Keshen Li

Interaction between Interleukin-8 and Methylenetetrahydrofolate Reductase Genes Modulates Alzheimer’s Disease Risk

Background/Aim: Interleukin-8 (IL-8), a potent chemoattractant for neutrophils, has been implicated in the pathogenesis of Alzheimer’s disease (AD). The ability of individuals to produce high levels of IL-8 is partially determined by the IL-8 –251 T/A polymorphism. Therefore, we investigated the association between this polymorphism and AD in a Chinese population. Additionally, in light of the stimulatory effect of homocysteine on the production of IL-8, we also sought to determine whether the methylenetetrahydrofolate reductase (MTHFR) gene 677 C/T variant, a genetic modifier of the serum homocysteine level, may interact with the IL-8 –251 polymorphism in determining the AD risk. Methods: Genotyping of 198 AD patients and 240 matched controls was performed by PCR-RFLP. Results: The presence of the MTHFR 677 C/T and 677 T/T genotypes conferred a marginally significant increase in the risk for AD (OR = 1.666, 95% CI = 1.022–2.715, and OR = 1.892, 95% CI = 1.124–3.187) and the presence of the IL-8 –251 polymorphism was not associated with AD. However, the OR for AD associated with joint occurrence of the MTHFR 677 T/T and the IL-8 –251 A/A genotypes was 2.512 (95% CI = 1.151–5.483). Conclusion: Our data suggest a critical role for IL-8/MTHFR interactions in the development of AD.

A functional p.82G>S polymorphism in the RAGE gene is associated with multiple sclerosis in the Chinese population

Background: The receptor for advanced glycation end products (RAGE) and its proinflammatory ligand, S100-calgranulins, are critically implicated in the pathological progression of multiple sclerosis (MS). A functional polymorphism within the V-type immunoglobulin domain of RAGE gene, p.82G>S (c.557G>A), has been shown to affect ligand binding affinity and thus may affect susceptibility to MS. Methods: The RAGE p.82G>S polymorphism was genotyped in 144 MS patients and 156 healthy controls using polymerase chain reaction – restriction fragment length polymorphism. A replication study was performed on a second cohort comprising 138 patients and 150 controls. The relationship between the RAGE p.82G>S polymorphism and circulating levels of soluble RAGE (sRAGE), a secreted decoy receptor against RAGE signaling, was also investigated. Results: In both initial and replication cohorts, an increased MS risk was detected in RAGE p.82G>S variant allele carriers (odds ratio [OR] = 1.786, p = 0.0134 and OR = 1.732, p = 0.0210, respectively). This association signal persisted in subgroups of women and patients with relapsing–remitting MS. Moreover, compared with the wild-type 82GG carriers, carriers of the variant allele presented a faster progression of disability and a reduced serum sRAGE level. Conclusions: The present study provides preliminary evidence that the gain-of-function p.82G>S polymorphism in the RAGE gene is associated with an increased risk of MS in the Chinese population.

Influence of the Pro12Ala polymorphism of PPAR-γ on age at onset and sRAGE levels in Alzheimer's disease

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been described to have a role in the modulation of various genes involved in Abeta homeostasis, inflammation, and energy metabolism, making it a candidate gene for risk of Alzheimers disease (AD). A functional polymorphism in exon 2 of the PPAR-gamma gene has been related to AD, but the effects are inconsistent across studies. To determine the role of PPAR-gamma in genetic susceptibility to AD in a representative Chinese sample, we genotyped 362 AD patients and 370 healthy controls for PPAR-gamma Pro12Ala polymorphism by polymerase chain reaction-restriction fragment length polymorphism method. We also examined the potential impact of this polymorphism on plasma level of soluble receptor for advanced glycation end products (sRAGE), a decoy receptor whose reduction has been associated with a higher risk of AD. Our results suggest that PPAR-gamma Pro12Ala polymorphism was not associated with an increased risk of AD in the overall sample. Stratification analysis revealed that the PPAR-gamma Pro/Ala genotype may be associated with the development of early-onset AD in the individuals without APOE epsilon4 allele (OR=3.76, 95% CI=1.10-12.84; p=0.03), but this association became insignificant after Bonferroni correction (p (corr)=0.10). Moreover, in the subgroup of APOE epsilon4 noncarriers, Kaplan-Meier survival analyses indicated that AD patients with the Pro/Ala genotype presented with disease onset 4.6 years earlier than carriers of Pro/Pro genotype. Further investigation revealed that AD patients carrying Pro/Ala genotype had significantly lower plasma sRAGE levels than patients with Pro/Pro genotype. These findings suggest that the functional PPAR-gamma Pro12Ala polymorphism may modify the age at onset of AD.

Genetic polymorphisms of interleukin 8 and risk of ulcerative colitis in the Chinese population

BACKGROUND Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of ulcerative colitis (UC). There are no studies on the association of single nucleotide polymorphisms (SNPs) of the IL-8 gene with the risk of UC. METHODS All 162 unrelated UC patients and 203 control subjects were analyzed for 5 IL-8 SNPs ((-845 (T/C), -738 (T/A), -353 (A/T), -251 (T/A) and +678 (T/C)) using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and PCR-sequence-specific primers (SSP) method. Serum IL-8 concentrations were measured in all subjects. RESULTS Individual SNPs were not associated with risk for UC. However, the frequency of -353A/-251A/+678T haplotype was significantly higher in UC patients than in healthy controls (OR=1.454, p=0.036). By subgroup analyses, this haplotype tended to be more common in severe UC patients than in those with mild-to-moderate disease (OR=2.281, p=0.027). Furthermore, patients with AAT diplotype showed significantly increased serum IL-8 concentrations than those with other diplotypes (p<0.001). CONCLUSION These results suggest that IL-8 is a novel susceptibility gene to UC in Chinese UC patients, and furthermore, that IL-8 polymorphisms may be related to severe clinical subtype of UC.

Association between the macrophage inflammatory protein-l alpha gene polymorphism and Alzheimer's disease in the Chinese population

Genetic polymorphisms in chemokine receptor and their natural ligand genes have been shown to modify the disease progression of Alzheimers disease (AD). Human macrophage inflammatory protein-1 alpha (MIP-1alpha) is a chemotactic cytokine which plays a considerable role in AD pathogenesis, but its genetic contribution to AD has never been investigated. Recently, a biallelic dinucleotide microsatellite repeat (TA repeat) polymorphism has been found in the MIP-1alpha gene promoter region at position -906. We investigated whether this promoter polymorphism of MIP-1alpha gene might be responsible for susceptibility to AD in a Chinese population, utilizing a clinically well-defined group of 138 sporadic AD patients and 180 age-matched controls. We also examined the combined gene effects between the MIP-1alpha and apolipoprotein E (APOE) genes. The overall distribution of MIP-1alpha-906 alleles and genotypes was significantly different between AD cases and controls (P<0.05). The odds ratio for AD associated with the (TA)(6)/(TA)(6) versus non-(TA)(6)/(TA)(6) genotype was 1.893 (95% CI=1.208-2.967), while that for APOE varepsilon4 and MIP-1alpha (TA)(6)/(TA)(6) carriers was 7.140 (95% CI=3.222-15.823). In addition, we found that serum MIP-1alpha levels in patients with (TA)(6)/(TA)(6) genotype were increased significantly when compared with non-(TA)(6)/(TA)(6) genotype. The results indicate that the MIP-1alpha-906 (TA)(6)/(TA)(6) genotype, either by itself or interacting with the APOE varepsilon4 gene seems to be a genetic risk factor for AD. This genotype is associated with elevated serum MIP-1alpha levels in patients, which can contribute to increase the inflammatory process occurring in AD.

The combination of polymorphisms within MCP‐1 and IL‐1β associated with ulcerative colitis

Monocyte chemoattractant protein‐1 (MCP‐1) is a chemokine involved in monocyte recruitment to sites of inflammation. Raised level of MCP‐1 has been widely demonstrated in the intestinal mucosa of patients with ulcerative colitis (UC), suggesting an important role of MCP‐1 in the pathogenesis of UC. The –2518A/G polymorphism in the promoter region of MCP‐1 gene affecting its transcriptional activation has been reported recently. In order to assess the potential role of this polymorphism in UC, we examined its distribution in 162 unrelated UC patients and 203 healthy controls. In addition, considering the gene regulatory association between interleukin‐1β (IL‐1β) and MCP‐1, we further examined whether the gene polymorphisms between MCP‐1 and IL‐1β exert synergetic effects on risk of UC. Our results show that the distribution of MCP‐1 genotype or allele frequencies between UC patients and controls was not significantly different; however, the association between the polymorphism of MCP‐1 –2518 GG and the polymorphism of IL‐1β–511 T in UC patients is significant (OR 2.062, 95% CI 1.034–4.113, P = 0.038). This is the first report describing the association between MCP‐1 polymorphism and UC, and our data suggest that the MCP‐1 –2518 polymorphism itself does not represent an independent genetic risk factor for UC. In contrast, the combination polymorphisms between MCP‐1 and IL‐1β can increase UC risk significantly, which might help us understand the molecular mechanism underlying the development of UC.

Identification of STC1 as an β-amyloid activated gene in human brain microvascular endothelial cells using cDNA microarray

To explore the molecular basis underlying beta-amyloid peptide (Abeta)-induced toxicity in the cerebrovasculature, we performed a cDNA microarray analysis to investigate the transcriptional profile induced by Abeta in human brain microvascular endothelial cells (HBMECs). This study identified 24 differentially expressed genes in HBMECs upon Abeta treatment. Among these genes, we found that the gene for a well-characterized calcium-regulating hormone, stanniocalcin-1 (STC1) was specifically up-regulated by Abeta treatment in a time and dose-dependent manner. Moreover, using overexpression and knock-down strategies, we found that overexpression of STC1 decreased transmigration of monocytes induced by Abeta and prevented Abeta-induced apoptosis of HBMECs. In addition, we explored the possible mechanisms underlying the effects of STC1, showing that overexpression of STC1 attenuated the effect of Abeta on up-regulating early growth response-1 (Egr-1), macrophage inflammatory protein-1beta (MIP-1beta), or cleaved caspase-8. Our data thus indicate a key role of STC1 in the response of HBMECs to Abeta exposure.

Meta-Analysis of the Association of the C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene with Hyperuricemia

Background: The association between the MTHFR C677T polymorphism and hyperuricemia has been investigated in several studies. Although these epidemiological studies have shown that genetic factors are determinants of serum uric acid levels, the power of the association is weak due to the small sample size. Methods: To study whether the MTHFR C677T polymorphism has an effect on hyperuricemia, we carried out a meta-analysis of case-control studies from PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases mainly in English and Chinese. We used the odds ratio (OR) as main effect size; explored potential sources of heterogeneity; performed subgroup analyses by race and performed sensitivity analyses of studies meeting the Hardy-Weinberg equilibrium (HWE). Results: Six studies with 1,470 subjects were included in the meta-analysis. Tests for heterogeneity showed the difference in OR among studies was not statistically significant (p = 0.63, I2 = 0). When excluding the study of Caucasians not in HWE, the association remained robust (OR = 1.82, 95% CI 1.52-2.17) in the East Asian subgroup and sensitivity analyses. Conclusions: Although the mechanism of the relationship between the C677T polymorphism and uric acid still remains unclear, these original articles showed that the MTHFR C677T polymorphism may be an independent risk factor for hyperuri-cemia.

Polymorphisms of the macrophage inflammatory protein 1 alpha and ApoE genes are associated with ulcerative colitis

Background and aimsAn increased production of macrophage inflammatory proteins 1 alpha (MIP-1α) has been reported to be associated with ulcerative colitis (UC). We investigated whether a polymorphism site in MIP-1α was associated with UC in a Chinese population. Additionally, considering the abnormal lipoprotein metabolism in subjects with UC, we also sought to determine whether genetic variation in the apolipoprotein E (ApoE) gene may play a role in the development of UC.Materials and methodsWe examined the MIP-1α −906 (TA)4/(TA)6 polymorphism and the ApoE polymorphism in a cohort of 162 unrelated UC patients and 220 healthy controls by using restriction fragment length polymorphism assay.ResultsA significantly increased frequency of the MIP-1α −906 (TA)6/(TA)6 genotype (P = 0.0031, odds ratio [OR] = 1.851, 95% confidence interval [CI] 1.228–2.791), as well as of the ApoE ε4+ genotype (P < 0.001, OR = 2.869, 95% CI 1.768–4.657), in patients with UC was proven. Moreover, the carriage of both MIP-1α −906 (TA)6/(TA)6 genotype and ApoE ε4+ genotype confers greater risk for the development of UC (P < 0.001, OR = 5.432, 95% CI 2.761–10.689).ConclusionThese findings suggest that variation in the MIP-1α and ApoE genes and their interaction may increase susceptibility to UC. Identifying these novel susceptibility genes, as well as their interactions, will help our understanding of the disease mechanisms of UC and may identify targets for developing novel treatment measures.

Exploring Teaching Methods on Biomedical Courses in Engineering Universities

Biomedical engineering plays an important role in the development of current medicine and biology. The education of biomedical engineering has made great improvements due to huge market potential today. As most biomedical engineering emphasizes on Biomedical Electronics in china, how to teach engineering students biomedical courses effectively is a new topic. Through the teaching reform, we explore a set of teaching methods. First of all, we break the teaching of traditional education model, and fully carry out research style teaching by selecting interesting topics. Accompanied with problem solving, learning and teaching could be finished. Considering weak biological knowledge background of engineering students, the simple words are used to elucidate the profound truth. Moreover, current multimedia technology is used to provide students an open teaching system. Due to biomedical engineering require a strong foundation in integrated capacity particularly, a series of research-oriented experiments for the scientific interest groups have been designed to train the students to develop their innovative thinking ability and practical skills. Finally in order to promote biomedical study, a variety of assessment methods is employed rather than rely on the single theory examination.