

RESUMO

The prevalence of dyslipidemia in Chinese adult is increasing dramatically, which poses a severe challenge to the prevention and treatment of atherosclerotic cardiovascular diseases. In recent years, a series of new research results have been published, providing a lot of new information for the management strategy of dyslipidemia. In order to apply these new research results to clinical practice for the further prevention and treatment of dyslipidemia more reasonably and effectively, the China Cholesterol Education Program (CCEP) Working Committee organized joint expert meeting and revised the "Expert Advice on Prevention and Treatment of Dyslipidemia in China Cholesterol Education Program 2014", in which a new classification standard for cardiovascular risk stratification has been proposed, and the target value of lipid-lowering therapy has been updated.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias , Guias de Prática Clínica como Assunto , Adulto , China , Dislipidemias/prevenção & controle , Dislipidemias/terapia , Humanos , Fatores de Risco
18.
Phys Chem Chem Phys ; 22(3): 1154-1167, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31848548

RESUMO

To the best of our knowledge, molecular dynamics simulations of an isolated cholesterol immersed in four different solvents of varying polarity, such as water, methanol, dimethyl sulfoxide and benzene, were reported for the first time to gain insights into the structural and dynamical properties. The study was mainly focused on the evaluation of solvation of cholesterol with respect to its hydrophilic and hydrophobic structural components in the form of respective functional groups interacting with the solvents. Structural evaluations suggested that both hydrophilic and hydrophobic groups of cholesterol were interacting with the solvents, in particular methanol and dimethyl sulfoxide, which presented both types of interactions that are polar and non-polar. On the other hand, the highly polar water and non-polar benzene demonstrated extreme solvation behavior, since water was involved only in hydrogen bonding to the solute hydroxyl group and non-polar benzene formed strong van der Waals interactions only. Furthermore, the hydrophobic effect of cholesterol was also analyzed mainly in polar solvents, as the effect was more pronounced in the polar environment thereby preventing the solvent mobility in the solvation layer(s). The dynamical properties in terms of lateral diffusion and hydrogen bond dynamics as well as free energies of solvation also corroborated the findings based on the structural data and the hydrophobic character of cholesterol was later quantified by the computation of the averaged solvent accessible surface area. The polarity effect of the solvents on the aggregation property of cholesterol was further investigated, which is of big concern from the clinical point of view due to its major role in cardiovascular ailments. It was another major finding of the present study that aggregation was shown to be facilitated by highly polar solvents like water.


Assuntos
Colesterol/química , Simulação de Dinâmica Molecular , Solventes/química , Estrutura Molecular
19.
Gut ; 69(1): 177-186, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954949

RESUMO

OBJECTIVE: Increased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DESIGN: We investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies. RESULTS: Ablation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. CONCLUSION: Our study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/biossíntese , Ácido Graxo Sintase Tipo I/metabolismo , Ácidos Graxos/biossíntese , Neoplasias Hepáticas/metabolismo , Animais , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Genômica , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Transcriptoma
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