BACKGROUND Many epidemiology studies have indicated that polymorphisms in ICAM-1 are associated with a variety of cancers, but published data are contradictory and inconclusive. Therefore, we conducted the current meta-analysis to elaborate the effects of ICAM-1 polymorphisms (rs5491, rs3093030, rs281432, and rs1799969) on cancer susceptibility. MATERIAL AND METHODS We conducted a comprehensive literature search in PubMed, Web of Science, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between ICAM-1 polymorphisms and cancer susceptibility. RESULTS We enrolled 14 published case-control studies including 4608 cancer cases and 4913 controls. We found an increased susceptibility of cancer in polymorphism rs1799969 (C vs. T: OR=1.662, 95%CI=1.288-2.143, p=0141; CT vs. TT: OR=1.860, 95%CI=1.398-2.474, p=0.507; CC+CT vs. TT: OR=1.812, 95%CI=1.373-2.391, p=0.284) of ICAM-1 among the overall population. However, no association between polymorphisms rs5491, rs3093030, or rs281432 of ICAM-1 and cancer susceptibility was identified. In the stratification analysis by ethnicity, we identified an increased susceptibility for Asians in rs3093030 polymorphism (CC vs. TC+TT: OR=1.728, 95% CI=1.234-2.421, p=0.787). CONCLUSIONS Our results suggest that the ICAM-1 polymorphism rs1799969 is significantly associated with increased susceptibility to overall cancer. Further studies (preferably prospective) are warranted to validate these relationships.

BACKGROUND Atherosclerosis is a progressive inflammatory disease that involves a variety of inflammatory and proinflammatory factors, including intercellular adhesion molecule (ICAM)-1. ICAM-1 plays an important role in atherosclerosis by promoting cell adhesion. Mixed lineage kinase domain-like (MLKL), a critical regulator of necroptotic cell death, is indicated to play an important role in atherosclerosis. This study investigated the effects of MLKL on ICAM-1 expression and cell adhesion, thus providing a new direction for the research of atherosclerosis pathogenesis. MATERIAL AND METHODS siRNA-MLKL and pcDNA-MLKL were designed, and the expression of MLKL and ICAM-1 were estimated by real-time polymerase chain reaction at the mRNA level and Western blotting at the protein level. The adhesion of human monocyte cells (THP-1) to human umbilical vein endothelial cells (HUVECs) was examined under immunofluorescence microscopy, and the ability of cell adhesion was evaluated by ImageJ software. RESULTS Overexpression of MLKL greatly enhanced ICAM-1 expression in HUVECs and the adherence of THP-1 cells to HUVECs. Knockdown of MLKL by siRNA dramatically inhibited the expression of ICAM-1 and the adherence of THP-1 cells to HUVECs. MLKL could promote THP-1 adhesion to HUVECs by activating ICAM-1 expression in HUVECs. CONCLUSIONS MLKL can promote THP-1 cell adhesion to HUVECs through up-regulation of ICAM-1 expression in HUVECs. Thus, MLKL might be a useful target for reducing adhesion of monocytes to endothelial cells and atherosclerosis.

BACKGROUND Raf kinase inhibitor protein (RKIP) regulates growth and differentiation and plays a role in key signal transduction cascades in mammalian cells. Nevertheless, the underlying mechanism for which RKIP regulates cell-cell adhesion remains unknown. Our study investigated the function of the RKIP overexpression on adhesion molecules expression induced by tumor necrosis factor (TNF)-α in cultured mouse vascular smooth muscle cells (MOVACs). MATERIAL AND METHODS The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were detected by ELISA kit, reverse transcription-PCR, and western blot assays. The protein expression of RKIP, p65, and inhibitor of nuclear factor (NF)-κBα (IκBα) were detected by western blot analysis. The activity of NF-kappaB was determined using a Dual-Luciferase Reporter assay. RESULTS The results showed that MOVACs transfected with pCMV5-HA-RKIP significantly inhibited TNF-α induced mRNA and protein expression of ICAM-1 and VCAM-1. The adhesion of THP-1 cells was also detected and inhibited by pCMV5-HA-RKIP in TNF-α-treated MOVACs. RKIP also suppressed the TNF-α-induced activation of NF-kappaB and the protein expression of phosphorylated IκB-α, and promoted the protein expression of IkB-α and nuclear translocation of p65 NF-kappaB. Furthermore, RKIP and the inhibitor of NF-kappaB (BAY11-7082) reduced the upregulation of ICAM-1 and VACM-1 induced by TNF-α. CONCLUSIONS Taken together, these results suggested that RKIP may inhibit the TNF-α-induced expression of adhesion molecules in MOVACs through inactivation of the NF-kappaB pathway.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, increases the activity of NF-κB (NF-κB) and then induces the expression of intercellular adhesion molecule-1 (ICAM-1). However, the mechanisms regulating ADMA-induced NF-κB activation are unknown. This study investigated the function of actin cytoskeleton for ADMA-induced NF-κB activation and ICAM-1 expression in endothelial cells.

BACKGROUND Simvastatin, an HMG-CoA reductase inhibitor, has been reported to exert multiple protective effects on the cardiovascular system. However, the molecular mechanism remains to be examined. The present study was designed to study the effects of simvastatin on cardiac hypertrophy in diabetic rats and to explore its potential mechanism. MATERIAL AND METHODS Sprague-Dawley rats were assigned into a control (Con) group, a streptozotocin (STZ) group, and a STZ+simvastatin (STZ+SIM) group. The level of reactive oxygen species (ROS) was measured by using dihydroethidium (DHE) staining. The protein expressions of p65, IκBα, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), calpain-1, and endothelial nitric oxide synthase (eNOS) were examined by Western blot analysis. qPCR was used to detect the levels of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). RESULTS Simvastatin improved the cardiac hypertrophy of diabetic rats, as demonstrated by decreases in the ratios of left ventricular weight/body weight (LVW/BW) and heart weight/body weight (HW/BW) and by the downregulation of mRNA expression of BNP and ANP in the heart tissue. Simvastatin decreased the protein expressions of VCAM-1, ICAM-1, IL-6, and TNF-α, increased eNOS protein expression, and limited an increase in ROS levels in the heart tissue. Simvastatin increased IkBa protein expression in cytoplasm and inhibited the translocation of p65, the subunit of nuclear factor-κB (NF-κB) to the nucleus from the cytoplasm of the heart tissue. Furthermore, simvastatin attenuated the activity of calpain and calpain-1 protein expression in heart tissue. CONCLUSIONS Simvastatin attenuates cardiac hypertrophy in diabetic rats, which might be due to the attenuation of oxidative stress and inflammation induced by calpain-1-mediated activation of NF-κB.

BACKGROUND ß-glucogallin (GG) is one of the major plant polyphenolic antioxidants that have been associated with positive effects on human health and are crucial in the developing defense mechanism against the risk of diseases. However, reports on the protective mechanism of GG in lens epithelial cells are limited. MATERIAL AND METHODS ARPE-19 cells (a human retinal epithelial cell line) were exposed to methylglyoxal (MG) with or without GG to illuminate the protective role of GG in counteracting the cataract signaling. RESULTS Cells predisposed to MG demonstrated an increase in oxidative stress with augmented (P<0.01) inflammatory cytokines such as cyclooxygenase (COX)-2, chemokine receptor CXCR4, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1) genes. In addition, the expression of aldose reductase (AR) was increased to 2-fold with accumulated sorbitol in MG exposed cells compared to control. On the other hand, cells exposed to MG evidenced a 3-fold increase in RAGE (receptor for advanced glycation end products) and a 2-fold increase in NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) expression compared to control cells. Intriguingly, lens epithelial cells pre-treated with GG attenuated the reactive oxygen species levels with improved antioxidant enzymes. Simultaneously, the levels of AR and other inflammatory cytokines were observed in the levels closer to control cells in GG pre-treated cells. CONCLUSIONS Thus, the results of the present investigation show that GG may be a potential drug for the prevention of cataract development and progression.

BACKGROUND This study aimed to investigate the effects of dimethyl fumarate (DMF) on thoracic aortic atherosclerosis in the apolipoprotein E (apo-E)-deficient mouse model with streptozotocin (STZ)-induced hyperglycemia, and the signaling pathways involved. MATERIAL AND METHODS Eight-week-old ApoE-/- male mice (n=30) were randomly divided into three groups: the Control group (ApoE-/-) (n=10); the diabetic model (STZ) group (n=10); and the DMF-treated (25 mg/kg) diabetic model (DMF+STZ) group (n=10). The area of the thoracic aortic atherosclerosis was determined by histology. Reactive oxygen species (ROS) levels in mouse serum and homogenates of the thoracic aorta were determined by colorimetry. Levels of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase subunit gp91phox were detected by immunological hybridization, and levels of heme oxygenase-1 (HO-1) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Compared with the Control group, in the STZ group, the area of aortic atherosclerosis was significantly increased, the levels of serum and aortic ROS, HO-1, nuclear factor-kappaB (NF-kappaB), intercellular adhesion molecule 1 (ICAM-1), and gp91phox were increased, and nuclear factor erythroid 2-related factor 2 (Nrf2), endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS (p-eNOS) were significantly reduced. Compared with the STZ group, in the DMF+STZ group, the area of aortic atherosclerosis was significantly reduced, the levels of serum and aortic ROS, HO-1, NF-kappaB, ICAM-1, and gp91phox were significantly reduced, and Nrf2, eNOS, and p-eNOS were significantly increased. CONCLUSIONS In the apo-E-deficient mouse model with STZ-induced hyperglycemia, DMF reduced the development of atherosclerosis of the thoracic aorta through the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway.

BACKGROUND Hypertension could induce many serious diseases, including damage to vascular endothelial cells. As a non-coding RNA, long noncoding RNA (lncRNA) has received much attention in scientific research and has a regulating efficacy on many critical life activities in human body. The level of lncRNA AK094457 is thought to be elevated in hypertensive rats. However, there is no research indicating the relationship between the level of lncRNA AK094457 and vascular endothelial injury. MATERIAL AND METHODS In our study, we used lentiviral to knockdown lncRNA AK094457, and the human umbilical vein endothelial cells (HUVECs) were stimulated by the Ang II to imitate the vascular endothelial cell damage caused by hypertension. The Cell Counting Kit-8 assays were used to detect the cells viability. Western blotting was performed to detect the endothelial nitric oxide synthase (eNOS), p-eNOS and endothelin-1 (ET-1). After that the production of the NO was monitored. At last, the reactive oxygen species (ROS) levels and apoptosis rates were detected in this study. RESULTS According to the results, we found that knockdown lncRNA AK094457 could alleviate the decrease of vascular endothelial cell viability induced by angiotensin II (Ang II). The knockdown of lncRNA AK094457 also relieved the downregulation of eNOS and p-eNOS, and the decreasing of NO release. At the same time, the knockdown of lncRNA inhibited the levels of Ang II-induced proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1, and IL-6) and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1], and monocyte chemoattractant protein-1 [MCP-1]). The levels of ROS and apoptosis rates also decreased after the knockdown of lncRNA AK094457. CONCLUSIONS All these results indicated that lncRNA AK094457 could promote Ang II-induced vascular endothelial cell injury. On the contrary, knockdown of lncRNA AK094457 could alleviate this damage.

BACKGROUND In China, the essential oil of the fruit, Fructus Alpiniae zerumbet (FAZ), is used to treat cardiovascular diseases. Recent in vitro studies have shown that the essential oil of FAZ (EOFAZ) can protect endothelial cells from injury. Because of the prevalence of diabetes mellitus and its effects on the cardiovascular system, the aim of this study was to investigate the mechanism of the effects of EOFAZ on human umbilical vein endothelial cells (HUVECs) treated with high levels of glucose in vitro. MATERIAL AND METHODS The lactate dehydrogenase (LDH) leakage assay was used to detect HUVEC injury. Tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and nuclear transcription factor-kappa B (NF-κB) p65 subunit DNA-binding activity was detected. The expression of NF-κB pathway-associated proteins, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) was studied by Western blotting. The cellular location of NF-κB in HUVECs was evaluated using immunofluorescence. RESULTS Cell viability and LDH leakage assays showed that high glucose-induced HUVEC injury was reduced by EOFAZ. High glucose-induced secretion of IL-8, TNF-α, ICAM-1, and VCAM-1 was reduced, and translocation of the p65 subunit of NF-κB to the endothelial cell nucleus was inhibited by EOFAZ. Western blotting confirmed that EOFAZ blocked the activation of NF-κB induced by high glucose levels. EOFAZ reduced high glucose-induced p65/DNA binding to inhibit NF-κB activation. CONCLUSIONS The findings of this in vitro study showed that treatment of HUVECs with EOFAZ had a protective role against the effects of high glucose levels via the NF-κB signaling pathway.

BACKGROUND The aim of this study was to assess the effect of combined use of Astragaloside IV(AsIV) and atorvastatin (AV) on the expression of PPAR-γ and inflammation-associated cytokines in atherosclerosis rats. MATERIAL AND METHODS High-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma were detected through automatic biochemical analyzer and the histopathological analysis was performed via HE staining. The levels of oxidized low-density lipoprotein (oxLDL) and tumor necrosis factor-α (TNF-α), and interleukins (IL)-6 and IL-18 in serum were detected by ELISA. The expressions of proliferator-activated receptor-gamma (PPAR-γ), cluster of differentiation 36 (CD36), matrix metalloprotein-9 (MMP-9), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), and p38 and P-p38 levels were detected by Western blot. RT-PCR was used to detect the mRNA expressions of nuclear factor-κB (NF-κB), PPAR-γ, CD36, MMP-9, ICAM-1, and VCAM-1. RESULTS Administration of AsIV and AV significantly decreased the lipid content and oxLDL in plasma. The levels of TNF-α, IL-6, and IL-18 were significantly decreased in AsIV, AV, and AsIV + AV groups, especially in the AsIV + AV group. Administration decreased the levels of NF-κB, CD36, MMP-9, ICAM-1, VCAM-1, and P-p38 expression and increased the expression of peroxisome PPAR-γ. Compared with the NC group, the atherosclerotic lesions significantly increased in the HD group, while the combined administration significantly inhibited the development of atherosclerotic disease. CONCLUSIONS Combined administration of AV and AsIV showed potent effects against atherosclerosis through the NF-κB/PPARγ pathway, which may be a new therapy for treatment of atherosclerosis in the future.

BACKGROUND This study aimed to decrease leukocytes counts by hydroxyurea (Hu) in an acute myocardial infarction (AMI) rat model and examine its effect on the inflammatory response of myocardial infarction and cardiac functions. MATERIAL AND METHODS AMI was successfully caused in 36 rats, and 12 control rats received sham operation. Rats in the AMI group were then randomly divided into Hu and vehicle group with 18 rats each. Rats in the Hu AMI group received Hu (200 mg/kg) intragastrically while vehicle AMI group received saline. Leukocytes counts, cardiac functions, myocardial tissue morphology, and levels of soluble intercellular adhesion molecule-1 (sICAM), P-selectin and platelet activating factor (PAF) were measured and compared among the three groups four weeks after AMI induction. RESULTS Leukocytes, neutrophils, and leukomonocyte counts in vehicle AMI rats were significantly higher than that of the normal control group (p<0.05). However, Hu treatment decreased their counts significantly (p<0.05). sICAM, P-selectin, and PAF level in vehicle AMI group were significantly higher than those of the normal group, and their level was also decreased by Hu treatment (p<0.05). Echocardiography analysis showed that Hu treatment increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) compared to that of vehicle AMI group (p<0.05). Histopathological examination showed that Hu significantly reduced the swelling of the heart muscle fiber in necrotic foci and the number of inflammatory cells infiltrated into myocardial interstitium compared to vehicle AMI group. CONCLUSIONS Decrease leukocytes counts by Hu significantly reduced inflammatory reaction and improved cardiac functions in AMI rats.

BACKGROUND Preclinical and clinical studies have shown that the extract of Cynanchum paniculatum (bunge) kitag and the fukeqianjin formulation have beneficial effects in pelvic inflammatory disease (PID). This study aimed to compare the effects of Cynanchum paniculatum and fukeqianjin with a new decoction, xiaoyuningkun, consisting of Melia toosendan, Angelica biserrata, and Cynanchum paniculatum, in a mouse model of PID. MATERIAL AND METHODS The mouse model of PID included injection of the upper genital tract with hydrochloric acid (HCl) and lipopolysaccharide (LPS). The control group underwent sham treatment with 0.9% physiological saline. Cynanchum paniculatum, fukeqianjin, and xiaoyuningkun decoction were administered orally for 15 days. Acetic acid-induced writhing and thermal nociception hot plate tests evaluated the analgesic effects of treatment. Mouse uterus and Fallopian tubes were examined histologically to evaluate the degree of inflammation. Immunohistochemistry was used to measure the protein expression of intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF). Enzyme-linked immunosorbent assay (ELISA) measured serum levels of inflammatory cytokines. RESULTS Treatment with xiaoyuningkun decoction significantly reduced the pain threshold in the mouse model of PID and the degree of inflammation in the uterus and Fallopian tubes compared with Cynanchum paniculatum and fukeqianjin. Cynanchum paniculatum decoction significantly reduced the serum levels of interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-alpha), ICAM-1, and VEGF, and the expression of ICAM-1 and VEGF in the mouse uterus and Fallopian tubes. CONCLUSIONS The new xiaoyuningkun decoction had analgesic and anti-inflammatory effects in the mouse model of PID, possibly by inhibiting ICAM-1, VEGF, and inflammatory cytokines.