The role of lactoferrin in atherosclerosis.

Atherosclerosis (AS) is a common pathological basis for many cardiovascular diseases (CVDs) and result in high mortality and immense health and economic burdens worldwide. Early prevention, diagnosis, and treatment are promising approaches for stemming the development and progression of AS. Lactoferrin (Lf) is an iron-binding glycoprotein belonging to the transferrin family. It is widely found in body fluids such as digestive tract fluids, tears, and milk. Lf possesses anti-inflammatory, antibacterial, immunoregulatory, antioxidant and many other physiological functions. The serum Lf level is reportedly associated with the risk of AS and AS-related CVDs. Lf administration is closely involved in several mechanisms, including cholesterol metabolism, foam cell formation, ICAM-1 expression, homocysteine and leptin levels, anti-inflammatory and antioxidant function. Moreover, Lf has also been applied in the sythesis of magnetic resonance imaging (MRI) contrast agents to detect AS. Lf plays an important role in AS and may therefore be used in its diagnosis and treatment. Thus, this article aims to review the association between Lf and the risk of AS and AS-related CVDs, the mechanisms of Lf administration on AS, and its potential application in AS diagnosis.

Glaucocalyxin A suppresses multiple myeloma progression in vitro and in vivo through inhibiting the activation of STAT3 signaling pathway.

BACKGROUND: Multiple myeloma (MM) is the most common malignant hematological disease in the people worldwide. Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid, that is derived from Rabdosia japonica var. GLA has been demonstrated that it had various pharmacological activities, such as anti-coagulation, anti-bacterial, anti-tumor, anti-inflammation, antioxidant activities. Although GLA has effective anti-tumor properties, its effects on multiple myeloma remain unclear. The aim of this study was to examine the possible anti-cancer effects of GLA and their molecular mechanisms on MM cells in vitro and in vivo. METHODS: To evaluate the role of GLA on the proliferation of MM cells in vitro and in vivo, we used MTT method to detect the role of GLA on the proliferation of MM cells. Cell apoptosis and cell cycle assay were evaluated by flow cytometry. Protein expressions in GLA-treated and untreated MM cells were evaluated by western blot analyses. MM xenograft nude mice model was used to investigate the role of GLA on the proliferation of MM cells in vivo. IHC assay was used to examine the role of GLA on the MM xenograft model in vivo. RESULTS: In the present study, we firstly reported the potent anti-myeloma activity of GLA on MM cells. We found that GLA could induce apoptosis in vitro and in vivo. GLA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and downregulate interleukin IL-6 induced STAT3 phosphorylation in MM. Overexpression of STAT3 could significantly prevent apoptosis induced by GLA; while knockdown of STAT3 enhanced it. Moreover, GLA could inhibit cell proliferation by inducing the cell cycle arrest. GLA reduced the expression of cell cycle-related proteins CCNB1, CCND1, CCND2, and CCND3 and increased the expression of p21 in MM cell lines. In addition, in the MM xenograft nude mice model, GLA exhibited very good anti-myeloma activity. Administration of GLA almost completely inhibited tumor growth within 19 days without physical toxicity. And the IHC results showed GLA significantly inhibited cell proliferation and interfered STAT3 pathway on MM xenograft model tumor tissues. CONCLUSIONS: Taken together, our present research indicated that GLA inhibits the MM cell proliferation, induces MM cell apoptosis and cell cycle arrest through blocking the activation of STAT3 pathway. Thus, GLA may be a potential therapeutic candidate for MM patients in the future.

School-based surveillance on visit-to-visit blood pressure variability and high blood pressure in children and adolescents.

BACKGROUND: The predictive importance of visit-to-visit blood pressure variability (VVV) for high blood pressure (HBP) in a pediatric population has been largely unsettled. We aimed to evaluate it based on Health Promotion Program for Children and Adolescents (HPPCA), a school-based surveillance conducted from 2012 to 2018 in Suzhou, China. METHODS: A total of 330,618 participants had BP measurement in 2018 and ≥ 3 BP records during 2012-2017, were recruited from HPPCA. Absolute BP values (in mmHg) were converted into age-, sex- and height- normalized z-scores. VVV was expressed as standard deviation (SD), coefficient of variation (CV) or average real variability (ARV) of BP z-scores during 2012-2017. Logistic regression models were used to assess the associations between VVV and HBP in 2018. RESULTS: In 2018, 42,554 (12.87%) subjects were defined as HBP. VVV, except for SBP-CV and DBP-CV, was significantly higher in the HBP group than normotensives group. After adjusting for covariates including mean BP values from 2012 to 2017, SBP-SD, SBP-ARV, DBP-SD and DBP-ARV, increased the risk of HBP by 5.70 [95% confidence interval (95% CI) 5.54-5.87], 4.10 (95% CI 4.01-4.20), 4.70 (95% CI 4.50-4.90) and 3.39 (95% CI 3.28-3.50) times, respectively. Notably, SBP-SD significantly improved risk discrimination of HBP based on other risk variables (c-statistics, net reclassification index and integrated discrimination improvement significantly increased). CONCLUSIONS: Higher SD or ARV of BP, was independently related with higher probability of HBP in Chinese pediatric population. SBP-SD could be potentially helpful for detecting HBP. Future researches investigating the predictive value of VVV are warrant.

Body mass index, waist circumference, and risk of hearing loss: a meta-analysis and systematic review of observational study.

BACKGROUND: Emerging evidence implicates excess weight as a potential risk factor for hearing loss. However, this association remained inconclusive. Therefore, we aimed to systematically and quantitatively review the published observational study on the association between body mass index (BMI) or waist circumference (WC) and hearing loss. METHODS: The odds ratios (ORs) or relative risks (RRs) with their 95% confidence intervals (CIs) were pooled under a random-effects model. Fourteen observational studies were eligible for the inclusion in the final analysis. RESULTS: In the meta-analysis of cross-sectional studies, the ORs for prevalent hearing loss were 1.10 (95% CI 0.88, 1.38) underweight, 1.14 (95% CI 0.99, 1.32) for overweight, OR 1.40 (95% CI 1.14, 1.72) for obesity, 1.14 (95% CI 1.04, 1.24) for each 5 kg/m2 increase in BMI, and 1.22 (95% CO 0.88. 1.68) for higher WC. In the meta-analysis of longitudinal studies, the RRs were 0.96 (95% CI 0.52, 1.79) for underweight, 1.15 (95% CI 1.04, 1.27) for overweight, 1.38 (95% CI 1.07, 1.79) for obesity, 1.15 (95% CI 1.01, 1.30) for each 5 kg/m2 increase in BMI, and 1.11 (95% CI 1.01, 1.22) for higher WC. CONCLUSIONS: In summary, our findings add weight to the evidence that elevated BMI and higher WC may be positively associated with the risk of hearing loss.

Lactoferrin ameliorated obesity-induced endothelial dysfunction by inhibiting the Tak1/IL-18/eNOS pathway between PVAT and vascular endothelium.

Vascular endothelial dysfunction (ED) is one of the mechanisms underlying obesity-related hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and influences the vascular endothelium function. Previous studies have demonstrated the antihypertensive effects of lactoferrin (LF) and its hydrolysates through various mechanisms. However, the effect of LF on ED and PVAT has not yet been investigated. In this study, we examined the influence of LF on ED and PVAT using high-fat diet mice as well as MAEC cells and 3T3-L1 adipocytes. Finally, LF supplementation decreases the systolic blood pressure (SBP), serum adhesion molecule (ICAM-1 and VCAM-1), and aorta ROS levels, and improves endothelium-dependent relaxation function in high-fat diet mice. Moreover, LF supplementation down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta and enhances the NO generation in high-fat diet mice. In addition, we observe that LF decreases the expression levels of IL-18 and p-Tak1 in 3T3-L1 adipocytes, but fails to influence the eNOS and p-eNOS expression levels in MAEC cells. Finally, the significant associations between LF and IL-18 and SBP and hypertension risk are also observed in obesity children only. These findings provide evidence that the Tak1/IL-18/eNOS pathway between the aorta and PVAT is important in obesity-related ED, and LF may improve ED or even hypertension by down-regulating this pathway.

Protective effect and mechanism of lactoferrin combined with hypoxia against high-fat diet induced obesity and non-alcoholic fatty liver disease in mice.

Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile.

Glomerular filtration rate estimated by differing measures and risk of all-cause mortality among Chinese individuals without or with diabetes: A nationwide prospective study.

BACKGROUND: Whether estimated glomerular filtration rates (eGFRs) by differing biomarkers are differentially associated with mortality or whether the associations differ by diabetes status remains unclear, especially in Chinese population. METHODS: We included 6995 participants without diabetes (mean age: 60.4 years) and 1543 with diabetes (mean age: 61.8 years). Each eGFR measure was divided into normal (≥90 mL/min/1.73 m2 ), modestly declined (60 to <90 mL/min/1.73 m2 ), and chronic kidney disease (CKD) (<60 mL/min/1.73 m2 ) groups. Cox proportional hazards models were used to estimate hazard ratio (HR) of all-cause mortality associated with each eGFR. RESULTS: Over a follow-up of 7 years, 677 and 215 deaths occurred among individuals without or with diabetes, respectively. Among those without diabetes, all measures of modestly declined eGFR were not associated with mortality, whereas CKD defined by eGFR cystatin C (eGFRcys) and eGFR creatinine (eGFRcr)-cys (HRs were 1.71 and 1.55, respectively) but not by eGFRcr were associated with higher risk of mortality. Among diabetes, all measures of modestly declined eGFR (HRs: 1.53, 1.56, and 2.09 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) and CKD (HRs: 2.57, 2.99, and 3.92 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) were associated with higher risk of mortality. Regardless of diabetes status, an addition of eGFRcys or eGFRcr-cys to traditional risk factors lead to a larger improvement in the prediction of all-cause mortality risk than adding eGFRcr. CONCLUSIONS: The association of eGFR with mortality risk appeared to be varied by its measures and by diabetes status among middle-aged and older Chinese, which needs to be considered in clinical practice.

The prevalence of hypertension and elevated blood pressure and its correlation with overweight/obesity among students aged 6-17 years in Suzhou.

OBJECTIVES: Lifestyle changes have led to an increase in the prevalence of hypertension in Chinese children and adolescents. The aim of this study was to analyze the prevalence of hypertension and its association with overweight and obesity among students aged 6-17 years in Suzhou. This retrospective analysis included physical examination data of primary and junior high school students in Suzhou Industrial Park from 2016 to 2019. METHODS: Elevated blood pressure and hypertension were defined using blood pressure criteria appropriate for age, sex, and height percentile. Overweight and obesity were defined using the 2007 diagnostic criteria proposed by the World Health Organization for school-age children. Logistic regression analysis was used to evaluate the association between hypertension and overweight and obesity. RESULTS: A total of 128,113 students were included. The prevalence of elevated BP and hypertension was 9.92% and 13.56%, respectively. The incidence of high blood pressure was higher in boys than in girls and increased with an increase in body mass index (BMI). The prevalence of hypertension in obese boys and girls (27.07% and 27.49%, respectively) was 2.3-fold and 2.8-fold higher than that in normal-weight boys and girls (11.58% and 9.83%, respectively). CONCLUSIONS: Blood pressure was positively correlated with BMI, and the risk of high blood pressure due to overweight/obesity was 10.44%. Overweight and obesity significantly increased the risk of hypertension in students aged 6-17 years in Suzhou. Targeted weight-loss programs during childhood and adolescence may reduce the risk of hypertension in adulthood.

Correlation of 18F-FDG PET/CT SUVmax with clinical features, D-dimer and LDH in patients with primary intestinal lymphoma.

OBJECTIVE: To investigate the characteristics of fluorine-18-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) maximum standardized uptake value (SUVmax) in primary intestinal lymphoma (PIL) and its correlation with D-dimer and lactate dehydrogenase (LDH). METHODS: Fifty-two patients diagnosed with PIL from June 2016 to December 2019 were analyzed. All patients underwent 18F-FDG PET/CT. The relationships between SUVmax and different pathological subtypes, clinical stages and risk grades were analyzed. The correlations between SUVmax and Ki-67, LDH and D-dimer were determined. Additionally, PET/CT imaging results were collected from 35 patients with primary intestinal cancer (PIC) and compared with the imaging features of PIL. RESULTS: SUVmax was significantly different between PIL and PIC groups and various PIL pathological subgroups. Patients in the high-risk PIL group had markedly higher SUVmax values than the intermediate-risk and low-risk groups. A significant positive correlation was observed between SUVmax and Ki-67 in patients with PIL. SUVmax was significantly different between the elevated and normal D-dimer groups. D-dimer showed a positive correlation with SUVmax. CONCLUSION: 18F-FDG PET/CT SUVmax reflects the aggressiveness of lymphoma to a certain degree, is correlated with Ki-67 and determines the risk grades of PIL. Moreover, it facilitates differential diagnosis, clinical staging and treatment based on D-dimer levels.

Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer.

Rationale: Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. Methods: The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Results: Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1α expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Conclusion: Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.

Overexpression of p53 accelerates puberty in high-fat diet-fed mice through Lin28/let-7 system.

IMPACT STATEMENT: High-fat intake and subsequent obesity are associated with premature onset of puberty, but the exact neuroendocrine mechanisms are still unclear. The transcriptional factor p53 has been predicted to be a central hub of the gene networks controlling the pubertal onset. Besides, p53 also plays crucial roles in metabolism. Here, we explored p53 in the hypothalami of mice fed a high-fat diet (HFD), which showed an up-regulated expression. Besides, we also revealed that overexpressed p53 may accelerate hypothalamo-pituitary-gonadal (HPG) axis activation partially through the c-Myc/Lin28/let-7 system. These results can deepen our understanding of the interaction between metabolic regulation and puberty onset control, and may shed light on the neuroendocrine mechanisms of obesity-related central precocious puberty.

Green Tea Consumption May Be Associated with Cardiovascular Disease Risk and Nonalcoholic Fatty Liver Disease in Type 2 Diabetics: A Cross-Sectional Study in Southeast China.

Dietary factors play a crucial role in the management of type 2 diabetes mellitus (T2DM) by reducing cardiovascular disease (CVD) risk. Therefore, we aimed to examine the associations between habitual green tea consumption and risk factors of CVD among T2DM patients. A total of 1013 patients with T2DM were included in a community-based cross-sectional study. Data on dietary habits, including tea consumption, were collected using a food frequency questionnaire. A multivariable logistic regression model was used to analyze the associations. In men, as compared with nongreen tea drinkers, odds ratios (ORs) (95% confidence interval [CI]) of nonalcoholic fatty liver disease (NAFLD) were 2.06 (95% CI, 1.20-3.55) for those with green tea consumption of once per day and 2.45 (95% CI, 1.31-4.58) for more than or equal to twice per day (P-trend = .004); ORs (95% CI) of general obesity were 2.19 (95% CI, 1.02-4.68) and 2.70 (95% CI, 1.18-6.21), respectively (P-trend = .021); whereas no such association was found in women. Sensitivity analysis according to self-awareness of their T2DM status revealed that the positive association between green tea consumption and general obesity was not reliable. Higher intake of green tea was still positively associated with NAFLD, but it only persisted in participants aged ≥52 years or the lower dietary quality subgroup in further analyses. Our findings suggest that tea consumption was associated with an increased risk of NAFLD among male T2DM patients aged 52 years or older, and those with lower dietary quality, which needs to be confirmed in future prospective studies.