HABP2 Encapsulated by Peripheral Blood-Derived Exosomes Suppresses Astrocyte Autophagy to Exacerbate Neuroinflammatory Injury in Mice with Ischemic Stroke.

Exosomes are shown to be involved in the regulation of neuroinflammatory injury. The current study analyzed how peripheral blood-derived exosomes affected hyaluronan-binding protein 2 (HABP2) expression to regulate neuroinflammatory injury after ischemic stroke (IS). An IS animal model was stimulated by middle cerebral artery occlusion (MCAO), followed by injection of lentivirus. Peripheral blood samples were collected from MCAO mice after different treatments. The cerebral infarction volume, astrocyte activation, and neuroinflammation were observed by TTC staining, immunofluorescence, and ELISA, respectively. HABP2 was highly expressed in the brain tissues of MCAO mice. Also, an enhancement of HABP2 was noted in their peripheral blood-derived exosomes, while loss of HABP2 in peripheral blood-derived exosomes promoted the astrocyte autophagy and reduced the release of the inflammatory factors as well as the apoptosis of neuronal cells. PAR1 overexpression reversed the effect of HABP2 loss on autophagy and neuroinflammation in MCAO mice. Additionally, the agonist of the PI3K/AKT/mTOR pathway, SC79, could also reverse the effect of sh-PAR1 on neuroinflammation. Mechanistically, HABP2 enhanced PAR1 to activate the PI3K/AKT/mTOR pathway, thereby suppressing cell autophagy. Overall, HABP2 in peripheral blood-derived exosomes can activate the PAR1/PI3K/AKT/mTOR pathway to reduce autophagy and aggravate neuroinflammatory injury after IS.

Impact of RTN4 gene polymorphism and its plasma level on susceptibility to nasopharyngeal carcinoma: A case-control study.

The RTN4 gene plays a role in the development and progression of cancer. This case-control study aimed to investigate the association between the RTN4 gene polymorphism and its plasma level with the risk of nasopharyngeal carcinoma (NPC) in a Chinese population.RTN4 gene polymorphisms (rs2920891, rs17046583, rs117465650, rs10496040, and rs2588519) in 220 patients with NPC and 300 healthy controls were analyzed using Snapshot single-nucleotide polymorphism genotyping assays. The plasma level of RTN4 was measured using the enzyme-linked immunosorbent assay.The allele frequencies of RTN4 gene polymorphisms showed no significant difference between the patients and controls (P > .05). Nevertheless, the rs2920891 polymorphism in a dominant model (A/C+C/C) and codominant model (A/C) was significantly associated with the susceptibility to NPC (P = .017, odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.08-2.21 and P = .034, OR = 1.64, 95% CI = 1.13-2.38, respectively). The plasma level of RTN4 was significantly higher in patients with NPC in comparison with the controls (P < .001). Furthermore, we observed that patients with NPC carrying the rs2920891 A/C+C/C genotype had a higher RTN4 level than those carrying the A/A genotype (P < .001).Our findings indicated that the rs2920891 polymorphism may be associated with increased susceptibility to NPC, possibly by increasing plasma RTN4.

Overexpression of osteopontin promotes cell proliferation and migration in human nasopharyngeal carcinoma and is associated with poor prognosis.

Nasopharyngeal carcinoma (NPC), a malignant tumor at the top and side of the nasopharyngeal cavity, highly occurs in the southern region of China. Cancer cell metastasis is one of the leading causes of death in NPC patients. Osteopontin (OPN), is a phosphorylated extracellular matrix protein with a variety of functions, was found to be overexpressed in many cancers. However, the expression and role of OPN in patients with NPC in Guangxi, China are unclear. Here, we observed that NPC patients had upregulated OPN at mRNA protein and levels. Immunochemistry (IHC) analysis of OPN expression in 68 NPC clinical specimens indicated that high expression of OPN had positive correlation with NPC lymph node metastasis (P = 0.012), distant metastasis (P = 0.001) and TNM staging (P = 0.018). Moreover, compared with relatively low OPN, NPC patients with higher expression of OPN showed a poorer overall survival rate (P = 0.001, log rank test). Multivariate analysis showed that OPN expression in NPC was an independent prognostic marker. The proliferation, apoptosis and migration ability of CEN-2Z cancer cells in NPC were determined by MTT, flow cytometry and wound-healing assays, respectively. Upregulation of OPN in CEN-2Z cancer cells promoted cancer cell proliferation and migration, and suppressed apoptosis. In sum, our result suggests OPN could be used as a valuable oncoprotein and show that overexpression of OPN in NPC may serve as a potential prognostic marker.

Polymorphisms of transforming growth factor beta 1 (RS#1800468 and RS#1800471) and esophageal squamous cell carcinoma among Zhuangese population, China.

Epidemiological evidence has shown two polymorphisms (namely RS#1800468G>A and RS#1800471G>C) of transforming growth factor-beta 1 (TGF-ß1) gene may be involved in the cancer development. However, their role in the carcinogenic process of esophageal squamous cell carcinoma (ESCC) has been less well elaborated. We conducted a hospital-based case-control study including 391 ESCC cases and 508 controls without any evidence of tumors to evaluate the association between these two polymorphisms and ESCC risk and prognosis for Zhuangese population by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS)-PCR techniques. We found that individuals with the genotypes with RS#1800471 C allele (namely RS#1800471-GC or -CC) had an increased risk of ESCC than those without above genotypes (namely RS#1800471-GG, adjusted odds ratio 3.26 and 5.65, respectively). Further stratification analysis showed that this polymorphism was correlated with tumor histological grades and TNM (tumor, node, and metastasis) stage, and modified the serum levels of TGF-ß1. Additionally, RS#1800471 polymorphism affected ESCC prognosis (hazard ratio, 3.40), especially under high serum levels of TGF-ß1 conditions. However, RS#1800468 polymorphism was not significantly related to ESCC risk. These findings indicated that TGF-ß1 RS#1800471G>C polymorphism may be a genetic modifier for developing ESCC in Zhuangese population.

[A dynamic observation on serum cytokine and immunoglobulin (IgG, IgA, IgM) in patients with esophageal cancer].

OBJECTIVE: To study the changes of serum interleukin-2 (IL-2), interleukin-8 (IL-8) and immunoglobulin (IgG, IgA, IgM) in patients with esophageal cancer, and to probe the relationship between the levels of IL-2, IL-8, IgG, IgA and IgM and the progress of cancer. METHODS: The serum levels of IL-2 and IL-8 were detected by enzyme-linked immunosorbent assay for 72 case of primary esophageal cancer, 68 advanced esophageal cancer and 120 healthy controls, and the level of immunoglobulin (IgG, IgA, IgM) in patients with esophageal cancer was dynamically observed. RESULTS: The IL-2 level in patients with early esophageal cancer [(1.69 +/- 0.53) ng/ml] or late esophageal cancer [(1.11 +/- 0.60) ng/ml] was lower than the control group [(2.78 +/- 0.51) ng/ml] (P < 0.01), the late esophageal cancer group was lower than early esophageal cancer group (P < 0.05). The level of IL-8 in patients with early esophageal cancer [(85.48 +/- 6.14) ng/L] or late esophageal cancer [(121.41 +/- 6.22) ng/L] was much higher than the control group [(54.48 +/- 12.20) ng/L] (P < 0.01), the late esophageal cancer group was much higher than early esophageal cancer group (P < 0.01); There was correlation between the levels of IL-2 and IL-8 and the worsen-extent of the tumour in patients with early esophageal cancer or late esophageal cancer. But the level of IgG [(12.23 +/- 2.50) g/L], IgM [(1.60 +/- 0.80) g/L] in the patients with esophageal cancer compared with the level of IgG [(11.65 +/- 3.70) g/L], IgM [(1.46 +/- 0.71) g/L] in the health control group have no significant difference (P > 0.05), the level of IgA [(3.50 +/- 1.10) g/L] in patients with esophageal cancer Compared with the control group [(1.88 +/- 1.08) g/L] has significant difference (P < 0.01), and along with the worsen-extent of the tumor in patients the level of IgA has the increased tendency. CONCLUSION: The IL-8 might accelerate the pathogenesis of esophageal cancer, and the IL-2 might restrain. The positive correlation between the level of IgA and the patients with esophageal cancer is observed in this study; the immune maladjustment of IL-2, IL-8 and IgA might be correlative to esophageal cancer, and the IL-2, IL-8 and IgA levels might be an available index for the severity of esophageal cancer, Which may be of some help for clinic practitioners to judge the progress, curative effect and prognosis of the cancer.

Interleukin-18 gene promoter polymorphisms and the risk of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is multifactorial, and the genetic background may be a crucial etiologic factor. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon (IFN)-gamma secretion and plays an important role in antitumor immunity. Variations in the DNA sequence in the IL-18 gene promoter may lead to altered IL-18 production and/or activity, and so this can modulate an individual's susceptibility to ESCC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607 C/A polymorphisms and their haplotypes with the risk of ESCC in a Chinese population. METHODS: Two hundred and thirty five patients with ESCC and 250 age- and sex-matched controls, using sequence specific primers-polymerase chain reaction (PCR-SSP). RESULTS: Two polymorphisms, -137 G/C and -607 C/A were in strong linkage disequilibrium (LD). There were significantly differences in the genotype and allele distribution of -137 G/C polymorphism of the IL-18 gene among cases and controls. The -137 GC and CC genotypes were associated with a significantly increased risk of ESCC as compared with the -137 GG genotypes (OR = 1.91, 95% CI, 1.29-2.82, p = 0.001 and OR = 2.95, 95% CI, 1.23-7.04, p = 0.012, respectively). Consistent with the results of the genotyping analyses, the -137 C/ -607 A haplotype was associated with a significantly increased risk of ESCC as compared with the -137G/-607 C haplotype (OR = 1.61; 95% CI, 1.16-2.23; p = 0.004). CONCLUSION: This study shows for the first time an association between IL-18 gene promoter -137 G/C polymorphism may contribute represent a genetic risk factor for ESCC in a Chinese population.

[Serum level and genotype of interleukin-6 in patients with esophageal cancer].

OBJECTIVE: To investigate the polymorphism of the interleukin-6 (IL-6) gene promoter-572C/G and -634C/G in patients with esophageal cancer, and to study the relation between the serum level and genotype of interleukin-6 and esophageal cancer. METHODS: Peripheral blood samples were collected from 118 patients with esophageal cancer and 130 healthy persons as controls. The polymorphism of IL-6 was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The serum level of IL-6 was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequency of the genotype GG of the IL-6 (-634) site in the cancer group was 12.7%, significantly higher that that of the control group (3.8%, P<0.05). The risk of esophageal cancer of the G allele carriers was 1.759 times that of the C allele carriers (OR=1.759, 95% CI=1.150-2.691). The serum level of IL-6 of the esophageal cancer group was (16.9+/-5.3) ng/L, significantly higher than that of the control group [(4.6+/-2.6) ng/L, P<0.01]. The serum level of IL-6 of the esophageal cancer with the G allele carriers was (18.8+/-6.1) ng/L, significantly higher than that of the esophageal cancer without the G allele carriers [(13.2+/-6.0) ng/L, P<0.01]. There was no significant difference in the distribution of the IL-6 gene-572C/G polymorphism between the 2 groups (P>0.05). CONCLUSION: IL-6 gene-634C/G polymorphism is associated with the esophageal cancer. The IL-6 allele G carriers may be at increased risk of the esophageal cancer because of the increase of the IL-6 expression.

Single nucleotide polymorphism and haplotype association of the interleukin-8 gene with nasopharyngeal carcinoma.

The cytokine interleukin-8 (IL-8) may play a role in the pathogenesis of nasopharyngeal carcinoma (NPC) through the modulation of tumor immune response or enhanced angiogenesis. Polymorphism of IL-8 gene, which may affect the production level of cytokine, has been inversely associated with a number of cancers. To test this hypothesis, we investigated the relationship of IL-8 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL-8 gene -845 T/C, -738 T/A, -353 A/T, -251 A/T and +678 T/C in 280 patients with NPC and 290 age and sex matched controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-sequence specific primers method (PCR-SSP). There were significant differences in the genotype and allele distribution of -251 A/T polymorphism of the IL-8 gene among cases and controls. The -251 AA and AT genotypes were associated with a significantly increased risk of NPC as compared with the -251 TT genotypes (OR=1.820, 95% CI, 1.120-2.959, P=0.015 and OR=1.590, 95% CI, 1.104-2.290, P=0.013, respectively). Haplotype analysis revealed that the homozygosity of the AAT haplotype (defined by SNPs at positions -353, -251 and +678) of IL-8 gene conveys the highest risk for NPC compared with the homozygosity for the TTC haplotype (OR=1.396; 95% CI, 1.064-1.831; P=0.016). The -251 A/T polymorphism of IL-8 and its haplotype are associated with NPC in a Chinese population. Our data suggests that IL-8 gene may play a role in the development of NPC.

[Relationship between interleukin-6 gene polymorphism and coronary heart disease and its effect on plasma lipid levels].

OBJECTIVE: To study the relationship between interleukin-6 (IL-6) gene promoter-572 C/G and -634 C/G polymorphism and coronary heart disease (CHD) and the influence of IL-6 gene polymorphism on plasma lipid and lipoprotein levels. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for the detection of IL-6 genotype in 165 patients with CHD and 170 healthy persons. The plasma lipid and lipoprotein levels were measured by routine method. RESULTS: Plasma total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) of the patients with CHD were significantly higher than those of the controls (all P<0.05). The distributions of IL-6 gene -634 C/G polymorphism were not different between CHD group and control group (P>0.05), but the IL-6 gene-572 C/G polymorphism was significantly different between them (P<0.05). The relative risk of CHD of C allele was 1.652 times to the G allele [odds ratio (OR)=1.652, 95% confidence interval (CI): 1.137-2.401]. The level of plasma lipid in G allele carriers was significantly higher than non-carriers (P<0.05). CONCLUSION: IL-6 gene -572 C/G polymorphism is associated with CHD, and G allele is an important genetic marker. IL-6 gene polymorphism may affect CHD through elevation of plasma lipid and lipoprotein levels.