Search

The association between betaine and hypertension risk remains uncertain. Few prospective studies were originally designed to investigate this association.

To explore the effects of occupational aluminum exposure on workers' cognitive function and blood glucose concentration, and to analyze whether blood glucose concentration can mediate the cognitive changes caused by aluminum.Our study recruited 375 workers from an aluminum factory in northern China. We collected the fasting elbow venous blood of the workers, measured their fasting blood glucose concentration (FBG), and used ICP-MS to determine plasma aluminum concentration (P-Al) as an indicator of internal exposure. The Montreal Cognitive Assessment (MoCA), was used to assess the cognitive function of workers. Generalized linear model was used to analyze the association of P-Al with cognitive function and blood glucose concentration, and the restricted cubic spline model was used to fit the dose-response relationship. We also conducted a mediation effect analysis.We observed the dose-response relationship, that is, as the P-Al increased, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased, and the blood glucose concentration increased. For every e-fold increase in P-Al, sum of MoCA, visuospatial/executive, naming, language, and abstraction scores decreased by 0.328 points, 0.120 points, 0.059 points, 0.060 points, and 0.083 points, respectively, and FBG rose by 0.109 mmol/L. FBG has a significant mediating effect between P-Al and sum of MoCA (P for mediator=0.042), and it could explain 10.7% of the effect of cognitive level related to P-Al.Occupational aluminum exposure negatively affected the cognitive function of workers and positively affected FBG. FBG may partially explain the impact of occupational aluminum exposure on workers' cognitive function.

Background & aims Epidemiological evidence linking fibroblast growth factor 21 (FGF21) with hepatocellular carcinoma (HCC) prognosis lacked. We aimed to evaluate the associations between serum FGF21 levels and HCC survival in a large prospective cohort. Methods 825 newly diagnosed, previously untreated HCC patients from the Guangdong Liver Cancer Cohort were enrolled between September 2013 and April 2017. Serum FGF21 levels were measured by ELISA. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Multivariable Cox proportional hazards models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results Compared with patients in the lowest tertile of serum FGF21 levels, patients in the highest tertile had inferior survival outcomes. HRs in the fully adjusted models were 1.44 (95% CI: 1.07, 1.94; P-trend = 0.014) and 1.48 (95% CI: 1.12, 1.97; P-trend = 0.002) for LCSS and OS, respectively. The associations were not significantly modified by selected metabolic disorder diseases or state such as arterial hypertension, diabetes, dyslipidemia, fatty liver, cirrhosis, and body mass index ≥25.0 kg/m2 , except for that stronger associations were observed in patients co-occurred more than three metabolic disorder diseases (P-interaction = 0.046 for OS and 0.151 for LCSS), with an HR of 2.01 (95% CI: 1.04, 3.85; P-trend = 0.009) for OS and 1.51 (95% CI: 0.73, 3.10; P-trend = 0.195) for LCSS. Conclusions Higher serum FGF21 levels were associated with worse survival in HCC patients, suggesting that serum FGF21 may be used as a novel metabolism-related prognostic biomarker for HCC.

The association between dietary Fe intake and diabetes risk remains inconsistent. We aimed to explore the association between dietary Fe intake and type 2 diabetes mellitus (T2DM) risk in middle-aged and older adults in urban China. This study used data from the Guangzhou Nutrition and Health Study, an on-going community-based prospective cohort study. Participants were recruited from 2008 to 2013 in Guangzhou community. A total of 2696 participants aged 40–75 years without T2DM at baseline were included in data analyses, with a median of 5·6 (interquartile range 4·1–5·9) years of follow-up. T2DM was identified by self-reported diagnosis, fasting glucose ≥ 7·0 mmol/l or glycosylated Hb ≥ 6·5 %. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95 % CI. We ascertained 205 incident T2DM cases during 13 476 person-years. The adjusted HR for T2DM risk in the fourth quartile of haem Fe intake was 1·92 (95 % CI 1·07, 3·46; Ptrend = 0·010), compared with the first quartile intake. These significant associations were found in haem Fe intake from total meat (HR 2·74; 95 % CI 1·22, 6·15; Ptrend = 0·011) and haem Fe intake from red meat (HR 1·86; 95 % CI 1·01, 3·44; Ptrend = 0·034), but not haem Fe intake from processed meat, poultry or fish/shellfish. The association between dietary intake of total Fe or non-haem Fe with T2DM risk had no significance. Our findings suggested that higher dietary intake of haem Fe (especially from red meat), but not total Fe or non-haem Fe, was associated with greater T2DM risk in middle-aged and older adults.

A higher dietary intake or serum concentration of betaine has been associated with greater lean body mass in middle-aged and older adults. However, it remains unknown whether betaine intake is associated with age-related loss of skeletal muscle mass (SMM). We assessed the association between dietary betaine intake and relative changes in SMM after 3 years in middle-aged adults. A total of 1242 participants aged 41–60 years from the Guangzhou Nutrition and Health Study 2011–2013 and 2014–2017 with body composition measurements by dual-energy X-ray absorptiometry were included. A face-to-face questionnaire was used to collect general baseline information. After adjustment for potential confounders, multiple linear regression found that energy-adjusted dietary betaine intake was significantly and positively associated with relative changes (i.e. percentage loss or increase) in SMM of legs, limbs and appendicular skeletal mass index (ASMI) over 3 years of follow-up (β 0·322 (se 0·157), 0·309 (se 0·142) and 0·303 (se 0·145), respectively; P < 0·05). The ANCOVA models revealed that participants in the highest betaine tertile had significantly less loss in SMM of limbs and ASMI and more increase in SMM of legs over 3 years of follow-up, compared with those in the bottom betaine tertile (all Ptrend < 0·05). In conclusion, our findings suggest that elevated higher dietary betaine intake may be associated with less loss of SMM of legs, limbs and ASMI in middle-aged adults.

Previous studies suggest that betaine and choline may be beneficial for body composition. However, no longitudinal study has been conducted to illustrate if choline and betaine have long-term effects on changes in body composition. This study aimed to prospectively investigate the association between serum choline and betaine concentrations and 3-year changes in body composition in community-dwelling Chinese adults. This present analysis used data from 1384 women and 554 men aged 40–75 years. Serum concentrations of betaine and choline at baseline were assessed using high-performance liquid chromatography-tandem mass spectrometry. Body composition parameters, i.e., muscle mass (MM), fat mass (FM), and body fat percentage (FM%) were measured using dual-energy X-ray absorptiometry at the first and the second follow-ups. After adjustment for potential cofounders, higher serum choline concentrations were associated with a lower decrease in MM in men (β = 0.022, P = 0.025) and a lower increase in FM and FM% in women with baseline choline concentrations below 21.5 μmol/L (all P for nonlinearity = 0.007); higher serum betaine concentrations were associated with a lower decline in MM and a lower increase in FM and FM% among men whose betaine concentrations were lower than 55 μmol/L (all P for nonlinearity < 0.05). These findings suggest that higher concentrations of serum choline and betaine may be associated with favorable changes in body composition profiles among men and women who have relatively low concentrations, especially in men. Novelty Higher concentrations of serum choline and betaine were associated with favorable changes in body composition. Such favorable associations were more pronounced in men.

Accumulating evidence indicates that the onset of myocardial infarction (MI) shows obvious circadian rhythmicity. Clinical studies have shown that MIs that occur in the early morning have a poor prognosis, but the mechanisms involved are still unknown. In this study, we showed that the expression level of Period 2 (per2) in the heart of mice is lower in the early morning than at noon and that increasing the expression of per2 in H9C2 cells and rat cardiomyocytes increases autophagy levels. Further studies indicated that overexpression of per2 after an MI improved cardiac function by increasing autophagy. In summary, this study has shown that the circadian clock protein, per2, may be a regulator of MI.

Obesity, as one of the major public health problems in the world, has attracted more and more attention. Rb1 is the most abundant active component of Panax ginseng and it has been reported to have benefit effects on obesity and diabetes. But the mechanisms of Rb1 in regulation of obesity are not very clear. In this study, by use of obese mice, we found that Rb1 not only reduced body weight but also decreased myostain (MSTN) expression,which plays a vital part in the regulation of obesity. In vitro, we found that Rb1 treatment also decreased MSTN expression in differentiated C2C12 cells (Myoblast cells) and 3T3-L1 cells (adipocytes). Fndc5, as the downstream of MSTN, was increased after Rb1 treatment. Conclusions Our results showed that Rb1 may ameliorate obesity in part through MSTN/Fndc5 signaling pathway. Our study provides important experimental evidences for the treatment of obesity by Rb1.

Atherosclerosis (AS) is a chronic cardiovascular disease endangering human health and is one of the most common causes of myocardial infarction and stroke. Macrophage polarization plays a vital role in regulating plaque stability. As an important component of sunlight, ultraviolet B (UVB) has been proven to promote vitamin D and nitric oxide synthesis. This research used an AS model in ApoE−/− mice to study the effects of UVB on macrophage polarization and atherosclerotic plaque stability. In vitro, UVB irradiation increased arginase-I (Arg-I, M2 macrophage) and macrophage mannose receptor (CD206) expression, while the expression of inducible nitric oxide synthase (iNOS) (M1 macrophage) and CD86 was decreased. UVB promoted Akt phosphorylation in vitro. In vivo, UVB irradiation promoted the stabilization of atherosclerotic lesion plaques, while the phenotype of M2 macrophages increased. Our research provides new evidence for UVB in preventing and treating atherosclerosis.

Previous studies reported the association between interleukin-6 (IL-6) -174G/C gene polymorphism and the risk of diabetic nephropathy in type 2 diabetes mellitus (T2DN). However, the results remain controversial. In the present study, we conducted a meta-analysis to further examine this relationship between IL-6-174G/C gene polymorphism and T2DN. Three databases (PubMed, SinoMed and ISI Web of Science) were used to search clinical case-control studies about IL-6-174G/C polymorphism and T2DN published until Apr. 14, 2018. Fixed- or random-effects models were used to calculate the effect sizes of odds ratio (OR) and 95% confidence intervals (95% CI). Moreover, subgroup analysis was performed in terms of the excretion rate of albuminuria. All the statistical analyses were conducted using Stata 12.0. A total of 11 case-control studies were included in this study, involving 1203 cases of T2DN and 1571 cases of T2DM without DN. Meta-analysis showed that there was an association between IL-6-174G/C polymorphism and increased risk of T2DN under the allelic and recessive genetic models (G vs. C: OR=1.10, 95%CI 1.03-1.18, P=0.006; GG vs. CC+GC: OR=1.11, 95%CI 1.02-1.21 P=0.016). In the subgroup analysis by albuminuria, a significant association of IL-6-174G/C polymorphism with risk of T2DN was noted in the microalbuminuria group under the recessive model (OR=1.54, 95% CI 1.02-2.32, _P=0.038). In conclusion, this meta-analysis suggests that IL-6-174G/C gene polymorphism is associated with the risk of T2DN.

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson’s trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

SCOPE The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis. METHODS AND RESULTS Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN-93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time-dependent (p

Phospholipids are critical for milk digestion and infant development. But the profile of phospholipid molecular species in human milk and its dynamic changes during the lactation period have never been reported. The present study elucidated precise qualitative and quantitative analysis of 258 phospholipid molecular species in 486 human milk samples. Phosphatidylcholine is the most abundant class, followed by phosphatidylserine, phosphatidylethanolamine and sphingomyelin as the second abundant class in different lactation period. The plasmalogens declined along the lactation period, and the polyunsaturated-phospholipids decreased after 10–15 days. The decrease of phosphatidylcholines and phosphatidylglycerols, and the increase of lysophosphatidylethanolamines and lysophosphatidylcholines are critical changes from 0 to 5 days to 10–15 days; increase of phosphatidylinositols, phosphatidylserines, lysophosphatidylethanolamines and lysophosphatidylcholines is the key changes from 10–15 days to 40–45 days; the decrease of most phospholipid molecular species is the characteristic change from 40–45 days to 200–240 days; and the phospholipid profile achieved stability after 200 days.

Period 2 (per2) is a core circadian clock gene. Dysregulation of the per2 gene has been identified in a number of types of human cancer and may be associated with a poor prognosis. To confirm the influence of per2 gene on MNNG/HOS human osteosarcoma cells, small interfering (si)RNA against per2 or plasmids containing per2 were transfected into MNNG/HOS cells, and the proliferation, apoptosis and migration were observed. The present study demonstrated that per2 knockdown significantly enhanced MNNG/HOS cell proliferation and migration and protected MNNG/HOS cells from apoptosis. Per2 overexpression inhibited MNNG/HOS cell proliferation and migration and promoted apoptosis. Furthermore, the protein expression of phosphorylated (p)-protein kinase B (Akt) and Bcl-2 were inhibited in per2-overexpressing cells, while the expression of p27, p21 and cleaved caspase-3 was promoted. In contrast, the expression of p-Akt and Bcl-2 was promoted in per2-knockdown cells, and p27, p21 and cleaved caspase-3 were decreased. This initial study may provide an alternative therapeutic strategy for the treatment of osteosarcoma.

Increased uptake of Tc-99m-methylene diphosphonate in the area of jaw is a common finding on the whole body bone scan. To study its incidence, causes and clinical significance, we performed static anterior and bilateral head views on 52 consecutive patients, followed by a dental examination and a panoramic radiograph. We demonstrated that increased uptake of bone tracer in the area of jaw was observed at a high incidence, as well as its characteristic distribution. The mainly causes are some common dental diseases. These findings would better guide the diagnosis and treatment for patients.

Autophagic dysfunction is observed in diabetes mellitus. Resveratrol has a beneficial effect on diabetic cardiomyopathy. Whether the resveratrol-induced improvement in cardiac function in diabetes is via regulating autophagy remains unclear. We investigated the mechanisms underlying resveratrol-mediated protection against heart failure in diabetic mice, with a focus on the role of sirtuin 1 (SIRT1) in regulating autophagic flux. Diabetic cardiomyopathy in mice was induced by streptozotocin (STZ). Long-term resveratrol treatment improved cardiac function, ameliorated oxidative injury and reduced apoptosis in the diabetic mouse heart. Western blot analysis revealed that resveratrol decreased p62 protein expression and promoted SIRT1 activity and Rab7 expression. Inhibiting autophagic flux with bafilomycin A1 increased diabetic mouse mortality and attenuated resveratrol-induced down-regulation of p62, but not SIRT1 activity or Rab7 expression in diabetic mouse hearts. In cultured H9C2 cells, redundant or overactive H₂O₂ increased p62 and cleaved caspase 3 expression as well as acetylated forkhead box protein O1 (FOXO1) and inhibited SIRT1 expression. Sirtinol, SIRT1 and Rab7 siRNA impaired the resveratrol amelioration of dysfunctional autophagic flux and reduced apoptosis under oxidative conditions. Furthermore, resveratrol enhanced FOXO1 DNA binding at the Rab7 promoter region through a SIRT1-dependent pathway. These results highlight the role of the SIRT1/FOXO1/Rab7 axis in the effect of resveratrol on autophagic flux in vivo and in vitro, which suggests a therapeutic strategy for diabetic cardiomyopathy.

Cellular therapeutic neovascularization has been successfully performed in clinical trials for patients with ischaemia diseases. Despite the vast knowledge of cardiovascular disease and circadian biology, the role of the circadian clock in regulating angiogenesis in myocardial infarction (MI) remains poorly understood. In this study, we aimed to investigate the role and underlying mechanisms of Period 2 (Per2) in endothelial progenitor cell (EPC) function. Flow cytometry revealed lower circulating EPC proportion in per2(-/-) than in wild-type (WT) mice. PER2 was abundantly expressed in early EPCs in mice. In vitro, EPCs from per2(-/-) mice showed impaired proliferation, migration, tube formation and adhesion. Western blot analysis demonstrated inhibited PI3k/Akt/FoxO signalling and reduced C-X-C chemokine receptor type 4 (CXCR4) protein level in EPCs of per2(-/-) mice. The impaired proliferation was blocked by activated PI3K/Akt/FoxO signalling. Direct interaction of CXCR4 and PER2 was detected in WT EPCs. To further study the effect of per2 on in vivo EPC survival and angiogenesis, we injected saline or DiI-labelled WT or per2(-/-) EPC intramyocardially into mice with induced MI. Per2(-/-) reduced the retention of transplanted EPCs in the myocardium, which was associated with significantly reduced DiI expression in the myocardium of MI mice. Decreased angiogenesis in the myocardium of per2(-/-) EPC-treated mice coincided with decreased LV function and increased infarct size in the myocardium. Per2 may be a key factor in maintaining EPC function in vitro and in therapeutic angiogenesis in vivo.

To investigate the mechanism of Panax notoginseng saponins (PNS), an effective component extracted from Panax notoginseng, on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice fed with high-fat, high-cholesterol diet. Twenty ApoE-KO mice were divided into two groups, the model group and the PNS group. Ten normal C57BL/6J mice were used as a control group. PNS (60 mg/kg) was orally administered daily for 12 weeks in the PNS group. The ratio of plaque area to vessel area was examined by histological staining. The tissue sample of aortic root was used to detect the CD34 and vascular endothelial growth factor (VEGF) expression areas by immunohistochemistry. The expression of VEGF and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) were measured by reverse transcription polymerase chain reaction and Western blotting respectively. After treatment with PNS, the plaque areas were decreased (P

γδ T cells play important roles in innate immunity against tumors and infections. Inhibitory effect of dihydroartemisinin on growth of cancer cells has been found in recent years. In this study, we investigated the effect of dihydroartemisinin on human γδ T cell proliferation by MTT assay and killing activity against pancreatic cancer cells SW1990, BxPC-3 and PANC-1 by LDH release assay in vitro. Intracellular molecule alterations were verified by flow cytometry. The results suggested that appropriate concentration of dihydroartemisinin favored the expansion of γδ T cells and enhanced γδ T cell mediated killing activity against pancreatic cancer cells. Up-regulation of intracellular perforin, granzyme B expression and IFN-γ production may be the important mechanism of dihydroartemisinin on increased antitumor activity of γδ T cells.

Chronic psychological stress is associated with an increased risk of atherosclerosis in humans. Experimental studies using various stress models have yielded controversial results. This study investigated the effects of unpredictable chronic mild stress (UCMS) on atherogenesis in New Zealand white rabbits. Rabbits were fed with a cholesterol-enriched (1%) diet for 4 to 16 weeks, with or without concomitant UCMS treatment. Atherosclerosis was assessed in the abdominal aorta by serial sectioning and morphological analysis. Expressions of inflammatory factors were measured with immunohistochemistry and quantitative polymerase chain reaction. Serum nitrate/nitrite levels were determined with Griess assay, and corticosterone and inflammatory markers were determined using enzyme-linked immunosorbent assay. High-cholesterol feeding resulted in hypercholesterolemia and formation of atherosclerotic plaques in the aorta. UCMS exposure significantly increased the plaque size (p = .003) and decreased the plaque stability (decreased the contents of collagen and smooth muscle and increased the amount of macrophage and matrix metalloproteinases). The proatherogenic effects of UCMS were unrelated to changes in serum cholesterol level but accompanied by increased blood pressure (p < .001) and vascular inflammation (up-regulation of tumor necrosis factor α, C-reactive protein, and monocyte chemoattractant protein 1, all p values < .01). Serum concentrations of nitrate/nitrite were lower in UCMS-treated animals (p = .01). Vessels from UCMS-treated animals exhibited augmented phosphorylation of p38 and c-Jun N-terminal kinase and activation of nuclear factor κB. Chronic psychological stress may contribute to the development of atherosclerosis by enhancing vascular inflammation and decreasing endothelial nitric oxide bioavailability. UCMS = unpredictable chronic mild stress CRP = C-reactive protein TNF-α = tumor necrosis factor α MCP-1 = monocyte chemoattractant protein 1 MIF = macrophage migration inhibitory factor eNOS = endothelial nitric oxide synthase TC = total cholesterol LDL-C = low-density lipoprotein cholesterol JNK = c-Jun N-terminal kinase ND = normal diet HD = high-cholesterol diet MMP = matrix metalloproteinase NF-κB = nuclear factor κB

To evaluate the reliability of velocity vector imaging (VVI) for detecting vulnerable plaques.After aortic balloon injury, 60 rabbits were fed a 1% cholesterol diet for 10 weeks and normal chow for another 6 weeks. Adenovirus containing p53 or lac Z was then injected into the aortic plaques and rabbits were divided into p53-treated group (n=20), lac Z-treated group (n=20) and blank control group (n=20). Peak longitudinal (LSp), radial (RSp) and circumferential (CSp) strain of plaques was measured using VVI at the end of week 18 before pharmacological triggering. Higher RSp and CSp and lower LSp were found in ruptured than those in non-ruptured plaques, and RSp, CSp and LSp correlated well with the fibrous cap thickness and plaque content of macrophages, smooth muscle cells and collagen (all p0.01). A logistic regression model showed that both RSp (RR: 8.96, 95% CI: 5.3575-10.4857, p0.001) and CSp (RR: 8.45, 95% CI: 5.9043-9.1043, p0.001) were significant predictors of plaque rupture. RSp and CSp had a sensitivity of 88.0% and 88.6% and a specificity of 88.6% and 92.0% to predict plaque disruption, respectively.VVI offers a new and noninvasive technique for measuring the peak strain of atherosclerotic plaques and RSp and CSp are a novel index with a high sensitivity and specificity for detecting plaques vulnerable to rupture.

Human serum albumin (HSA) is an abundant protein in blood and tissue fluids and has been used as a carrier for drug delivery. HSA can improve the pharmacokinetic profiles of drugs, such as extending the blood half-life of existing drugs and reducing toxic side effects. At the same time, more and more molecular imaging probes conjugated or fused with HSA have been studied to achieve higher specificity and better pharmacokinetic performance. These molecular probes can be attached to HSA covalently or non-covalently. They can also be fused with HSA as a fusion protein or coupled with HSA in vivo. Importantly, HSA conjugated probes have been applied to many imaging modalities such as the single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET) and optical imaging alone or in combination with more than one modality. Besides in vivo molecular imaging, HSA conjugated probes can be used for molecular therapeutics, image-guided therapy, such as photodynamic imaging and photodynamic therapy (PDI/PDT). Some potential problems also need to be considered when using of HSA based probe strategy which are discussed in detail in the paper. Overall, HSA based probe design represents a very useful and powerful strategy for developing more molecular probes for theranostics of diseases.

BackgroundEctopic angiogenesis within the intima and media is considered to be a hallmark of advanced vulnerable atherosclerotic lesions. Some studies have shown that specific matrix metalloproteinases (MMPs) might play different roles in angiogenesis. Therefore, we investigated the predominant effects of specific MMPs in intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis.Methods and resultsNew Zealand rabbits underwent balloon injury of the abdominal artery and ingestion of a high-cholesterol (1%) diet to establish an atherosclerotic animal model. At weeks 4, 6, 8, 10, and 12 after balloon injury, five rabbits were euthanized and the abdominal aorta was harvested. Blood lipid analysis, intravascular ultrasound imaging, pathologic and immunohistochemical expression studies, and western blotting were performed. From weeks 4 to 12, the expression of MMP-1, -2, -3, and -9 and vascular endothelial growth factor A (VEGF-A) increased with atherosclerotic plaque development in the abdominal aorta, while the expression of MMP-14 substantially decreased. The vulnerability index (VI) gradually increased over time. Intraplaque neovessels appeared at week 8. The microvessel density (MVD) was greater at week 12 than at week 8. The VI, MVD, and VEGF-A level were positively correlated with the MMP-1, -2,-3, and -9 levels within plaques. Negative correlations were noted between the MMP-14 level and the VI, MVD, and VEGF-A level.ConclusionUpregulation of MMP-1, -2, -3, and -9 and downregulation of MMP-14 may contribute to intraplaque angiogenesis and plaque instability at the advanced stage of atherosclerosis in rabbits.

BACKGROUND:It has been demonstrated that Tongxinluo (TXL), a traditional Chinese medicine compound, improves ischemic heart disease in animal models via vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The present study aimed to investigate whether TXL protects against pressure overload-induced heart failure in mice and explore the possible mechanism of action. METHODS AND RESULTS:Transverse aortic constriction (TAC) surgery was performed in mice to induce heart failure. Cardiac function was evaluated by echocardiography. Myocardial pathology was detected using hematoxylin and eosin or Masson trichrome staining. We investigated cardiomyocyte ultrastructure using transmission electron microscopy. Angiogenesis and oxidative stress levels were determined using CD31 and 8-hydroxydeoxyguanosine immunostaining and malondialdehyde assay, respectively. Fetal gene expression was measured using real-time PCR. Protein expression of VEGF, phosphorylated (p)-VEGF receptor 2 (VEGFR2), p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p-eNOS, heme oxygenase-1 (HO-1), and NADPH oxidase 4 (Nox4) were measured with western blotting. Twelve-week low- and high-dose TXL treatment following TAC improved cardiac systolic and diastolic function and ameliorated left ventricular hypertrophy, fibrosis, and myocardial ultrastructure derangement. Importantly, TXL increased myocardial capillary density significantly and attenuated oxidative stress injury in failing hearts. Moreover, TXL upregulated cardiac nitrite content and the protein expression of VEGF, p-VEGFR2, p-PI3K, p-Akt, p-eNOS, and HO-1, but decreased Nox4 expression in mouse heart following TAC. CONCLUSION:Our findings indicate that TXL protects against pressure overload-induced heart failure in mice. Activation of the VEGF/Akt/eNOS signaling pathway might be involved in TXL improvement of the failing heart.

Lupeol, a triterpene, was reported to possess beneficial effects as a therapeutic and preventive agent for a range of disorders. Many studies have confirmed that lupeol possesses strong activities such as antioxidative, antiinflammatory, antiarthritic, antimutagenic, and antimalarial, both in vitro and in vivo, and at its effective therapeutic doses exhibit no toxicity to normal cells and tissues. Lupeol was observed to inhibit the proliferation of gastric tumour cells in a dose-dependent manner, as assessed by MTT assay, and induce the proliferation of NK cells, as assessed by flow cytometry and Western blotting. The killing effect of NK cells on gastric tumour cells was assessed by LDH. Our experiment demonstrated that lupeol at appropriate concentrations could promote the proliferation of NK cells, inhibit the proliferation of gastric cancer cell lines BGC823, N87 and HGC27, and increase the killing effect of NK cells on gastric cancer cells. We speculated that lupeol might increase the expression of PFP, IFN-γ, and CD107a via the activation of PI3K/Akt and Wnt/β-catenin signalling pathways. Lupeol could serve as a potential agent against gastric cancer; however, further in-depth in vivo studies are still required.

To clarify the effect of aluminum exposure on the cognitive function in electrolytic workers and the prevalence of mild cognitive impairment (MCI) among them by prevalence survey, and to investigate its influential factors.Sixty-six retired workers from the electrolysis workshop of an electrolytic aluminum plant were selected as an aluminum exposure group, while 70 retired workers from a flour mill in the same region were selected as a control group. MCI patients were screened out by Mini-Mental State Examination (MMSE); the blood aluminum level was measured by inductively coupled plasma-mass spectrometry; multivariate statistical analysis was used to investigate the influential factors for MMSE scores and the correlation between blood aluminum level and MCI prevalence.The aluminum exposure group showed a significantly higher blood aluminum level than the control group (25.18 ± 2.65 µg/L vs 9.97 ± 2.83 µg/L, P0.01). The total MMSE score of the aluminum exposure group (26.13 ± 2.57) was significantly lower than that of the control group (27.89 ± 1.91) (P0.05), particularly the scores on time and place orientation, short-term memory, calculation ability, and language skill (P0.05). The detection rate of MCI was significantly higher in the aluminum exposure group (18.2%) than in the control group (5.7%) (P0.01). The main influential factors for MMSE scores were gender, age, education level, and blood aluminum level. The logistic regression analysis indicated that the MCI prevalence was significantly correlated with blood aluminum level in the study population (OR = 1.168, P0.01).Long-term exposure to aluminum can cause cognitive disorders in electrolytic workers and may be one of the risk factors for MCI. Advanced age, male, low education level, and high blood aluminum level may be high-risk factors for cognitive impairment.

To investigate the effect of aluminum trichloride on the abnormal phosphorylation of tau protein in SH-SY5Y cells.SH-SY5Y cells were assigned to control group and aluminum trichloride exposure groups (200, 400, and 800 µmol/L Al(3+)). The cell morphology was observed after 48 hours of exposure; the cell viability was measured by CCK-8 assay; total protein was extracted from the cells, and the expression of phospho-tau (p-tau) 181, 231, 262, and 396 and tau 5 was measured by Western blot.As the Al(3+) concentration rose, the number of living SH-SY5Y cells decreased, and the synapses of the cells retracted. The viability of cells exposed to 800 µmol/L Al(3+) was significantly lower than that of the control group (P0.05). The 200, 400, and 800 µmol/L Al(3+) exposure groups showed significantly higher expression of p-tau 181, 231, and 396 and tau5 than the control group (P0.05), and the 800 µmol/L Al(3+) exposure group showed significantly higher expression of p-tau 262 than the control group (P0.05).Under the present experimental conditions, aluminum trichloride has toxic effect on SH-SY5Y cells and can lead to abnormal expression of p-tau 181, 231, and 396 and tau 5 at low Al(3+) concentration.

Cardiovascular disease is a major cause of morbidity and mortality worldwide. Epidemiological studies have clearly demonstrated that chronic psychosocial stress increases the risk of atherosclerotic cardiovascular disease and this may involve multiple mediators and regulating pathways, whereas the precise mechanisms underlying the effects of stress on development of atherosclerosis are not completely understood. In this mini review, we summarize current information from various animal studies suggesting that stress may promote atherogenesis by stimulating vascular inflammation via elevating the level of circulating proinflammatory cytokines (such as tumor necrosis factor α and interleukin 6). Although circulating cytokines can serve as reliable biomarkers of systemic inflammation, in light of the emerging evidence, we propose that these molecules may also have a causal role in mediating stress-triggered vascular inflammatory reaction and atherogenesis. Further studies are warranted to clarify whether targeting circulating cytokines may be an effective approach to reduce the detrimental effects of chronic stress.

Background. Myocardial infarction (MI) is a major cause of morbidity and mortality in the world. Tongxinluo (TXL) is a traditional Chinese compound prescription which has cardioprotective functions. The present study was aimed to determine the effect of TXL on postischemic cardiac dysfunction and cardiac remodeling and to elucidate the underlying mechanisms.Methods and Results. MI was performed by ligation of left anterior descending coronary artery (LAD) in male adult mice. Mice were randomly divided into four groups: (1) sham group (Sham); (2) MI-control group (Control); (3) MI-low dose TXL group (TXL-L); and (4) MI-high dose TXL (TXL-H) group. Compared with the control group, TXL treatment restored cardiac function, increased revascularization, attenuated cardiomyocyte apoptosis, and reduced interstitial fibrosis. TXL treatment increased the phosphorylation of Akt, extracellular signal regulated kinase (ERK), and endothelial nitric oxide synthase (eNOS); the expression of phosphatidylinositol3-kinase (PI3K), hypoxia-inducible factors 1α(HIF-1α), and vascular endothelial growth factor (VEGF); and the DNA binding activity of HIF-1αafter MI.Conclusion. TXL may improve cardiac function and ameliorate cardiac remodeling by increasing neovascularization through enhancing the phosphorylation of Akt and ERK, the expression and activity of HIF-1α, and the protein level of VEGF and p-eNOS.

OBJECTIVES:Endothelial progenitor cells (EPCs) can be used to repair tissues after myocardial infarction (MI) but EPC activators have adverse reactions. Rehmannia glutinosa is a herb used in traditional Chinese medicine, which can promote bone-marrow proliferation and protect the ischemic myocardium. We investigated the effects of Rehmannia glutinosa extract (RGE) on EPCs in a rat model of MI. METHODS:A total of 120 male Wistar rats were randomized to 2 groups (n=60 each) for treatment: high-dose RGE (1.5 g·kg(-1)·day(-1) orally) for 8 weeks, then left anterior descending coronary artery ligation, mock surgery or no treatment, then RGE orally for 4 weeks; or normal saline (NS) as the above protocol. The infarct region of the left ventricle was assessed by serial sectioning and morphology. EPCs were evaluated by number and function. Protein and mRNA levels of CD133, vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-X-C motif receptor 4 (CXCR4), stromal cell-derived factor-1α (SDF-1α) were measured by immunohistochemistry, Western blot and quantitative PCR analysis. RESULTS:RGE significantly improved left ventricular function, decreased the ischemic area and the apoptotic index in the infarct myocardium, also decreased the concentration of serum cardiac troponin T and brain natriuretic peptide at the chronic stage after MI (from week 2 to week 4). RGE increased EPC number, proliferation, migration and tube-formation capacity. It was able to up-regulate the expression of angiogenesis-associated ligand/receptor, including CD133, VEGFR2 and SDF-1α/CXCR4. In vitro, the effect of RGE on SDF-1α/CXCR4 cascade was reversed by the CXCR4 specific antagonist AMD3100. CONCLUSION:RGE may enhance the mobilization, migration and therapeutic angiogenesis of EPCs after MI by activating the SDF-1α/CXCR4 cascade.

To examine whether danshensu could protect vascular endothelia in a rat model of hyperhomocysteinemia. The model was established by feeding rats with a methionine-rich diet (1 g·kg−1·d−1) for 3 months. Immediately following the discontinuation of methionine-rich diet, rats were treated with danshensu (67.5 mg·kg−1·d−1, po) or saline for 3 additional months. One group of rats receiving vitamin mixture (folic acid, vitamin B12 and vitamin B6) was included as a positive control. One group of rats not exposed to methionine-rich diet was also included as a blank control. The expression of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) protein in the descending aorta was examined using immunohistochemistry and Western blot. Homocysteine and blood concentration of endothelin and nitric oxide (NO) was also examined. Methionine-rich diet resulted in accumulation of “foam cells”, up-regulated expression of TNF-alpha and ICAM-1 in the descending aorta, and significantly increased serum homocysteine. Plasma endothelin concentration was significantly increased; NO was decreased. Danshensu treatment, either simultaneous to methionine-rich diet or afterwards, attenuated the above mentioned changes. Chronic treatment with danshensu could prevent/attenuate the formation of atherosclerosis. Potential mechanisms include inhibited expression of representative proinflammatory cytokines and adhesion molecules in arterial endothelia. Changes in homocysteine and circulating molecules that control vascular contraction/relaxation via endothelial cells (eg, endothelin and NO) were also implicated.

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.

Introduces the design and implementation of a Remote System for Parallel Computing.Based on Multi-platform.This system support remote operating and running linux system parallel programes on Windows system and provide a kind of uniform mode for the applied customer to operation, The customer does not need to know the concrete structure of the parallel computing system,can operate the parallel system and complete the computation or simulation what they need.This system reduces the complication on developing parallel programs and improves the efficiency on using parallel computing system,and solves the problem of real-time data transmission between server and client machine.It has highly practical value.

The purpose of this study was to test the hypothesis that overexpression of angiotensin-converting enzyme 2 (ACE2) may favorably affect left ventricular (LV) remodeling and function after myocardial infarction (MI). The left anterior descending coronary artery was ligated to produce anterior MI in 100 Wistar-Kyoto rats that were randomly divided into Ad-ACE2, Ad-ACE2+A779, Ad-EGFP, model, and sham groups. Two weeks later, rats in the Ad-ACE2 and Ad-EGFP groups received direct intramyocardial injection of Ad-ACE2 and Ad-EGFP, respectively. Rats in the Ad-ACE2+A779 group received both intramyocardial injection of Ad-ACE2 and a continuous intravenous infusion of A779 for 15 days. LV volume and systolic function, the extent of myocardial fibrosis, and levels of ACE2, angiotensin II (Ang II), and collagen I protein expression were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed reduced LV volume, extent of myocardial fibrosis, and expression levels of ACE, Ang II, and collagen I in the myocardium, and increased LV ejection fraction and levels of ACE2 activity and expression in comparison with the Ad-EGFP and model groups. These results suggest that ACE2 overexpression attenuated LV fibrosis and improved LV remodeling and systolic function. In conclusion, overexpression of ACE2 favorably affected the pathological process of LV remodeling after MI by inhibiting ACE activity, reducing AngII levels, and up-regulating Ang-(1-7) expression, thus providing a potential therapeutic target in the treatment of heart failure.