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Dairy products have been suggested to be related to the prevention of overweight or obesity, hypertension, and type 2 diabetes mellitus (T2DM). These associations are currently controversial, however, and a systematic quantitative meta-analysis is lacking. In this study, we examined the associations between dairy products and the risk of overweight or obesity, hypertension, and T2DM and tested for dose–response relations. We comprehensively searched PubMed, Embase, and Web of Science up to April 2021. Cohort studies were included if dairy food consumption was reported at a minimum of 3 levels or as continuous variables, and the associations were assessed with overweight or obesity, hypertension, and T2DM. Summary RRs and 95% CIs were estimated for the dose–response association. Restricted cubic splines were used to evaluate the linear or nonlinear relations. Among the 9887 articles retrieved, 42 articles were included. For overweight or obesity, a linear association was observed for total dairy, milk, and yogurt. The risk decreased by 25%, 7%, and 12% per 200-g/d increase for total dairy, high-fat dairy, and milk, respectively, and by 13% per 50-g/d increment of yogurt. For hypertension, a nonlinear association was observed with total dairy, whereas significant inverse associations were found for low-fat dairy (RR: 0.94; 95% CI: 0.90, 0.98) and milk (RR: 0.94; 95% CI: 0.92, 0.97) per 200-g/d intake increase. For T2DM, all types of dairy food consumption except for milk and low-fat dairy products showed nonlinear associations, with total dairy and yogurt intake associated with 3% and 7% lower risk per 200-g/d and 50-g/d intake increase, respectively. In conclusion, our study suggests that total dairy is associated with a low risk of overweight or obesity, hypertension, and T2DM, especially milk and yogurt for overweight or obesity, low-fat dairy and milk for hypertension, and yogurt for T2DM.

Background: Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy. Methods: We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF. Results: A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p

A 57-year-old male suffering from cardiogenic syncope was found to have preexcited QRS on surface ECG at admission. A dual-chamber ICD was implanted after discovering intermittent high degree A–V block and ventricular tachycardia during hospitalization. An EP study was performed 2 days later. Fasciculoventricular accessory pathway was diagnosed based on the fixed H–V interval with different A–H interval when atrial activation conducted to ventricle. However, the H–V interval was normal, which can be explained by intra-His block based on the findings of two split His potentials, the second of which was closely followed by local ventricular electrogram. The conduction delay in His bundle led to pseudo normalization of H–V interval.

Hepatic stellate cell (HSC)-targeted delivery is an attractive strategy for liver fibrosis therapy, but the efficacy is hampered by poor delivery of nanomaterials and complicated microenvironments of the fibrotic liver. Here, we report a versatile CXCR4-inhibiting nanocomplex composed of polymeric CXCR4 antagonism (PAMD, PA), CLD (clodronate) and siPAI-1 (siRNA of plasminogen activator inhibitor-1) that surmounts multiple barriers to improve the outcome by co-regulating Kupffer cells (KCs), extracellular matrix (ECM) and HSCs. Upon encountering biological barriers, the nanocomplex exerted penetrating and targeting functions, efficiently overcoming KCs capture, ECM trapping and nonspecific recognition of HSCs, finally contributing to the enhanced HSCs uptake. Moreover, an enlarged antifibrotic activity is realized through synergetic regulation of KCs apoptosis, ECM degradation and HSCs inactivation. Overall, such a versatile nanocomplex provides a framework for designing HSC-targeted delivery system and has valuable potential as a novel antifibrotic strategy.

Aim To investigate the association of type 2 diabetes mellitus (T2DM) risk and plasma lipid levels in rural Chinese. Methods Each lipid variable was divided into quartiles and dichotomized by clinical cutoff points. Cox proportional-hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of T2DM risk and plasma lipid levels and explore the interaction between plasma lipid levels and other risk factors. Results 11,929 participants were included in the analysis. We documented 720 incident cases of T2DM over 70,720.84 person-years of follow-up, for an incidence of 10.18/1,000 person-years. In the multivariable-adjusted model, risk of T2DM was increased with the highest versus lowest quartiles of total cholesterol (TC) and triglycerides (TG) levels and TC/high-density lipoprotein-cholesterol (HDL-C) and TG/HDL-C ratios. The HRs (95% CIs) for the fourth quartiles, for example, were 1.34 (1.03–1.74), 2.32 (1.73–3.13), 1.66 (1.23–2.25), and 1.84 (1.38–2.45), respectively. In addition, risk of T2DM was increased with high TG level and TC/HDL-C and TG/HDL-C ratios by clinical cutoffs. The HRs (95% CIs) were 1.50 (1.25–1.80), 1.24 (1.03–1.48), and 1.44 (1.18–1.75), respectively. Risk of T2DM was associated with interactions between all lipid variables and age and BMI. TG level and TG/HDL-C ratio additionally interacted with gender (all Pinteraction Conclusions Risk of T2DM was increased with elevated serum levels of TC and TG and TC/HDL-C and TG/HDL-C ratios and also with interactions between high TC and TG levels and TC/HDL-C and TG/HDL-C ratios and age and BMI in a rural Chinese population.

Aims The association of long-term ambient air pollution and hypertension has been inconsistently reported. We performed an updated systematic review and meta-analysis to assess the association between long-term exposure to ambient air pollution and risk of hypertension in adults and in children. Methods PubMed, EMBASE, and Web of Science were searched up to August 7, 2020 for published articles examining the association of long-term exposure to ambient air pollution, including particulate matter (PM; ultrafine particles, PM1, PM1–2.5, PM2.5, PM2.5–10 and PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and hypertension. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for hypertension with each 10-μg/m3 increase in air pollutants were calculated by random-effects models. Results We included 57 studies (53 of adults and 4 of children) in the meta-analysis. Risk of hypertension was significantly increased in adults with each 10-μg/m3 increase in exposure to PM2.5 (OR 1.10, 95% CI 1.07–1.14; I2 = 93.1%; n = 37), PM10 (1.04, 1.02–1.07; I2 = 44.8%; n = 22), and SO2 (1.21, 1.08–1.36; I2 = 96.6%; n = 3). Hypertension was not significantly associated with PM1 (n = 2), PM2.5–10 (n = 16), NO2 (n = 27), or NOx (n = 17). In children, the summary ORs (95% CIs) for each 10-μg/m3 increase in PM2.5, PM10, SO2 and O3 were 2.82 (0.51–15.68; I2 = 83.8%; n = 2), 1.15 (1.01–1.32; I2 = 0; n = 2), 8.57 (0.13–575.58; I2 = 94.2%; n = 2), and 1.26 (0.81–1.09, I2 = 91.6%; n = 2), respectively. Conclusions Long-term ambient air pollution is a potential risk factor for hypertension in adults. More studies are needed to explore the effects of long-term air pollution on hypertension in children.

A deep-seated flexural toppling failure of rock masses is located on the right bank upstream of the Lancang River, Southwest China. The rock masses unloaded intensely in two directions and formed intense toppled rock masses with lengths and widths of 1200 m and 950 m, respectively, and volumes over 1.5 × 108 m3. The toppled rock masses could be classified into three grades from surface to deep rock masses: strongly, moderately and weakly toppled rock masses. The strong unloading of rock masses during the rapid downcutting process of rivers was one of the main external factors that induced deep-seated toppling failure. The mechanism could be summarized as follows: intense unloading destroyed the structure of rock masses and weakened the mechanical properties of rock masses by forming many unloading cracks in rock masses; additionally, the stress field of the slope was further redistributed and a stress relaxation zone formed in the strong unloading zone. Then, the stresses of rock masses in the relaxation zone were dominated by gravity, and the deep-seated toppling failure formed in the strongly unloaded rock masses under the action of gravity.

To investigate whether impaired fasting glucose (IFG) is an independent risk factor for incident hypertension in a rural Chinese population.We selected 9583 eligible participants 18 to 75years old, who were without hypertension and diabetes at baseline (from 2007 to 2008) and were from a rural area in the middle of China. Concentration of fasting glucose at baseline was assessed in quartiles to predict hypertension risk by gender. Odds ratios (ORs) and 95% confidence intervals (CIs) for IFG (fasting glucose of 100 to 125mg/dl) associated with hypertension were estimated by logistic regression models.Risk of hypertension was increased for females with glucose levels in quartile 2 (90-96mg/dl), quartile 3 (96-102mg/dl), and quartile 4 (102-125mg/dl) versus quartile 1 (90mg/dl): OR=1.27 (95% CI=1.01-1.60), 1.30 (1.04-1.63), and 1.55 (1.24-1.93), respectively. During the 6-year follow-up, the cumulative incidence of hypertension was greater for people with IFG than normal fasting glucose (NFG) at baseline (23.9% vs 18.4%, p0.001 for males and 23.8% vs 16.4%, p0.001 for females). Risk of incident hypertension was significantly increased for females with IFG versus NFG (OR=1.23 95% CI=1.05-1.45).IFG may be an independent risk factor for hypertension in normotensive nondiabetic Chinese females.

Objectives To examine the effect of change in body mass index (BMI) on incident hypertension by gender and age groups. Methods A total of 10,145 non-hypertensive participants 18–75years old from rural areas in the middle of China were selected for this cohort study. Questionnaire interview and anthropometric and laboratory measurements were performed at baseline (during July to August 2007 and July to August 2008) and follow-up (during July to August 2013 and July to October 2014). Multiple logistic regression analysis was used to examine the relationship between change in BMI and incident hypertension. Results During a mean follow-up of 6.03±0.69years, hypertension developed in 794 of 3986 men and 1184 of 6159 women. Both genders who were obese (BMI ≥28kg/m 2 for Chinese people) at follow-up, regardless of their obesity status at baseline, showed greater risk of hypertension than those who were non-obese (BMI 2 ) at both baseline and follow-up. We found a dose-response relationship between change in BMI and incident hypertension. Risk of hypertension was markedly greater with a BMI gain of the highest quartile or more as compared with a BMI reduction of the lowest quartile or more, except for women 60–75years old. Conclusions Risk of hypertension was high for non-hypertensive people in rural China with stable obesity. BMI dynamic gain may be related to incident hypertension for men of all ages and young and middle-aged women.

Background Tissue factor pathway inhibitor-1 ( TFPI-1 ) has multiple functions and its precise role and molecular mechanism during the development of atherosclerosis are not clear. Objectives To determine the effect and molecular mechanism of TFPI-1 deficiency in vascular smooth muscle cells (VSMCs) in atherosclerosis in the apolipoprotein E knockout ( ApoE −/− ) mouse. Methods and results A mouse model with a conditional knockout of TFPI-1 in VSMCs in an atherosclerosis-prone background ( ApoE −/− ) was generated. Mice were fed a high fat diet for 18weeks and were then euthanized. Arterial trees and aortas were stained with Sudan IV and were labeled via immunohistochemistry. Cell proliferation and migration of VSMCs in atherosclerotic plaques were assessed. More atherosclerotic lesions and higher levels of proliferation and migration of VSMCs were observed in TFPI-1 fl/fl /Sma-Cre + ApoE −/− mice. An interaction between TFPI-1 and angiomotin (AMOT) was identified in human VSMCs by mass spectrometry, immunoprecipitation and co-localization analyses. Signal pathway changes were detected by Western blot analysis, and the expression levels of target genes were determined by real-time PCR. Decreased phosphorylation of AMOT and Yes-associated protein 1 (YAP) in TFPI-1 fl/fl / Sma-Cre + ApoE −/− mice resulted in increased expression levels of snail family zinc finger 2 ( SLUG ) and connective tissue growth factor ( CTGF ), which are target genes of the Hippo signaling pathway that have been verified as atherosclerosis candidate genes. Conclusion Deficiency in TFPI-1 in the VSMCs of ApoE −/− mice accelerated the development of atherosclerosis by promoting the proliferation and migration of VSMCs which may be caused by the decreased phosphorylation of AMOT and YAP. Significance TFPI-1 has been found to has an anticoagulant activity, induce cell apoptosis and prevent cell proliferation. For the first time, we constructed a line of conditional knockout mice in which the TPFI-1 gene is deleted in VSMCs. We found that TFPI-1 deficiency clearly promoted the development of atherosclerosis when these mice were crossed into an ApoE −/− background. One notable feature of atherosclerosis is the proliferation and migration of smooth muscle cells. Previous reports involved TFPI-1 do not completely explain the proliferation and migration of VSMCs because heterozygous TF deficient ( TF ± ) mice bred in an ApoE −/− background did not show diminished atherosclerosis compared to TF +/+ mice bred in the same background. Our results first confirmed that TFPI-1 interacts with AMOT, which led to a decrease in the phosphorylation of YAP and further increased the genes expression of the proliferation and migration involved. Our results further confirmed that atherosclerosis was a localized disease.

The treatment options of liver fibrosis remain limited except for liver transplantation due to the complexity and slow development in its progression. Besides, liver fibrosis recurrence and intervention time have not been reported as significant indicators to affect the anti-fibrotic efficacy of tested drugs/strategies. Herein, a novel fluoropolymer is developed to achieve high drug loading of sorafenib and efficient delivery of miR155 inhibitor (anti-miR155) for dual-targeting of hepatic stellate cells (HSCs) and kupffer cells (KCs), and we report a detailed plan on the design of treatment regimen to reveal the relationship between chemogene therapy, intervention time and fibrosis recurrence. Such a combined chemo-gene therapy of sorafenib and anti-miR155 can achieve superior therapeutic efficiency by polarizing the pro-inflammatory M1 to anti-inflammatory M2 of KCs and inhibiting the proliferation of HSCs. Importantly, efficacy and recurrence prevention of chemogene therapy earlier in the liver fibrosis will be more effective than the treatment at later stage. In conclusion, this work proposes a novel strategy to improve the efficacy and prevent recurrence of liver fibrosis by dual-regulating of KCs and HSCs, and emphasizes the importance of therapy earlier in the treatment of liver fibrosis.

Background Tissue factor pathway inhibitor-2 (TFPI-2) regulates matrix metalloproteinases activation and extracellular matrix degradation. Over-expression of TFPI-2 enhances atherosclerotic plaque stability. The aim of this study is to investigate the effect of conditional knockout (KO) of TFPI-2 in vascular endothelial cells on the initiation and development of atherosclerotic plaque. Methods A Cre/mloxP conditional KO system and Tek-Cre mice were used to generate offsprings with monoallelic deletion of the TFPI-2 gene in endothelial cells. TFPI-2fl/+/Tek-Cre mice, TFPI-2fl/+ mice and ApoE−/− mice (n = 6 for each group) were included. Arteries were obtained. HE, EVG and anti-α-SMA staining were used to examine the morphology of vessel and plaque. Protein expression and phosphorylation were detected by Western blot or immunohistochemistry. Results TFPI-2fl/+/Tek-Cre mice were generated. TFPI-2 level decreased to 40.68% in TFPI-2fl/+/Tek-Cre group. TFPI-2fl/+/Tek-Cre developed plaques when no plaque was found in TFPI-2fl/+ mice. Compared with ApoE−/− group, TFPI-2fl/+/Tek-Cre group has smaller plaque area, decreased lipid content and less buried fibrous cap layers. MMP-2 and MMP-9 in TFPI-2fl/+/Tek-Cre group was higher than in TFPI-2fl/+ group. The phosphorylation of PPAR-α and PPAR-γ was decreased in TFPI-2fl/+/Tek-Cre group. Conclusions A novel mouse model is presented and can be used to investigate the role of TFPI-2 in the process of atherosclerosis. Our findings suggest that monoallelic deletion of TFPI-2 gene in vascular endothelial cells leads to significant downregulation of TFPI-2. TFPI-2 deficiency may accelerate initiation of atherosclerotic lesion in mice. Elevated MMP-2 and 9 and decreased phosphorylation of PPAR-α and PPAR-γ may contribute to this phenotype.

High-mobility group box 1 (HMGB1) is a proinflammatory mediator playing an important role in the pathogenesis of cardiac dysfunction in many diseases. In this study, we explored the effects of HMGB1 on Ca(2+) handling and cellular contractility in cardiomyocytes to seek for the mechanisms underlying HMGB1-induced cardiac dysfunction. Our results show that HMGB1 increased the frequency of Ca(2+) sparks, reduced the sarcoplasmic reticulum (SR) Ca(2+) content, and decreased the amplitude of systolic Ca(2+) transient and myocyte contractility in dose-dependent manners in adult rat ventricular myocytes. Inhibiting high-frequent Ca(2+) sparks with tetracaine largely inhibited the alterations of SR load and Ca(2+) transient. Blocking Toll-like receptor 4 (TLR4) with TAK-242 or knockdown of TLR4 by RNA interference remarkably inhibited HMGB1 induced high-frequent Ca(2+) sparks and restored the SR Ca(2+) content. Concomitantly, the amplitude of systolic Ca(2+) transient and myocyte contractility had significantly increased. Furthermore, HMGB1 increased the level of intracellular reactive oxygen species (ROS) and consequently enhanced oxidative stress and CaMKII-activated phosphorylation (pSer2814) in ryanodine receptor 2 (RyR2). TAK-242 pretreatment significantly decreased intracellular ROS levels and oxidative stress and hyperphosphorylation in RyR2, similar to the effects of antioxidant MnTBAP. Consistently, MnTBAP normalized HMGB1-impaired Ca(2+) handling and myocyte contractility. Taken together, our findings suggest that HMGB1 enhances Ca(2+) spark-mediated SR Ca(2+) leak through TLR4-ROS signaling pathway, which causes partial depletion of SR Ca(2+) content and hence decreases systolic Ca(2+) transient and myocyte contractility. Prevention of SR Ca(2+) leak may be an effective therapeutic strategy for the treatment of cardiac dysfunction related to HMGB1 overproduction.

Introduction Tissue factor pathway inhibitor-2 (TFPI-2) is a member of the Kunitz-type family of serine protease inhibitors, which inhibits several matrix metalloproteinases activity involved in extracellular matrix degradation. Studies have shown low TFPI-2 expression in the shoulder regions of atherosclerotic plaques. But studies evaluating its role in the progression of atherosclerotic plaque are scarce. Vascular smooth muscle cells (VSMCs) are important components of atherosclerotic plaques and oxidized low density lipoprotein (ox-LDL) is an important detrimental factor of atherosclerosis. The aim of this study is to elucidate the effect of TFPI-2 on smooth muscle cell proliferation and migration induced by ox-LDL. Methods Retroviruses expressing human TFPI-2 were constructed. Cell proliferation was determined by CCK-8 assay. Cell apoptosis was analyzed by double staining of FITC-Annexin V and propidium iodide. Cell migration was studied through a Transwell chamber and with a scratch-wound assay. The matrix metalloproteinase-2 and − 9 activities were analyzed by gelatin zymography. Phosphorylation of FAK was analyzed by western blot. Results TFPI-2 over-expression of mRNA and protein was confirmed in infected cells. CCK-8 assay showed that TFPI-2 inhibit VSMCs proliferation induced by ox-LDL while without cytotoxicity to VSMCs. Transwell and scratch wound assay confirmed TFPI-2 over-expression can inhibit VSMC migration. Zymography assay showed that TFPI-2 can inhibit MMP-2, 9 activity induced by ox-LDL. Western blot assay showed TFPI-2 can inhibit cyclinD1 expression and FAK phosphorylation. Conclusion TFPI-2 over-expression may strongly inhibit the proliferation and migration of VSMCs and suppresses MMP-2, 9 activity induced by ox-LDL, making it a promising candidate for treatment of atherosclerotic process.