Factors Significantly Associated With the Increased Prevalence of Carotid Atherosclerosis in a Northeast Chinese Middle-aged and Elderly Population: A Cross-sectional Study.

Carotid atherosclerosis is associated with many serious cardiovascular diseases; hence, it is necessary to identify factors related to its occurrence in order to develop preventive and therapeutic strategies. This study was conducted to identify risk factors associated with carotid atherosclerosis among the population residing in Northeast China.This epidemiological survey was conducted in a representative group of relatively healthy community residents. All participants answered questions about their medical histories and underwent physical examination, blood biochemical analysis, and ultrasonography examinations of their necks and abdomens. The prevalence rates of carotid atherosclerosis under different factors and conditions were then analyzed.The results of this study showed that age, gender, and diabetes significantly affected the prevalence of carotid atherosclerosis in this Northeast Chinese population. In addition, gender-based subgroup analysis revealed additional factors correlated with the prevalence of carotid atherosclerosis in men or women, although their correlations were not significant in the overall population. While high serum TC and LDL-C levels were risk factors for carotid atherosclerosis in men, it showed no clear correlation with the prevalence of carotid atherosclerosis in women. In contrast, the prevalence of carotid atherosclerosis in female participants with high serum TG level, hypertension, obesity and nonalcoholic fatty liver disease were higher than that of the control population, a trend not observed in male participants.Older age, male sex, and diabetes were independently associated with increased risk of carotid atherosclerosis in Northeast China. These findings could lead to improved screening for carotid atherosclerosis for better disease management.

Pycnogenol Attenuates the Release of Proinflammatory Cytokines and Expression of Perilipin 2 in Lipopolysaccharide-Stimulated Microglia in Part via Inhibition of NF-κB and AP-1 Activation.

Over activation of microglia results in the production of proinflammatory agents that have been implicated in various brain diseases. Pycnogenol is a patented extract from French maritime pine bark (Pinus pinaster Aiton) with strong antioxidant and anti-inflammatory potency. The present study investigated whether pycnogenol may be associated with the production of proinflammatory mediators in lipopolysaccharide-stimulated BV2 (mouse-derived) microglia. It was found that pycnogenol treatment was dose-dependently associated with significantly less release of nitricoxide (NO), TNF-α, IL-6 and IL-1ß, and lower levels of intercellular adhesion molecule1 (ICAM-1) and perilipin 2 (PLIN2). Furthermore, this effect was replicated in primary brain microglia. Levels of inducible NO synthase mRNA and protein were attenuated, whereas there was no change in the production of the anti-inflammatory cytokine IL-10. Further evidence indicated that pycnogenol treatment led to the suppression of NF-κB activation through inhibition of p65 translocation into the nucleus and inhibited DNA binding of AP-1, suggesting that these proinflammatory factors are associated with NF-κB and AP-1. We conclude that pycnogenol exerts anti-inflammatory effects through inhibition of the NF-κB and AP-1pathway, and may be useful as a therapeutic agent in the prevention of diseases caused by over activation of microglia.

Type 1 Diabetic Populations Have an Increased Prevalence of Parietal Cell Antibody: A Systematic Review and Meta-Analysis.

The presence of parietal cell antibody (PCA) in serum is a biomarker of autoimmune gastritis. PCA directly recognizes the H/K ATPase expressed in parietal cells, which is responsible for the active transport of hydrogen ions in exchange for potassium ions to increase the acidity of gastric secretions. Type 1 diabetes mellitus (T1DM) mainly results from pancreatic ß-cell destruction due to cell-type specific autoimmunity. Considering autoimmune factors may be the common characteristics of both PCA positivity and T1DM, it is likely that both disorders may coexist within the same patient. The main objective of this meta-analysis is to provide a reliable evaluation to clarify the association between PCA positivity and T1DM by combining the raw data from all of the relevant studies.Literature databases, including the Medline, Embase, and Web of Science, were systematically queried for studies investigating the association between PCA positivity and T1DM and were published from January 1980 to December 2014. A total of 3,584 T1DM cases and 2,650 non-T1DM controls were included in this meta-analysis, which showed that PCA positivity was more prevalent in patients with T1DM than healthy controls. Publication bias testing found no significant biases and sensitivity analysis demonstrated that our statistics were relatively stable and credible.Our findings suggested that T1DM was associated with an increased risk of PCA positivity compared to control populations.

Suppression of phosphatase and tensin homolog protects insulin-resistant cells from apoptosis.

In the present study, a glucosamine-induced model of insulin-resistant skeletal muscle cells was established in order to investigate the effect of inhibition of phosphatase and tensin homolog (PTEN)/5'-adenosine monophosphate-activated protein kinase (AMPK) on these cells. The glucosamine-induced insulin-resistant skeletal muscle cells were produced and the rate of glucose uptake was measured using the glucose oxidase-peroxidase method. The expression levels of PTEN and phosphorylated PTEN (p-PTEN) were assessed using western blotting. Glucose transporter 4 (GLUT4) translocation was detected by immunofluorescence. Cell apoptosis was evaluated using flow cytometry. Following insulin stimulation, the rate of glucose uptake was significantly reduced in the cells with glucosamine-induced insulin-resistance in comparison with those in the control group. The expression and translocation of GLUT4 were reduced in the insulin-resistant muscle cells. By contrast, the expression of PTEN and p-PTEN as well as apoptosis were significantly increased. Following treatment with bisperoxopicolinatooxovanadate (BPV) or metformin in the insulin-resistant skeletal muscle cells, there was an increase in the rate of glucose uptake, an increase in GLUT4 expression and its translocation, a reduction in the expression of PTEN and p-PTEN, and a decrease in cell apoptosis compared with untreated insulin-resistant cells. Glucosamine may be used to produce an effective model of insulin-resistant skeletal muscle cells. Cells with glucosamine-induced insulin-resistance exhibited a reduced expression of GLUT4 and dysfunction in GLUT4 translocation, as well as increased activation of PTEN and increased cell apoptosis. Inhibition of PTEN or its upstream regulator, AMPK, protects glucosamine-induced insulin-resistant skeletal muscle cells from apoptosis.

Patients with systemic lupus erythematosus have higher prevalence of thyroid autoantibodies: a systematic review and meta-analysis.

BACKGROUND: Thyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients. METHODS AND FINDINGS: A number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls (TgAb: OR = 2.99, 95% CI = 1.83-4.89; TPOAb: OR = 2.20, 95% CI = 1.27-3.82, respectively). CONCLUSION: The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group.

Increased risk of thyroid autoimmunity in rheumatoid arthritis: a systematic review and meta-analysis.

Thyroid autoimmunity, which is the most common immune-mediated disease, is frequently together with other organ- as well as nonorgan-specific autoimmune disorders. Meanwhile, rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder that mainly results in cartilage destruction as well as synovial joint inflammation, and both the adaptive and innate immune responses involve in the progression of this disease. Considering that autoimmune elements may be common characteristics of thyroid autoimmunity and RA, it is likely that both disorders may coexist within some patients. A great number of studies have researched whether an association between thyroid autoimmunity and RA exists; however, the results of these studies have been inconsistent. Most of these studies have included relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is a relationship between RA and thyroid autoimmunity. The main objective of this meta-analysis was to provide reliable estimates of the extent of any association between thyroid autoimmunity and RA by combining the primary data from all related studies. Literature databases, including the Embase, Medline, Web of Science, Chinese Wanfang, and CBM databases, were searched for studies published from January 1980 to May 2014, with a language restriction of English and Chinese. A total of 1,021 RA cases and 1,500 healthy controls were included in this study. From these data, the odds ratios (OR) and the corresponding 95 % confidence intervals (95 % CI) were calculated. The results of the meta-analysis showed that the prevalence of thyroid autoantibody positivity in patients with RA was higher than that in healthy controls (TgAb: OR 3.17, 95 % CI 2.24-4.49; TPOAb: OR 2.33, 95 % CI 1.24-4.39). The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with RA than in the control population.

The prevalence of thyroid autoimmunity in patients with urticaria: a systematic review and meta-analysis.

Thyroid autoimmunity is the most common organ-specific autoimmune disorder, which is characterized by the production of thyroid autoantibodies and lymphocytic infiltration into the thyroid. The majority cases of chronic urticaria have unknown (idiopathic) causes, with about 30-40 % possibly having an autoimmune substrate. Considering that autoimmune factors may be the common features of both thyroid autoimmunity and urticaria, it is likely that both entities may coexist within the same patient. A number of studies have investigated the association between thyroid autoimmunity and urticaria. However, most of these studies are relatively small sample size, the power achieved in those studies was not sufficient to detect whether there is an association between urticaria and thyroid autoimmunity. The aim of this study is to combine primary data from all relevant studies to produce reliable estimates of the associations between thyroid autoantibodies and urticaria. Literature databases were searched including Medline, Embase, Web of Science, Chinese Wanfang, and CBM databases from January 1980 to December 2013. A total of 14,203 urticaria cases and 12,339 non-urticaria controls were included in this study. From these data, the odds ratio (OR) with 95% confidence interval (95% CI) was calculated. The meta-analysis results showed that the prevalence of positive thyroid autoantibodies in patients with urticaria was higher than non-urticaria controls (TgAb: OR 6.55, 95% CI 3.19-13.42, P<0.00001, I2=67%; TmAb: OR 4.51, 95% CI 2.78-7.33, P<0.00001, I2=47%; TPOAb: OR 8.71, 95% CI 6.89-11.01, P<0.00001, I2=20%, respectively). The results of this meta-analysis suggested that patients with urticaria were more likely to have thyroid autoimmunity than the control groups.

High glucose, insulin and free fatty acid concentrations synergistically enhance perilipin 3 expression and lipid accumulation in macrophages.

OBJECTIVE: Perilipin (PLIN) 3, an intracellular lipid droplet (LD)-associated protein, is implicated in foam cell formation. Since metabolic derangements found in metabolic syndrome, such as high serum levels of glucose, insulin and free fatty acids (FFAs), are major risk factors promoting atherosclerosis, we investigated whether PLIN3 expression is affected by glucose, insulin and oleic acid (OA) using RAW264.7 cells. METHODS: Real-time PCR and Western blotting were performed to detect PLIN3 or PLIN2 expression. Oil-red O staining and Lipid Analysis were employed to measure cellular content of triacylglycerides (TAG) and cholesterol. RESULTS: PLIN3 mRNA was stimulated by high glucose or insulin concentrations individually, but not by OA. A combination of any two factors did not enhance PLIN3 expression any more than that evoked by glucose alone at 24h. Interestingly, however, simultaneous addition of all three factors synergistically enhanced the PLIN3 expression. This synergistic effect was not apparent for PLIN2 mRNA expression. Inhibitors of Src family tyrosine kinase and/or phosphatidylinositol 3-kinase, both of which are activated by insulin and FFA signaling, partially suppressed PLIN3 expression induced by the combination of the three factors. While simultaneous addition of glucose, insulin and OA remarkably increased the cellular content of TAG and cholesterol, knocking-down of PLIN3 predominantly reduced TAG content. CONCLUSIONS: These results indicate that PLIN3 expression is synergistically stimulated by high glucose, insulin and FFA concentrations, in parallel with TAG accumulation in macrophages. This finding raises new evidence of PLIN3 involvement in conversion of macrophages into foam cells.

A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages.

Excessive accumulation of lipids in macrophages results in formation of foam cells and is a hallmark of atherosclerosis. The PAT family of proteins has been implicated in this process, but details of their involvement in foam cell formation have not been fully elucidated. One of dominant members of the PAT proteins, perilipin 3 (TIP47), is likely to be involved in such a regulatory mechanism. In this study, we demonstrated that the Toll-like receptor 9 (TLR9)-mediated pathway stimulates perilipin 3 expression and accumulation of lipids, especially triglycerides, in macrophages. Oligodeoxynucleotide (ODN) 1826, a ligand of TLR9, significantly enhanced perilipin 3 expression in RAW264.7 cells, and chloroquine, a TLR9 inhibitor, almost completely inhibited ODN1826-induced perilipin 3 expression. The inhibitors of c-jun NH2-terminal kinase and PI 3-kinase suppressed the level of perilipin 3 mRNA induced by ODN1826. ODN1826 induced the expression of IL-1α and IFNß, both of which increased perilipin 3 expression. Antibodies against these cytokines suppressed the ODN1826-induced perilipin 3 mRNA levels. These results suggest that the expression of perilipin 3 in macrophages is in part regulated through the TLR9-mediated mechanism. Furthermore, ODN1826 increased intracellular lipid accumulation in the presence of oxLDL, which was reduced by perilipin 3 siRNA. Perilipin 3 expression was not stimulated by oxLDL. Depletion of perilipin 3 by siRNA specifically reduced triglyceride content in the cells but not cholesterol content, indicating that perilipin 3 is involved mainly in triglyceride accumulation. In conclusion, the TLR9-mediated pathway facilitates foam cell formation in part through increased expression of perilipin 3.

Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells.

Fatty acids stimulate lipid accumulation in parallel with increased expression of adipose differentiation-related protein (ADRP) in liver cells. Although it is generally considered that the fatty acid effect on ADRP expression is mediated by peroxisome proliferator-activated receptors (PPARs), we identified here an additional molecular mechanism using the NMuLi mouse liver nonparenchymal cell line, which expresses PPARgamma and delta but not alpha. Oleic acid (OA) and specific ligands for PPARgamma and -delta stimulated ADRP expression as well as the -2,090-bp ADRP promoter activity which encompasses the PPAR response element (PPRE) adjacent to an Ets/activator protein (AP)-1 site. When the AP-1 site was mutated, OA failed to stimulate the activity despite the presence of the PPRE, whereas ligands for PPARgamma and -delta did stimulate it and so did a PPARalpha ligand under the coexpression of PPARalpha. DNA binding of AP-1 was stimulated by OA but not by PPAR ligands. Because we previously demonstrated that Pycnogenol (PYC), a French maritime pine bark extract, suppressed ADRP expression in macrophages partly by suppression of AP-1 activity, we tested the effect of PYC on NMuLi cells. PYC reduced the OA-induced ADRP expression along with suppression of lipid droplet formation. However, PYC neither suppressed the OA-stimulated ADRP promoter activity nor DNA binding of AP-1 but, instead, reduced the ADRP mRNA half-life. All these results indicate that the effect of OA on ADRP expression requires AP-1 as well as PPRE, and PYC suppresses the ADRP expression in part by facilitating mRNA degradation. PYC, a widely used dietary supplement, could be beneficial for the prevention of excessive lipid accumulation such as hepatic steatosis.

Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages.

Adipose differentiation-related protein (ADRP) is highly expressed in macrophages and human atherosclerotic lesions. We demonstrated that Toll-like receptor (TLR) 4-mediated signals, which are involved in atherosclerosis formation, enhanced the expression of ADRP in macrophages. Lipopolysaccharide (LPS) enhanced the ADRP expression in RAW264.7 cells or peritoneal macrophages from wild-type mice, but not in macrophages from TLR4-deficient mice. Actinomycin D almost completely abolished the LPS effect, whereas cycloheximide decreased the expression at 12 h, indicating that the LPS-induced ADRP expression was stimulated at the transcriptional level and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating activator protein (AP)-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of interleukin (IL)-6, IL-1alpha, and interferon-beta mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of c-Jun NH(2)-terminal kinase and nuclear factor (NF)-kappaB suppressed the ADRP mRNA level. Thus TLR4 signals stimulate the ADRP expression both in direct and indirect manners. Pycnogenol (PYC), an extract of French maritime pine, suppressed the expression of ADRP and the above-mentioned cytokines. PYC suppressed the ADRP promoter activity and enhancer activity of AP-1 and NF-kappaB, whereas it did not affect the LPS-induced DNA binding of these factors. In conclusion, TLR4-mediated signals stimulate the ADRP expression in macrophages while PYC antagonizes this process. PYC, a widely used dietary supplement, might be useful for prevention of atherosclerosis.