Sphingosine 1-Phosphate and Apolipoprotein M Levels and Their Correlations with Inflammatory Biomarkers in Patients with Untreated Familial Hypercholesterolemia.

High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. To date, S1P and ApoM in patients with untreated heterozygous familial hypercholesterolemia (HeFH) have not been extensively studied. Eighty-one untreated patients with HeFH and 32 healthy control subjects were included in this study. Serum S1P, ApoM, sCD40L, sICAM-1, sVCAM-1, oxLDL, and TNFα concentrations were determined by ELISA. PON1 activities were measured spectrophotometrically. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly higher serum S1P and ApoM levels were found in HeFH patients compared to controls. S1P negatively correlated with large HDL and positively with small HDL subfractions in HeFH patients and the whole study population. S1P showed significant positive correlations with sCD40L and MMP-9 levels and PON1 arylesterase activity, while we found significant negative correlation between sVCAM-1 and S1P in HeFH patients. A backward stepwise multiple regression analysis showed that the best predictors of serum S1P were large HDL subfraction and arylesterase activity. Higher S1P and ApoM levels and their correlations with HDL subfractions and inflammatory markers in HeFH patients implied their possible role in endothelial protection.

Histidine decarboxylase deficiency inhibits NBP-induced extramedullary hematopoiesis by modifying bone marrow and spleen microenvironments.

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.

The anti-inflammatory properties of HDLs are impaired in gout.

OBJECTIVE: We sought to determine whether high-density lipoprotein (HDL) function was altered in gout patients. RESEARCH DESIGN AND METHODS: The study included 95 gout patients and 68 healthy controls. The concentrations of interleukin (IL)-1ß and IL-9 were measured by ELISA, and indicators such as blood uric acid, liver and kidney function, blood glucose, and blood lipids were detected. To test for the anti-inflammatory and reverse cholesterol transport (RCT) function of HDL, 11 gout patients and 11 healthy controls were randomly selected for the BioVision cholesterol efflux test, which detects the RCT activity of HDL. To assess the anti-inflammatory function of HDL, cells in co-culture with HDL were treated with inflammatory stimuli such as tumor necrosis factor-α (TNF-α), and then, the cells were assayed for the expression of intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule-1 (VCAM-1). RESULTS: In total, this study enrolled 163 participants, including 95 non-hyperlipidemic gout patients and 68 healthy controls. IL-1ß and IL-9 levels were significantly higher in the gout group than in the control group (85.26 ± 23.16 vs. 41.47 ± 6.48 and 33.77 ± 12.68 vs. 23.66 ± 4.53, respectively, P < 0.001). Additionally, plasma IL-1ß and IL-9 levels were increased along with those of blood uric acid (R2 = 0.4116 and R2 = 0.4150, respectively, P < 0.001). Compared with the healthy controls, gout patients showed no differences in plasma apoA-1 levels or in the cholesterol efflux assay. Gout patients had increased ICAM-1 expression compared with the healthy controls (88.79 ± 3.68 vs. 86.27 ± 4.64, P < 0.05), but no difference in VCAM-1 expression was found (0.87 ± 0.43 vs. 0.98 ± 0.96, P > 0.05). In this assay, higher values indicate less suppression of ICAM-1 induction, which correlates with a reduced anti-inflammatory capacity. CONCLUSIONS: The anti-inflammatory activities of HDLs are impaired in gout patients. Key Points • Gout patients show chronic inflammation. • The anti-inflammatory activity of high-density lipoprotein is impaired in gout patients.

Role of some natural anti-oxidants in the down regulation of Kim, VCAM1, Cystatin C protein expression in lead acetate-induced acute kidney injury.

BACKGROUND: Lead is a dangerous systemic toxicant and can provoke life-threatening renal injury. The plan of this study was to evaluate the potential impact of curcumin (CRMN) and L-ascorbic acid (L-ascb) alone or together to counteract lead acetate (Pb-acetate)-induced renal damage in rats and to find out the underlying mechanisms of action of these nutraceuticals. METHODS: Pb-acetate (100 mg/kg/day, i.p.) was injected in male rats along with L-ascb (250 mg/kg/day) and/or CRMN (200 mg/kg/day) orally for 7 days. RESULTS: Pb-acetate administration increased serum urea, creatinine and uric acid. Renal tissue showed a marked depletion in reduced glutathione level and superoxide dismutase activity and elevation in nitric oxide and malondialdehyde levels. Serum C-reactive protein and IL-1ß levels were elevated. Up-regulation of the expression of kidney injury molecule, vascular adhesion molecule-1 and Cystatin C were noticed after Pb-acetate administration. DNA fragmentation was also increased in renal tissues. Histopathological examination revealed a destructed partial layer of Bowman's capsule, proximal and distal convoluted tubules. Treatment with the aforementioned antioxidants ameliorated most of the altered measured biomarker levels. CONCLUSION: Interestingly, the combination of L-ascb and CRMN showed the superlative protective effect against Pb-acetate-induced nephrotoxicity.

Adsorption of Soluble Immunoglobulin-Type Adhesion Molecules to Cellulose Acetate Beads.

Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) are elevated in patients with inflammatory bowel disease. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis (GMA). We investigated the effect of CA beads on sICAM-1 and sVCAM-1 plasma concentrations in vitro. Because GM adsorption to CA beads increased with a rise in the incubation temperature in our previous study, peripheral blood was incubated with and without CA beads at 5, 25, 37, or 43 °C and plasma sICAM-1 and sVCAM-1 was measured. The sICAM-1 and sVCAM-1 concentrations in samples incubated with CA beads were significantly lower than those without CA beads at all four temperatures. However, no significant differences were observed both sICAM-1 and sVCAM-1 plasma levels at the four different temperatures after incubation with CA beads. These results suggest that independent of incubation temperature, sICAM-1 and sVCAM-1 are likely to adsorb CA beads. These molecules may be a new index for predicting the therapeutic effects of GMA.

Beneficial effects of rosiglitazone and losartan combination in diabetic rats.

Diabetes with vascular complication needs strict interventions to retard possible serious complications. This research estimated the possible interaction of rosiglitazone (RGN) with losartan (Los) in diabetic rats. Male Sprague-Dawley rats were randomly divided into nondiabetic rats, diabetic rats, and diabetic rats that received RGN, Los, or a combination of RGN and Los. Measurement of serum glucose, vascular adhesion molecule-1, interleukin-6, tumor necrosis factor-α, aortic lipid peroxide (malondialdehyde), glutathione, superoxide dismutase, and total nitrate/nitrite levels was done. Also, the effects of RGN on the relaxation created by acetylcholine and sodium nitroprusside, contraction of isolated aortic rings provoked by phenylephrine and angiotensin II were determined. Results revealed that RGN or Los had a vasodilating effect to variable degrees indicated by enhanced effects on both acetylcholine-induced relaxation and the antagonistic effect on angiotensin II and phenylephrine-stimulated contraction of diabetic aortas with significant amelioration in serum glucose, vascular adhesion molecule-1, interleukin-6, and tumor necrosis factor-α levels and aortic oxidant/antioxidant balance. Treatment of diabetic rats with a combination of RGN and Los produced a more pronounced effect on the measured parameters compared to the diabetic, RGN-, and Los-treated groups. These findings point out the beneficial effects of RGN and Los combination in diabetic rats.

Influence of alpha-lipoic acid on nicotine-induced lung and liver damage in experimental rats.

Nicotine mediates some of the injurious effects caused by consuming tobacco products. This work aimed at investigating the defensive role of alpha-lipoic acid (ALA) with its known antioxidant and antiinflammatory effect in nicotine-induced lung and liver damage. Rats were arranged into 4 groups: control, nicotine, ALA, and ALA-nicotine groups. Oxidative stress and antioxidant status were determined by assessing thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), and glutathione (GSH) levels in lung and liver. Liver enzymes and lipid profiles were measured and pulmonary and hepatic damage were assessed by histopathological examination. Also, serum levels of transforming growth factor beta 1 (TGF-ß1) and vascular cell adhesion molecule 1 (VCAM-1) were determined. The results revealed an increase in TBARS in tissues and a reduction in both SOD and GSH activity in the nicotine-treated rats. Nicotine induced high levels of liver enzymes, TGF-ß1, VCAM-1, and dyslipidemia with histopathological changes in the lung and liver. ALA administration along with nicotine attenuated oxidative stress and normalized the SOD and GSH levels, ameliorated dyslipidemia, and improved TGF-ß1 and VCAM-1 with better histopathology of the lung and liver. The study data revealed that ALA may be beneficial in alleviating nicotine-induced oxidative stress, dyslipidemia, and both lung and liver damage.

Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage.

Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage.

Prognostic value of serum von Willebrand factor, but not soluble ICAM and VCAM, for mortality and cardiovascular events is independent of residual renal function in peritoneal dialysis patients.

OBJECTIVE: We explored associations between markers of endothelial dysfunction and outcome events, and whether those associations were independent of residual renal function (RRF) in patients on peritoneal dialysis. METHODS: The study enrolled 261 incident patients and 68 healthy control subjects who were followed till death, censoring, or study end. Demographics, biochemistry, markers of inflammation (C-reactive protein) and endothelial dysfunction [soluble intercellular adhesion molecule 1 (sICAM), soluble vascular adhesion molecule 1 (sVCAM), and von Willebrand factor (vWf)] were examined at baseline. Outcome events included all-cause death and fatal and nonfatal cardiovascular (CV) events. RESULTS: Mean levels of vWf, sICAM, and sVCAM were significantly higher in patients than in healthy control subjects. Levels of sICAM and sVCAM, but not vWf, were significantly correlated with RRF. Levels of sICAM and vWf both predicted all-cause mortality and fatal and nonfatal CV events after adjustment for recognizable CV risk factors. The association between sICAM and outcome events disappeared after further adjustment for RRF. However, RRF did not change the predictive role of vWf for outcome events. Compared with the lowest vWf quartile (6.6% - 73.9%), the highest vWf quartile (240.9% - 1161%) predicted the highest risk for fatal and nonfatal CV events (adjusted hazard ratio: 2.05; 95% confidence interval: 1.15 to 3.64; p = 0.014). We observed no associations between sVCAM and RRF, or sVCAM and any outcome event. CONCLUSIONS: The prognostic value of vWf, but not sICAM, is independent of RRF in predicting mortality and CV events.

Changes and significances of interleukin-6, interleukin-10 and vascular adhesion molecule-1 in children with obstructive sleep apnea-hypopnea syndrome / 中华实用儿科临床杂志

Objective To discuss the variation in serum factor IL-6,anti-inflammatory cytokine IL-10,and vascular cell adhesion molecule-1 (ICAM-1) level of children with obstructive sleep apnea-hypopnea syndrome (OSAHS) and their clinical significances.Methods One hundred and forty-two hospitalized children were divided into 2 groups:OSAHS group (47 cases) and the control group (95 cases),according to test result of polysomnography (the golden standard).The differences of IL-6,IL-10,high-sensitivity C-reactive protein (hsCRP) and ICAM-1 level between the two groups were measured and compared by using enzyme linked immunosorbent assay,and correlation analysis between IL-6,IL-10,ICAM-1 and each sleep-breathing parameter of OSAHS group was performed.The children of OSAHS group were divided into 3 groups:mild,moderate and severe group,according to the level of apnea hypopnea index(AHI).Statistical analysis was performed on the above indexes among the 3 groups.Reassessment of the children diagnosed with OSAHS was performed after 12 weeks of treatment.Results The serum levels of IL-6,ICAM-1 and hsCRP [(2.98 ± 0.27) ng/L,(391.7 ± 115.6) μg/L,(15.4 ± 4.9) mg/L] of OSAHS group were significantly higher than those of the control group[(1.67 ± 0.07) rng/L,(189.8 ± 106.4) μg/L,(2.5 ± 2.1) mg/L],while its serum IL-10 level was lower than that of the control group[(195.2 ± 33.6) ng/L vs (458.5 ± 102.2)ng/L],and there were significant differences between the 2 groups (t =33.26,32.45,10.94,-53.72,all P ＜0.01) ; there were significant differences in terms of IL-6,IL-10 and ICAM-1 level among the mild,the moderate and the severe groups (F =128.90,102.60,8.25,all P ＜0.05).Of which the serum levels of IL-6,ICAM-1 and hsCRP of the severe group[(3.22 0.27) ng/L,(427.7 ± 95.4) μg/L,(21.0 ± 3.9) mg/L] were higher than those of the mild group [(1.92 ± 0.24) ng/L,(236.5 ± 115.6) μg/L,(11.0 ± 3.8) mg/L] and the moderate group [(2.02 ± 0.31) ng/L,(401.5 ± 105.6) μg/L,(17.0 ± 2.8)mg/L],and serum levels of IL-6,ICAM-1 as well as hsCRP were increased accompanied with the raise of AHI.While the serum level of IL-10[(115.2 ±30.6) ng/L] in the severe group was lower than that of the mild and the moderate groups [(400.2 ± 55.6) ng/L,(203.2 ± 27.6) ng/L] ; serum levels of IL-6 and ICAM-1 of OSAHS children were positively correlated with AHI and micro-arousal index (r =0.341,0.427,all P ＜0.05),negatively correlated with lowest oxygen saturation (LSaO2) at night (r =-0.190,P ＜ 0.01),and without correlation with body mass index (BMI) (r =-0.121,P ＞ 0.05).Serum level of IL-10 was negatively correlated with AHI (r =-0.266,P ＜ 0.05),positively correlated with LSaO2 (r =0.240,P ＜ 0.01),and without correlation with BMI or micro-arousal index (r =-0.183,-0.159,all P ＞ 0.05) ; After 12-week treatment,the IL-6 and ICAM-1 levels of OSAHS group [(2.02 ± 0.13)ng/L,(269.9 ± 107.2) μg/L] were decreased,while IL-10 [(476.3 ± 86.t2) ng/L] were increased compared with pre-treatment[(3.08 ± 0.30) ng/L,(187.2 ± 29.63) ng/L,(379.9 ± 105.2) μg/L] (t =24.22,22.32,66.96,all P ＜ 0.05).Conclusions OSAHS children have systemic inflammatory response,which may increase the risk of cardiovascular disease; this inflammatory response is reversible,so early identification and treatment of OSAHS is beneficial.

Correlation between ICAM1 and VCAM1 gene polymorphisms and histopathological changes in kidney allograft biopsies.

INTRODUCTION: The immunoglobulin-like molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) are responsible for endothelial cell-leukocyte adhesion followed by transmigration of leukocytes through the endothelial cell lining. The aim of this study was to examine the correlation between polymorphisms in ICAM1 and VCAM1 genes and histopathological changes in transplanted kidney biopsies. MATERIAL AND METHODS: The study enrolled 82 Caucasian renal transplant recipients (48 males, 34 females). Genotyping of the rs5498 ICAM1 and the rs1041163 and rs3170794 VCAM1 gene polymorphisms was performed using real-time polymerase chain reaction (PCR). Biopsies were performed in 82 patients and were reviewed by a renal pathologist and the Banff working classification criteria were used. RESULTS: There were no significant associations between VCAM gene polymorphisms and histopathological changes in kidney allograft biopsies. ICAM1 gene polymorphism was associated with the grade of interstitial fibrosis. Interstitial fibrosis was more severe among individuals with the G allele than those with the A allele (AA vs. GG+AG, p = 0.017). There were no statistically significant associations between ICAM1 gene polymorphism and other histopathological changes in kidney allograft biopsies. CONCLUSIONS: The results of our study suggest that rs5498 ICAM1 gene polymorphism is associated with the grade of interstitial fibrosis in kidney recipients and the changes are more severe in patients with the G allele.

Complete artificial saliva alters expression of proinflammatory cytokines in human dermal fibroblasts.

Complete artificial saliva (CAS) is a saliva substitute often used as a vehicle for test articles, including smokeless tobacco products. In the course of a study employing normal adult human dermal fibroblasts (HDFa) as a model in vitro, we discovered that CAS as a vehicle introduced a significant change in the expression of proinflammatory cytokines. To determine the effects of CAS on gene expression, real-time quantitative reverse-transcriptase PCR gene array analysis was used. Results indicate that robust changes in the expression of the proinflammatory cytokine interleukin 8 (IL8) and the vascular cell adhesion molecule 1 (VCAM1) occur within 5h of exposure to CAS. To determine whether CAS also alters cytokine release into the culture media, cytometric bead array assays for human inflammatory cytokines were performed. Analysis shows that CAS induced the release of IL8 and IL6. This study focused on determining which components in CAS were responsible for the proinflammatory response in HDFa. The following components were investigated: α-amylase, lysozyme, acid phosphatase, and urea. Results demonstrated that enzymatically active α-amylase induced gene expression for proinflammatory cytokines IL8, IL6, tumor necrosis factor-α, and IL1α and for VCAM1. Therefore, it is important to carefully evaluate the "vehicle effects" of CAS and its components in in vitro toxicology research.

Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice.

Genistein, a soy isoflavone, has received wide attention for its potential to improve vascular function, but the mechanism of this effect is unclear. Here, we report that genistein at physiological concentrations (0.1 µM-5 µM) significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis. Genistein also significantly suppressed TNF-α-induced production of adhesion molecules and chemokines such as sICAM-1, sVCAM-1, sE-Selectin, MCP-1 and IL-8, which play key role in the firm adhesion of monocytes to activated endothelial cells (ECs). Genistein at physiologically relevant concentrations didn't significantly induce antioxidant enzyme activities or scavenge free radicals. Further, blocking the estrogen receptors (ERs) in ECs didn't alter the preventive effect of genistein on endothelial inflammation. However, inhibition of protein kinase A (PKA) significantly attenuated the inhibitory effects of genistein on TNF-α-induced monocyte adhesion to ECs as well as the production of MCP-1 and IL-8. In animal study, dietary genistein significantly suppressed TNF-α-induced increase in circulating chemokines and adhesion molecules in C57BL/6 mice. Genistein treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, genistein protects against TNF-α-induced vascular endothelial inflammation both in vitro and in vivo models. This anti-inflammatory effect of genistein is independent of the ER-mediated signaling machinery or antioxidant activity, but mediated via the PKA signaling pathway.