RESUMO
BACKGROUND: S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular disease; inhibition of SAH hydrolase (SAHH) results in SAH accumulation and induces endothelial dysfunction and atherosclerosis. However, the effect and mechanism of SAHH in atherosclerotic calcification is still unclear. We aimed to explore the role and mechanism of SAHH in atherosclerotic calcification. METHODS: The relationship between SAHH and atherosclerotic calcification was investigated in patients with coronary atherosclerotic calcification. Different in vivo genetic models were used to examine the effect of SAHH deficiency on atherosclerotic calcification. Human aortic and murine vascular smooth muscle cells (VSMCs) were cultured to explore the underlying mechanism of SAHH on osteoblastic differentiation of VSMCs. RESULTS: The expression and activity of SAHH were decreased in calcified human coronary arteries and inversely associated with coronary atherosclerotic calcification severity, whereas plasma SAH and total homocysteine levels were positively associated with coronary atherosclerotic calcification severity. Heterozygote knockout of SAHH promoted atherosclerotic calcification. Specifically, VSMC-deficient but not endothelial cell-deficient or macrophage-deficient SAHH promoted atherosclerotic calcification. Mechanistically, SAHH deficiency accumulated SAH levels and induced H19-mediated Runx2 (runt-related transcription factor 2)-dependent osteoblastic differentiation of VSMCs by inhibiting DNMT3b (DNA methyltransferase 3b) and leading to hypomethylation of the H19 promoter. On the contrary, SAHH deficiency resulted in lower intracellular levels of adenosine and reduced AMPK (AMP-activated protein kinase) activation. Adenosine supplementation activated AMPK and abolished SAHH deficiency-induced expression of H19 and Runx2 and osteoblastic differentiation of VSMCs. Finally, AMPK activation by adenosine inhibited H19 expression by inducing Sirt1 (sirtuin-1)-mediated histone H3 hypoacetylation and DNMT3b-mediated hypermethylation of the H19 promoter in SAHH deficiency VSMCs. CONCLUSIONS: We have confirmed a novel correlation between SAHH deficiency and atherosclerotic calcification and clarified a new mechanism that epigenetic upregulation of H19 and AMPK inhibition concurrently contribute to SAHH deficiency-promoted Runx2-dependent atherosclerotic calcification.
Assuntos
Aterosclerose , Calcinose , Calcificação Vascular , Proteínas Quinases Ativadas por AMP/metabolismo , Adenosina/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos , Animais , Aterosclerose/metabolismo , Calcinose/genética , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Epigênese Genética , Glicina N-Metiltransferase/deficiência , Humanos , Camundongos , Miócitos de Músculo Liso/metabolismo , RNA Longo não Codificante , S-Adenosil-Homocisteína/metabolismo , Regulação para Cima , Calcificação Vascular/genética , Calcificação Vascular/metabolismoRESUMO
SRC is the first identified oncogene, and its aberrant activation has been implicated as a driving event in tumor initiation and progression. However, its role in cancer stemness regulation and the underlying regulatory mechanism are still elusive. Here, we identified a YAP1 tyrosine phosphorylation-dependent YAP1-KLF5 oncogenic module, as the key downstream mediator of SRC kinase regulating cancer stemness and metastasis in triple-negative breast cancer (TNBC). SRC was overexpressed in TNBC patient tissues and its expression level was highly correlated with the tumor malignancy. SRC activation induced, while inhibition of SRC kinase reduced the cancer stemness, tumor cell growth and metastasis in vitro and in vivo. Transcriptomic and proteomic analysis revealed that SRC-mediated YAP1 tyrosine phosphorylation induced its interaction with Kruppel-like factor 5 (KLF5) to form a YAP1/TEAD-KLF5 complex in TNBC cells. YAP1-KLF5 association further promoted TEAD-mediated transcriptional program independently of canonical Hippo kinases, which eventually gave rise to the enhanced cancer stemness and metastasis. Disruption of YAP1-KLF5 module in TNBC cells dramatically attenuated the SRC-induced cancer stemness and metastasis in vitro and in vivo. Accordingly, co-upregulations of SRC and YAP1-KLF5 module in TNBC tissues were significantly positively correlated with the tumor malignance. Altogether, our work presents a novel tyrosine phosphorylation-dependent YAP1-KLF5 oncogenic module governing SRC-induced cancer stemness and metastasis in TNBC. Therefore, targeting YAP1/KLF5-mediated transcription may provide a promising strategy for TNBC treatment with SRC aberrantly activation.
Assuntos
Proteínas Tirosina Quinases , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Proteômica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Quinases da Família src/metabolismo , Proliferação de Células , Tirosina , Linhagem Celular Tumoral , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
Breast cancer (BC) is the most commonly diagnosed form of cancer and a leading cause of cancer-related deaths among women worldwide. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are homologous transcriptional coactivators and downstream effectors of Hippo signalling. YAP/TAZ activation has been revealed to play essential roles in multiple events of BC development, including tumour initiation, progression, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of YAP/TAZ-mediated oncogenesis in BC, and then systematically summarise the oncogenic roles of YAP/TAZ in various BC subtypes, BC stem cells (BCSCs) and tumour microenvironments (TMEs). Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based targeted therapies in BC and the potential future direction.
Assuntos
Neoplasias da Mama , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Feminino , Humanos , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: Hepatic cholesterol accumulation is a significant risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis. However, the precise mechanism by which stigmasterol (STG) mitigates this process remains unclear. OBJECTIVES: This study aimed to investigate the potential mechanism underlying the protective effect of STG in mice with NAFLD progressing to steatohepatitis while being fed a high-fat and high-cholesterol (HFHC) diet. METHODS: Male C57BL/6 mice were fed an HFHC diet for 16 wk to establish the NAFLD model. Subsequently, the mice received STG or a vehicle via oral gavage while continuing the HFHC diet for an additional 10 wk. The study evaluated hepatic lipid deposition and inflammation as well as the expression of key rate-limiting enzymes involved in the bile acid (BA) synthesis pathways. BAs in the colonic contents were quantified using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: Compared with the vehicle control group, STG significantly reduced hepatic cholesterol accumulation (P < 0.01) and suppressed the gene expression of NLRP3 inflammasome and interleukin-18 (P < 0.05) in the livers of HFHC diet-fed mice. The total fecal BA content in the STG group was nearly double that of the vehicle control group. Additionally, the administration of STG increased the concentrations of representative hydrophilic BAs in the colonic contents (P < 0.05) along with the upregulation of gene and protein expression of CYP7B1 (P < 0.01). Furthermore, STG enhanced the α-diversity of the gut microbiota and partially reversed the alterations in the relative abundance of the gut microbiota induced by the HFHC diet. CONCLUSIONS: STG mitigates steatohepatitis by enhancing the alternative pathway for BA synthesis.
Assuntos
Hipercolesterolemia , Hepatopatia Gordurosa não Alcoólica , Camundongos , Masculino , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estigmasterol/metabolismo , Estigmasterol/farmacologia , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Colesterol/metabolismo , Hipercolesterolemia/complicações , Ácidos e Sais Biliares/metabolismoRESUMO
This study is designed to explore the association between dietary betaine intake and risk of all-cause and cardiovascular death in patients with coronary artery diseases (CAD). In this cohort study, 1292 patients with CAD were followed up for a median of 9·2 years. Baseline dietary betaine intake was collected using a paper-based semi-quantitative FFQ and assessed according to the US Department of Agriculture (USDA) database and the data of betaine in common foods. Cox proportional hazards regression models were used to analyse the association between dietary betaine intake and risks of all-cause and cardiovascular mortality. During the follow-up periods, 259 deaths recorded in 1292 participants, of which 167 died of CVD. Patients in the highest tertile of dietary betaine intake had a lower risk of all-cause (P = 0·007) and cardiovascular death (P < 0·001) than those in the lowest tertile after adjusting for age and sex, traditional cardiovascular risk factors and other potential confounders. After further adjusting for plasma methionine metabolites and vitamins, hazard ratio across tertiles of dietary betaine intake were 1·00, 0·84 and 0·72 for all-cause mortality (Pfor trend = 0·124), and 1·00, 0·77 and 0·55 for cardiovascular mortality (Pfor trend = 0·021). Higher dietary betaine intake was associated with a decreased risk of cardiovascular death after fully adjustment for cardiovascular risk factors, other potential confounders and plasma methionine metabolites and vitamins. However, the association between dietary betaine intake and risk of all-cause mortality was not statistically significant after further adjusting for plasma methionine metabolites and vitamins.
Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Humanos , Betaína , Estudos de Coortes , Estudos Prospectivos , Dieta , Fatores de Risco , Vitaminas , Metionina , Racemetionina , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Elevated levels of S-adenosylhomocysteine (SAH), the precursor of homocysteine, are positively associated with the risk of cardiovascular disease and with the development and progression of atherosclerosis. However, the role of SAH in endothelial dysfunction is unclear. METHODS: Apolipoprotein E-deficient ( apoE-/-) mice received dietary supplementation with the SAH hydrolase (SAHH) inhibitor adenosine dialdehyde or were intravenously injected with a retrovirus expressing SAHH shRNA. These 2 approaches, along with the heterozygous SAHH gene knockout ( SAHH+/-) mouse model, were used to elevate plasma SAH levels and to examine the role of SAH in aortic endothelial dysfunction. The relationship between plasma SAH levels and endothelial dysfunction was also investigated in human patients with coronary artery disease and healthy control subjects. RESULTS: Plasma SAH levels were increased in SAHH+/- mice and in apoE-/- mice after dietary administration of adenosine dialdehyde or intravenous injection with SAHH shRNA. SAHH+/- mice or apoE-/- mice with SAHH inhibition showed impaired endothelium-dependent vascular relaxation and decreased nitric oxide bioavailability after treatment with acetylcholine; this was completely abolished by the administration of the endothelial nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Furthermore, SAHH inhibition induced production of reactive oxygen species and p66shc expression in the mouse aorta and human aortic endothelial cells. Antioxidants and p66shc siRNA prevented SAHH inhibition-induced generation of reactive oxygen species and attenuated the impaired endothelial vasomotor responses in high-SAH mice. Moreover, inhibition of SAHH induced hypomethylation in the p66shc gene promoter and inhibited expression of DNA methyltransferase 1. Overexpression of DNA methyltransferase 1, induced by transduction of an adenovirus, was sufficient to abrogate SAHH inhibition-induced upregulation of p66shc expression. Finally, plasma SAH levels were inversely associated with flow-mediated dilation and hypomethylation of the p66shc gene promoter and positively associated with oxidative stress levels in patients with coronary artery disease and healthy control subjects. CONCLUSIONS: Our findings indicate that inhibition of SAHH results in elevated plasma SAH levels and induces endothelial dysfunction via epigenetic upregulation of the p66shc-mediated oxidative stress pathway. Our study provides novel molecular insight into mechanisms of SAH-associated endothelial injury that may contribute to the development of atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03345927.
Assuntos
Adenosil-Homocisteinase/metabolismo , Aterosclerose/metabolismo , Doença da Artéria Coronariana/metabolismo , Endotélio Vascular/fisiologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosil-Homocisteinase/antagonistas & inibidores , Adenosil-Homocisteinase/genética , Idoso , Animais , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Estresse Oxidativo , RNA Interferente Pequeno/genética , S-Adenosil-Homocisteína/sangue , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genéticaRESUMO
The lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) requires sustained extracellular signal-regulated kinase (ERK)-p90 ribosomal S6 kinase (RSK) activation, which is induced by an immediate early (IE) gene-encoded tegument protein called ORF45, to promote the late transcription and translation of viral lytic genes. An ORF45-null or single-point F66A mutation in ORF45 abolishes ORF45-RSK interaction and sustained ERK-RSK activation during lytic reactivation and subsequently results in a significant decrease in late lytic gene expression and virion production, indicating that ORF45-mediated RSK activation plays a critical role in KSHV lytic replication. Here, we demonstrate that a short ORF45-derived peptide in the RSK-binding region is sufficient for disrupting ORF45-RSK interaction, consequently suppressing lytic gene expression and virion production. We designed a nontoxic cell-permeable peptide derived from ORF45, TAT-10F10, which is composed of the ORF45 56 to 76 amino acid (aa) region and the HIV Tat protein transduction domain, and this peptide markedly inhibits KSHV lytic replication in iSLK.219 and BCBL1 cells. Importantly, this peptide enhances the inhibitory effect of rapamycin on KSHV-infected cells and decreases spontaneous and hypoxia-induced lytic replication in KSHV-positive lymphoma cells. These findings suggest that a small peptide that disrupts ORF45-RSK interaction might be a promising agent for controlling KSHV lytic infection and pathogenesis.IMPORTANCE ORF45-induced RSK activation plays an essential role in KSHV lytic replication, and ORF45-null or ORF45 F66A mutagenesis that abolishes sustained RSK activation and RSK inhibitors significantly decreases lytic replication, indicating that the ORF45-RSK association is a unique target for KSHV-related diseases. However, the side effects, low affinity, and poor efficacy of RSK modulators limit their clinical application. In this study, we developed a nontoxic cell-permeable ORF45-derived peptide from the RSK-binding region to disrupt ORF45-RSK associations and block ORF45-induced RSK activation without interfering with S6K1 activation. This peptide effectively suppresses spontaneous, hypoxia-induced, or chemically induced KSHV lytic replication and enhances the inhibitory effect of rapamycin on lytic replication and sensitivity to rapamycin in lytic KSHV-infected cells. Our results reveal that the ORF45-RSK signaling axis and KSHV lytic replication can be effectively targeted by a short peptide and provide a specific approach for treating KSHV lytic and persistent infection.
Assuntos
Herpesvirus Humano 8/efeitos dos fármacos , Proteínas Imediatamente Precoces/imunologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Linhagem Celular , Regulação Viral da Expressão Gênica/genética , Genes Virais/genética , Células HEK293 , Infecções por Herpesviridae/genética , Herpesvirus Humano 8/patogenicidade , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Ligação Proteica , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Vírion/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologiaRESUMO
OBJECTIVE: To establish a mouse lung cancer model induced by benzo[a]pyrene(B[a]P) dynamic inhalation exposure. METHODS: A total of 96 C57 BL/6 J mice weighing 18 to 20 g were randomly divided into the control group(n=48)and the experimental group(n=48), male and female in half. The experimental group was treated with 10. 0 µg/m~3 BaP for 13 weeks or 25 weeks(6 h per day and 5 days per week) by dynamic inhalation exposure, while the control group was given dimethyl sulfoxide(DMSO). The 13 weeks or 25 weeks after B[a]P exposure, 24 mice were sacrificed and their lung tissues dissected and observed for tumor formation. During B[a]P exposure, the gas in the poisoning cabinet was collected by the active carbon tube method regularly, and the concentration of B[a]P in the poisoning cabinet was analyzed by gas chromatography mass spectrometer, and the(7 R, 8 S)-dihydroxy-(9 S, 10 R)-epoxy-7, 8, 9, 10-tetrahydrobenzo [a] pyrene(BPDE)-DNA adduct content in the whole blood of mice was determined by ELISA. RESULTS: Concentration of B[a]P in the dynamic inhalation cabinet was stable at(12. 794±0. 518)µg/m~3. There was no significant difference in the BPDE-DNA content in the experimental objects between 13 weeks and 25 weeks after B[a]P exposure(P>0. 05). After 25 weeks of B[a]P exposure, the lung cancer formation rate in the experimental group was significantly higher than that in the control group(P<0. 05), the tumor formation rate of female mice was up to 100%. CONCLUSION: The mice lung cancer model induced by B[a]P dynamic inhalation exposure was established successfully.
Assuntos
Benzo(a)pireno , Neoplasias Pulmonares , Animais , DNA , Adutos de DNA , Feminino , Exposição por Inalação , Pulmão , Masculino , CamundongosRESUMO
BACKGROUND: Epidemiologic evidence suggests that certain dietary patterns were associated with breast cancer risk, but the results have been inconclusive. We assessed the associations between different dietary patterns and the risk of breast cancer by conducting a meta-analysis of observational studies. METHODS: Relevant articles were searched in PubMed, Embase, and Cochrane library databases through September 2017. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) comparing the highest and lowest categories of Western and prudent dietary patterns were combined by using the random-effects meta-analyses. RESULTS: We identified 32 eligible articles including 14 cohort and 18 case-control studies (34 Western and 35 prudent studies). The pooled analyses found that a Western dietary pattern was associated with a 14% increased risk (RR 1.14, 95% CI 1.02, 1.28), whereas a prudent dietary pattern was associated with an 18% reduced risk of breast cancer (RR 0.82, 95% CI 0.75, 0.89). In addition, sub-group analyses showed that the positive association between a Western dietary pattern and breast cancer risk was significant among postmenopausal (RR 1.20, 95% CI 1.06, 1.35), but not premenopausal women (RR 1.18, 95% CI 0.99, 1.40), and significant for hormone receptor-positive tumors (RR 1.18, 95% CI 1.04, 1.33), but not receptor-negative tumors (RR 0.97, 95% CI 0.83, 1.12). In contrast, the inverse association between a prudent dietary pattern and breast cancer was significant in premenopausal (RR 0.77, 95% CI 0.61, 0.98), but not postmenopausal women (RR 0.88, 95% CI 0.74, 1.03), and significant for both hormone receptor-positive and receptor-negative tumors. CONCLUSIONS: The results of the current meta-analysis suggest a possible increased risk of breast cancer associated with a Western dietary pattern and a reduced risk with a prudent dietary pattern. Large-scale cohort studies with a high quality need to be conducted to further confirm the findings of the current meta-analysis. As dietary patterns are modifiable, these findings may provide viable strategies for breast cancer prevention through changes in dietary intake.
Assuntos
Neoplasias da Mama/epidemiologia , Dieta Saudável , Dieta Ocidental/efeitos adversos , Comportamento Alimentar/fisiologia , Neoplasias da Mama/etiologia , Feminino , Humanos , Avaliação Nutricional , Estudos Observacionais como Assunto , Fatores de RiscoRESUMO
BACKGROUND: Information on the association between iron metabolism and dyslipidaemia in children is limited. Thus, this study aims to evaluate the iron metabolic status of children with different body mass index (BMI) and to examine the association between iron metabolism and dyslipidaemia risk. METHOD: In total, 1866 children and adolescents aged 7-18 were enrolled in this study, including 912 boys and 954 girls. In this cross-sectional study, parameters for anthropometry, lipids and iron metabolism including transferrin, soluble transferrin receptor (sTfR), ferritin and serum iron (SF) were evaluated. Data regarding demographic characteristics, diet, and physical activity were collected by self-reported questionnaires. RESULTS: The prevalence of dyslipidaemia and iron deficiency in children and adolescents increased based on BMI categories (both P < 0.05) and were 58.3 and 8.9% in subjects with obesity, respectively. The lowest SF and the highest ferritin levels were observed in subjects who were obese (both P < 0.001). Subjects with dyslipidaemia had lower SF, transferrin and sTfR levels by different BMI categories, and those who were obese had higher ferritin levels (all P < 0.05). Most importantly, higher concentrations of transferrin and sTfR were related to lower dyslipidaemia risk (OR for transferrin: 0.49, 95% CI: 0.33-0.71; OR for sTfR: 0.68, 95% CI: 0.46-0.99). CONCLUSIONS: A downward trend in SF level by BMI categories and the highest ferritin level in subjects with obesity suggested that iron storage was associated with BMI in children and adolescents. Moreover, an inverse relationship was observed between transferrin and sTfR concentrations and dyslipidaemia risk in children with different BMI.
Assuntos
Anemia Ferropriva/sangue , Dislipidemias/sangue , Ferritinas/sangue , Ferro/sangue , Receptores da Transferrina/sangue , Transferrina/metabolismo , Adolescente , Anemia Ferropriva/complicações , Anemia Ferropriva/diagnóstico , Antropometria , Índice de Massa Corporal , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Dieta , Dislipidemias/complicações , Dislipidemias/diagnóstico , Exercício Físico , Feminino , Humanos , Masculino , Inquéritos e Questionários , Triglicerídeos/sangueRESUMO
BACKGROUND: Epidemiological studies have found that high whole grain intake may be associated with a reduced risk of breast cancer. However, the evidence has not been consistent. We conducted a meta-analysis to quantitatively assess the association between whole grain intake and breast cancer risk. METHODS: Relevant observational studies were identified by searching PubMed, Embase, Cochrane library databases, and Google Scholar through April 2017. Summary relative risk (RR) estimates were calculated using random-effects meta-analysis. RESULTS: A total of 11 studies, including 4 cohort and 7 case-control studies and involving 131,151 participants and 11,589 breast cancer cases, were included in the current meta-analysis. The pooled RR of breast cancer for those with high versus low whole grain intake was 0.84 (95% confidence interval [CI]: 0.74 to 0.96, p = 0.009; I2 = 63.8%, p for heterogeneity = 0.002). Subgroup analysis by study design found a significant inverse association in the case-control studies (RR: 0.69; 95% CI: 0.56 to 0.87, p = 0.001; I2 = 58.2%, p for heterogeneity = 0.026), but not in the cohort studies (RR, 0.96; 95% CI: 0.82 to 1.14, p = 0.69; I2 = 66.7%, p for heterogeneity = 0.029). In addition, stratified analysis suggested that sample size could be a potential source of heterogeneity. CONCLUSIONS: Results of the current meta-analysis suggest that high intake of whole grains might be inversely associated with a reduced risk of breast cancer, and the inverse association was only observed in case-control but not cohort studies. More large-scale cohort studies are needed to confirm the inverse association observed.
Assuntos
Neoplasias da Mama/prevenção & controle , Dieta/métodos , Dieta/estatística & dados numéricos , Grãos Integrais , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Fatores de RiscoRESUMO
BACKGROUND: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies.MethodsâandâResults:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models. On meta-analysis of 6 cohort and 1 nested case-control study, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events (overall RR, 1.12; 95% CI: 0.98-1.29; P=0.09), with significant heterogeneity (I2=55.1%, Pheterogeneity=0.038). The highest but not middle categories of circulating PCSK9 was significantly associated with the risk of cardiovascular events. On subgroup analysis of study design, mean age at baseline, sample size, follow-up time, and pre-existing disease, there was no significant association between PCSK9 and cardiovascular events. Sensitivity analysis with various exclusion and inclusion criteria did not materially change the results. CONCLUSIONS: Circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events. More well-designed studies are needed to clarify the role of PCSK9 in cardiovascular risk.
Assuntos
Doenças Cardiovasculares/sangue , Modelos Cardiovasculares , Pró-Proteína Convertase 9/sangue , Fatores Etários , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVE: S-Adenosylhomocysteine (SAH) is a better predictor of cardiovascular disease than homocysteine is, and it has been implicated in mediating the pathogenicity of hyperhomocysteinemia in atherosclerosis via an epigenetic mechanism. However, the underlying mechanism remains unclear. Here, we tested the hypothesis whether the effect of SAH on atherosclerosis is involved in epigenetic regulation of endoplasmic reticulum stress. APPROACH AND RESULTS: A total of 48 apolipoprotein E-deficient mice at 8 weeks were randomly divided into 4 groups (n=12 for each group). The control group was fed a conventional diet, the adenosine dialdehyde group was fed a diet that was supplemented with the SAH hydrolase inhibitor adenosine dialdehyde, and the other 2 groups were intravenously injected with a retrovirus that expressed either SAH hydrolase short hairpin RNA or scrambled short hairpin RNA semiweekly for 16 weeks. Plasma SAH levels and atherosclerotic lesion size were significantly increased in adenosine dialdehyde and SAH hydrolase short hairpin RNA groups when compared with control group. Expression of endoplasmic reticulum stress markers glucose-regulated protein-78 and CEBP-homologous protein was significantly increased in the mice with elevated plasma SAH levels. Moreover, plasma SAH was negatively associated with a decrease in the expression of trimethylated histone H3 lysine 9 and histone methyltransferases. Chromatin immunoprecipitation assays showed a significant decrease in trimethylated histone H3 lysine 9 occupancy at the glucose-regulated protein-78 and CEBP-homologous protein promoters in mice treated with adenosine dialdehyde and SAH hydrolase short hairpin RNA when compared with control mice. CONCLUSIONS: Our results suggest that elevated plasma SAH levels-accelerated atherosclerosis was associated with the activation of endoplasmic reticulum stress via modulation of histone methylation.
Assuntos
Doenças da Aorta/sangue , Apolipoproteínas E/deficiência , Aterosclerose/sangue , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Epigênese Genética , S-Adenosil-Homocisteína/sangue , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosil-Homocisteinase/antagonistas & inibidores , Adenosil-Homocisteinase/genética , Adenosil-Homocisteinase/metabolismo , Animais , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Sítios de Ligação , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Retículo Endoplasmático/patologia , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/genética , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Fatores de Tempo , Regulação para CimaRESUMO
BACKGROUND: Dietary patterns are associated with plasma total homocysteine (tHcy) concentrations in healthy populations, but the associations between dietary protein and tHcy, total cysteine (tCys) in high risk populations are unclear. We therefore examined the association between dietary protein and tHcy and tCys concentrations in coronary angiographic subjects. METHODS: We conducted a cross-sectional study of 1015 Chinese patients who underwent coronary angiography (40-85 y old). With the use of food-frequency questionnaires, we divided the total protein intakes into high animal-protein and high plant-protein diets. Circulating concentrations of tHcy and tCys were simultaneously measured by high-performance liquid chromatography with fluorescence detection. RESULTS: We found that high animal-protein diet was positively associated with hyperhomocysteinemia after adjustment for potential confounders, with the subjects in the highest quartile of intake having the greatest increase in risk (OR: 4.14, 95% CI: 2.67-6.43), whereas high plant-protein diet was inversely related to hyperhomocysteinemia, with a higher intake being protective. Compared with the first quartile of intake, the adjusted OR was 0.59 (95% CI: 0.38-0.91) for the fourth quartile. The total protein intake was positively associated with the risk of hypercysteinemia and the participants in highest quartile had significant OR of 1.69 (95% CI: 1.02-2.87) compared with those in lowest quartile. In multivariate linear regression analyses, high animal-protein and total-protein intakes were positively associated with plasma tHcy and tCys concentrations. The plant-protein intake was a negative determinant of plasma tHcy concentrations. CONCLUSIONS: High animal-protein diet was positively associated with high tHcy concentrations, whereas high plant-protein diet was inversely associated with tHcy concentrations. Furthermore the total protein intake was strongly related to tCys concentrations.
Assuntos
Cisteína/sangue , Proteínas Alimentares/administração & dosagem , Homocisteína/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Doenças Cardiovasculares/sangue , Cromatografia Líquida de Alta Pressão , Angiografia Coronária , Estudos Transversais , Proteínas Alimentares/efeitos adversos , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/etiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Since universal salt iodization (USI) was implemented in Shenzhen, China, in 1996, evaluation of the time trend of USI to indicate the control of iodine-deficiency disorders has not been performed. OBJECTIVE: To assess the time trend of median urinary iodine and total goiter rates from 1997 to 2011. METHODS: Probability-proportionate-to-size sampling was employed in the surveillance of iodine-deficiency disorders, for which schoolchildren aged 8 to 10 years were randomly selected from five districts of the city during each iodine-deficiency disorders survey. Urinary iodine content and thyroid size were measured by ammonium persulfate oxidation and B ultrasound, respectively. RESULTS: The coverage of iodized salt increased from 73.2% in 1997 to more than 90% in 2011. The median urinary iodine of children aged 8 to 10 years varied between 207.1 and 278.8 microg/L; these levels were above the urinary iodine level in 1995. The proportion of urine samples with iodine content above 300 microg/L was 45.6% in 1997 and decreased to 20.8% in 2011, indicating excessive consumption of iodine by the children. The goiter rate among children dropped from 10.8% in 1997 to 1.3% in 2011; both values were lower than the goiter rate in 1995, indicating that the spread of endemic goiter was under control. CONCLUSIONS: Preliminary elimination of iodine-deficiency disorders was achieved by USI in Shenzhen. Nevertheless, some problems still existed, such as over-iodization. To clarify the causes of excessive urinary iodine content, the various sources of iodine from the diet need to be investigated in the future.
Assuntos
Bócio Endêmico/prevenção & controle , Iodo/deficiência , Cloreto de Sódio na Dieta/administração & dosagem , Adolescente , Adulto , Biomarcadores/urina , Criança , China/epidemiologia , Feminino , Bócio Endêmico/epidemiologia , Bócio Endêmico/urina , Promoção da Saúde/métodos , Promoção da Saúde/estatística & dados numéricos , Humanos , Iodo/administração & dosagem , Iodo/urina , Masculino , Tamanho do Órgão , Vigilância da População/métodos , Avaliação de Programas e Projetos de Saúde/métodos , Avaliação de Programas e Projetos de Saúde/estatística & dados numéricos , Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , População Urbana/estatística & dados numéricos , Adulto JovemRESUMO
SCOPE: Intermittent fasting (IF) has a protective role across a wide range of chronic disorders, including obesity, diabetes, and cardiovascular disease, but its protection against non-alcoholic steatohepatitis (NASH) is still lacking. This study seeks to investigate how IF alleviates NASH by regulating gut microbiota and bile acids (BAs) composition. METHODS AND RESULTS: Male C57BL/6 mice are fed a high-fat and high-cholesterol (HFHC) diet for 16 weeks to establish a NASH model. Mice then continued HFHC feeding and are treated with or without every other day fasting for 10 weeks. Hepatic pathology is assessed using hematoxylin-eosin staining. Gut microbiota of the cecum are profiled using 16S rDNA gene sequencing and the levels of BAs in serum, colon contents, and feces are measured using ultra-performance liquid chromatography-tandem mass spectrometry. Results indicate that IF significantly decreases murine body weight, insulin resistance, hepatic steatosis, ballooning, and lobular inflammation. IF reshapes the gut microbiota, reduces the accumulation of serum BAs, and increases total colonic and fecal BAs. Moreover, IF increases the expression of cholesterol 7α-hydroxylase 1 in liver, but decreases the expressions of both farnesoid-X-receptor and fibroblast growth factor 15 in the ileum. CONCLUSION: IF alleviates NASH by regulating bile acid metabolism and promoting fecal bile acid excretion.
Assuntos
Hipercolesterolemia , Hepatopatia Gordurosa não Alcoólica , Masculino , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácidos e Sais Biliares/metabolismo , Jejum Intermitente , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Hipercolesterolemia/metabolismo , Colesterol/metabolismoRESUMO
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.
RESUMO
Cyanidin-3-glucoside (C3G) is a member of the anthocyanin family which belongs to the flavonoid class and possesses antiatherogenic properties. Many studies have demonstrated the protective effects of C3G on vascular endothelial cells and monocytes, however, the precise effects on vascular smooth muscle cells (VSMCs) have been less thoroughly studied. Hence, we investigated the role of C3G in TNF-α-induced VSMCs proliferation and explored the possible mechanisms. TNF-α stimulated VSMCs proliferation, and pretreatment with C3G inhibited the proliferation in dose- and time-dependent manners. Then, we found that C3G attenuated TNF-α-induced ROS over generation by Dihydroethidium staining. The combination of 50 µM C3G and 100 µM apocynin significantly reduced ROS generation. Moreover, C3G pretreatment significantly suppressed the expression of Nox activator 1, a subunit of NADPH oxidase in mouse VSMCs. C3G also inhibited TNF-α-induced signal transducer and activator of transcription (STAT3) phosphorylation, and the inhibitory effect was more prominent in C3G and apocynin co-pretreated cells than that pretreated with C3G or apocynin alone. Administration of the ROS scavenger catalase (2,000 U/ml) remarkably inhibited TNF-α-induced cell proliferation and STAT3 activation. These data suggest that C3G exerts its antiproliferative effect on TNF-α-induced VSMCs proliferation through inhibiting STAT3 activation by attenuating NoxA1-derived ROS over production.
Assuntos
Antocianinas/farmacologia , Glucosídeos/farmacologia , Músculo Liso Vascular/metabolismo , Proteínas/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Acetofenonas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Catalase/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The aim of the present study was to explore risk variants for coronary artery disease (CAD) and to evaluate their joint effects (quantified by genetic risk score; GRS) on the discrimination of CAD in a Chinese Han sample. METHODS AND RESULTS: An association analysis of 91 single nucleotide polymorphisms (SNPs) with CAD risk was undertaken in 1,007 CAD patients and 889 healthy controls. Two GRSs, counted GRS (cGRS) and weighted GRS (wGRS), were calculated using the significant SNPs, and their discriminant power for CAD was assessed using receiver-operating characteristic (ROC) curve analysis. Eight SNPs (rs11206510, rs10118757, rs2383206, rs501120, rs2075292, rs174547, rs173539, and rs255052) were nominally significantly associated with CAD (P<0.05), and 5 of them were newly reported. The GRSs derived from the 8 SNPs improved the discrimination of CAD compared to that using 4 conventional risk factors (P=0.002 for cGRS and P=0.009 for wGRS). After 10-fold cross-validation 100 times, the average areas under the curve were 0.668 (95% confidence interval [CI]: 0.667-0.669), 0.686 (95% CI: 0.685-0.687) and 0.690 (95% CI: 0.689-0.691) for models with conventional risk factors only, conventional risk factors plus cGRS, and conventional risk factors plus wGRS, respectively. CONCLUSIONS: A multigenic GRS, generated by combining multiple gene variants, can improve discrimination of CAD, thereby confirming the joint effects of these gene variants on CAD in this Chinese Han population.
Assuntos
Doença da Artéria Coronariana/genética , Loci Gênicos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Idoso , Povo Asiático , China/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de RiscoRESUMO
S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular diseases and atherosclerosis. However, the causal association between SAH and atherosclerosis is still uncertain. In the present study, heterozygous SAH hydrolase (SAHH+/-) knockout mice were bred with apolipoprotein E-deficient mice to produce ApoE-/-/SAHH+/- mice. At 8 weeks of age, these mice were fed on AIN-93G diets added with or without betaine (4 g betaine/100 g diet) for 8 weeks. Compared with ApoE-/-/SAHHWT mice, SAHH deficiency caused an accumulation of plasma SAH concentration and a decrease in S-adenosylmethionine (SAM)/SAH ratio as well as plasma homocysteine levels. Betaine supplementation lowered SAH levels and increased SAM/SAH ratio and homocysteine levels in ApoE-/-/SAHH+/- mice. Furthermore, SAHH deficiency promoted the development of atherosclerosis, which was reduced by betaine supplementation. The atheroprotective effects of betaine on SAHH-deficiency-promoted atherosclerosis were associated with inhibition of NFκB inflammation signaling pathway and inhibition of proliferation and migration of smooth muscle cells. In conclusion, our results suggest that betaine supplementation lowered plasma SAH levels and protected against SAHH-deficiency-promoted atherosclerosis through repressing inflammation and proliferation and migration of smooth muscle cells.