miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.

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.

Stigmasterol Protects Against Steatohepatitis Induced by High-Fat and High-Cholesterol Diet in Mice by Enhancing the Alternative Bile Acid Synthesis Pathway.

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.

Intermittent Fasting Alleviates Non-Alcoholic Steatohepatitis by Regulating Bile Acid Metabolism and Promoting Fecal Bile Acid Excretion in High-Fat and High-Cholesterol Diet Fed Mice.

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.

The oncogenic roles and clinical implications of YAP/TAZ in breast cancer.

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.

Tyrosine kinase SRC-induced YAP1-KLF5 module regulates cancer stemness and metastasis in triple-negative breast cancer.

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.

Dietary betaine intake and risk of mortality in patients with coronary artery disease: the prospective Guangdong Coronary Artery Disease Cohort.

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.

Epigenetic Upregulation of H19 and AMPK Inhibition Concurrently Contribute to S-Adenosylhomocysteine Hydrolase Deficiency-Promoted Atherosclerotic Calcification.

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.

Betaine Supplementation Attenuates S-Adenosylhomocysteine Hydrolase-Deficiency-Accelerated Atherosclerosis in Apolipoprotein E-Deficient Mice.

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.

Association between plasma S-adenosylmethionine and risk of mortality in patients with coronary artery disease: A cohort study.

BACKGROUND: S-adenosylmethionine (SAM) as methyl donors participates in methylation and is converted into S-adenosylhomocysteine (SAH), which is a precursor of homocysteine. Increased plasma SAH and homocysteine are associated with increased risk of cardiovascular disease. However, the relation of plasma SAM with cardiovascular risk is still unclear. OBJECTIVES: To determine the relation between plasma SAM and risk of mortality among patients with coronary artery disease (CAD). METHODS: Baseline plasma SAM concentrations were measured in 1553 patients with CAD from the Guangdong Coronary Artery Disease Cohort between October 2008 and December 2011. Proportional hazards Cox analyses were performed to ascertain associations between SAM and risk of all-cause and cardiovascular mortality. RESULTS: After a median follow-up of 9.2 (IQR: 8.5-10.2) y, of 1553 participants, 321 had died, including 227 deaths from cardiovascular diseases. Patients in the lowest quartile of SAM concentrations had a higher risk of all-cause death (HR, 1.59; 95% CI: 1.14, 2.21) and cardiovascular death (HR, 2.14; 95% CI: 1.41, 3.27) than those in the highest quartile in multivariable adjusted analysis. Each 1-SD decrease in the SAM concentration remained associated with a 42% greater risk of total death (HR, 1.42; 95% CI: 1.23, 1.64) and a 66% higher risk of cardiovascular death (HR, 1.66; 95% CI: 1.37, 2.01) after fully adjusting for other cardiovascular risk factors. Furthermore, each 1-SD decrease in plasma SAM/SAH ratio, as the methylation index, was also inversely associated with the risk of all-cause (HR, 1.80; 95% CI: 1.42, 2.29) and cardiovascular mortality (HR, 1.68; 95% CI: 1.29, 2.19) in fully adjusted analyses. CONCLUSIONS: Our data show a significant inverse relation between plasma SAM and risk of mortality in patients with CAD after adjustment for homocysteine, SAH, and other cardiovascular disease risk factors.

Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy.

S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. Increased plasma SAH levels were associated with disturbed renal function in patients with diabetes. However, the role and mechanism of SAHH in diabetic nephropathy is still unknown. In the present study, we found that inhibition of SAHH by using its inhibitor adenosine dialdehyde (ADA) accumulates intracellular or plasma SAH levels and increases high glucose-induced podocyte injury and aggravates STZ-induced diabetic nephropathy, which is associated with Nod-like receptor protein 3 (NLRP3) inflammasome activation. Inhibition or knockout of NLRP3 attenuates SAHH inhibition-aggravated podocyte injury and diabetic nephropathy. Additionally, SAHH inhibition increases thioredoxin-interacting protein (TXNIP)-mediated oxidative stress and NLRP3 inflammasome activation, but these effects were not observed in TXNIP knockout mice. Mechanistically, SAHH inhibition increased TXNIP by inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2) and reduced trimethylation of histone H3 lysine 27 and its enrichment at promoter of early growth response 1 (EGR1). Moreover, EGR1 is activated and enriched at promoters of TXNIP by SAHH inhibition and is essential for SAHH inhibition-induced TXNIP expression. Inhibition of EGR1 protected against SAHH inhibition-induced NLRP3 inflammasome activation and oxidative stress and diabetic nephropathy. Finally, the harmful effects of SAHH inhibition on inflammation and oxidative stress and diabetic nephropathy were also observed in heterozygote SAHH knockout mice. These findings suggest that EZH2/EGR1/TXNIP/NLRP3 signaling cascade contributes to SAHH inhibition-aggravated diabetic nephropathy. Our study firstly provides a novel insight into the role and mechanism of SAHH inhibition in diabetic nephropathy.

[Establishment of mouse lung cancer model induced by benzo[a]pyrene dynamic inhalation exposure].

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.

Development of an ORF45-Derived Peptide To Inhibit the Sustained RSK Activation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus.

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.

Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway.

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.

Iron metabolism and its association with dyslipidemia risk in children and adolescents: a cross-sectional study.

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.

Associations between dietary patterns and the risk of breast cancer: a systematic review and meta-analysis of observational studies.

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.

Curcumin Inhibits Acute Vascular Inflammation through the Activation of Heme Oxygenase-1.

Curcumin has several therapeutic properties such as anti-inflammatory effect. Heme oxygenase-1 (HO-1) has been showed to have cytoprotective effects in some pathological conditions. However, the role of HO-1 in anti-inflammatory effect of curcumin is unknown. In this study, we investigate whether the anti-inflammatory effect of curcumin in vascular may be involved in the activation of HO-1. New Zealand white rabbits were fed regular control diet or control diet added with 0.3% curcumin (wt/wt) for four weeks. Acute vascular inflammation of rabbits was induced by putting a collar on the left common carotid artery for 24 hours. HO-1 inhibitor and siRNA were used to investigate the role of HO-1 in the anti-inflammatory effect of curcumin in collared vascular. We also explored the mechanism of curcumin-induced activation of HO-1 in vitro. The serum bilirubin and vascular, liver, and spleen HO-1 mRNA levels were significantly increased in curcumin-treated rabbits. The vascular inflammation was significantly decreased in the curcumin-treated animals compared with the control. Treatment of the rabbits with an inhibitor of HO or HO-1 siRNA to knock down the carotid artery HO-1 abolished the ability of curcumin to inhibit vascular inflammation. Treatment of cultured human artery endothelial cells with curcumin induced the HO-1 expression through the activation of nuclear factor-E2-related factor 2 (Nrf2) and an antioxidant responsive element via the p38 MAPK signalling pathway. In conclusion, curcumin inhibits vascular inflammation in vivo and in vitro through the activation of HO-1.

Association between whole grain intake and breast cancer risk: a systematic review and meta-analysis of observational studies.

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.

Effects of nut consumption on selected inflammatory markers: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Several randomized controlled trials (RCTs) have assessed the effects of nut consumption on inflammatory markers. However, the results have been inconsistent. The aim of this meta-analysis of RCTs was to quantitatively evaluate the effects of nut consumption on selected inflammatory markers. METHODS: PubMed, Embase, Cochrane Library database, and Google Scholar were searched for published RCTs that reported the effects of nuts on inflammatory markers as primary or secondary outcomes in an adult population (aged ≥18 y). Summary estimates of weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated using random-effects meta-analysis. RESULTS: Twenty-three RCTs met the inclusion criteria. Overall, nut consumption significantly reduced the levels of intercellular adhesion molecule (ICAM)-1 (WMD, -0.17; 95% CI, -0.32 to -0.03; P = 0.01), but had no significant effect on other inflammatory markers. In the subgroup analyses by nut types, mixed nuts had a significant effect on ICAM-1 reduction. The significant effect of nuts on ICAM-1 reduction was only observed in parallel, but not crossover RCTs. Additionally, nut consumption significantly reduced ICAM-1 and vascular cell adhesion molecule-1 levels in long-term (≥12 wk), but not short-term (<12 wk) RCTs. No significant heterogeneity or publication bias was observed in the studies included. CONCLUSIONS: Nut consumption significantly reduced ICAM-1 levels, but had no effect on other inflammatory markers. More studies are needed to assess the effects of nuts on inflammation.

Effect of nut consumption on vascular endothelial function: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: nut consumption has consistently been found to be associated with a reduced risk of cardiovascular diseases (CVD) and mortality in prospective studies. However, its effect on endothelial function, a prognostic marker of CVD, is still controversial in clinical trials. This meta-analysis of randomized controlled trials (RCTs) aimed to quantitatively assess the effect of nuts on vascular endothelial function. METHODS: Major electronic databases were searched for published RCTs that reported the effect of nuts on flow mediated dilation (FMD) as a measurement of endothelial function in the adult population (age eighteen years or over). We calculated the pooled estimates of weighted mean differences (WMDs) and their 95% confidence intervals (CIs) by using random-effects models. RESULTS: A total of nine papers (10 trials) involving 374 participants were included. The pooled estimates found that nut consumption significantly improved FMD (WMD: 0.41%; 95% CI: 0.18%, 0.63%; P = 0.001). Moderate and marginally significant heterogeneity was observed among the studies (I2 = 39.5%, P = 0.094). Subgroup analyses indicated that walnuts significantly improved FMD (WMD: 0.39%; 95% CI: 0.16%, 0.63%; P = 0.001). In addition, nut consumption had a significant effect on FMD in the trials with study duration <18 weeks, nut dose <67 g/d, or subjects with baseline FMD ≥8.6%. CONCLUSIONS: Nut consumption significantly improved endothelial function. However, the beneficial effect was limited to walnuts. More studies examining the effect of other nuts on endothelial function are needed in the future.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　- Systematic Review and Meta-Analysis of Prospective Studies.

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.Methods and Results: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.