Kwang-Ho Cho

Association of interleukin-1 alpha gene polymorphism with cerebral infarction

Interleukin-1 (IL-1) has pleiotropic actions in the central nervous system. During the last decade, a growing corpus of evidence has indicated an important role of this cytokine in the development of brain damage following cerebral ischemia. The expression of IL-1 in the brain is dramatically increased during the early and chronic stage of infarction. The IL-1 gene cluster on chromosome 2q14 contains three related genes (IL1alpha, IL1beta, and IL1 receptor antagonist) located within a 430-kb region. T and C alleles exist for the IL-1alpha-889 regulatory region and the TT genotype has been reported to increase the production of the protein in lipopolysaccharide (LPS)-stimulated mononuclear cells from IL-1alpha-889 TT carriers. We examined whether the IL-1alpha polymorphism affects the probability of cerebral infarction (CI). We genotyped 360 CI patients and 519 healthy controls for the same polymorphism. A significant increase was found for the IL-1alpha T allele in CI patients compared with controls (chi2=5.026, P=0.025). We conclude that the IL-1alpha-889 polymorphism is a major risk factor for CI in Koreans.

Polymorphism of Angiotensin-Converting Enzyme, Angiotensinogen, and Apolipoprotein E Genes in Korean Patients with Cerebral Infarction

The homozygous deletion allele of the angiotensin-converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the ɛ4 allele of the apolipoprotein E gene (apoE/ɛ4) are reported to be associated with ischemic heart disease. Cerebral infarction (CI) is another atherosclerotic disease, and the effects of these polymorphisms on CI have been confusing. The frequency of the DD genotype of the ACE gene, but not the TT genotype of the AGN gene and the ɛ4 allele of ApoE, was significantly higher in subjects with than those without CI in Japan. In this study, we investigated whether ACE/DD, AGN/TT, and apoE/ɛ4 genotypes are associated with CI and whether genetic risk is enhanced by the effect of one upon another. We ascertained these genotypes in patients with CI (n=365), diagnosed by brain computed tomography. Control subjects for the infarction group were randomly selected from 319 subjects matched for age, gender, and history of hypertension with patients. The ACE/DD genotype was not associated with CI. Frequency of the AGN/TT genotype was higher in patients with CI than in controls (x2=12.287, p<0.05). The frequency of t allele was 0.88 in patients and 0.82 in controls (x2=11.041, p<0.05; odds ratio, 1.7). Furthermore, the AGN/TT genotype increased the relative risk for CI in subjects with the ACE/DD genotype (x2=7.8, p<0.05; odds ratio, 1.9). There was no significant association between apoE/ɛ4 and CI. These results suggest that AGN/TT predicts CI and ACE/DD enhances the risk for CI associated with AGN/TT in a Korean population.

Correlation Between Insulin Resistance and Intracranial Atherosclerosis in Patients With Ischemic Stroke Without Diabetes

BACKGROUND Insulin resistance (IR) is associated with an increased risk for cardiovascular morbidity and mortality including ischemic stroke. Its final complications are cardiovascular and cerebrovascular disease caused by atherosclerosis. However, few studies on the relationship between IR and intracranial (IC) atherosclerosis have been reported. METHODS We analyzed 110 patients with acute stroke without diabetes who underwent brain magnetic resonance angiography and cerebral angiography. Patients were divided into 3 equal groups according to the tertiles of homeostasis model assessment of IR (HOMA-IR): group I (n = 36; HOMA-IR < 0.92), group II (n = 37; 0.92 <or= HOMA-IR < 1.55), and group III (n = 37; HOMA-IR >or= 1.55). Cerebral artery atherosclerosis was classified as either IC or extracranial (EC). RESULTS Patients with IC or EC atherosclerosis showed higher level of HOMA-IR than those without. When the association was assessed according to the site of atherosclerosis, HOMA-IR showed a significant association with the site of atherosclerosis (IC + EC > IC > EC, P < .01). Multivariate analysis revealed that HOMA-IR was an independent predictor of IC atherosclerosis. CONCLUSIONS Although the association between IR and stroke patterns in patients with atherosclerosis remains uncertain, IR is associated with IC atherosclerosis in patients with acute ischemic stroke without diabetes.

Scrub typhus as a possible aetiology of Guillain–Barré syndrome: two cases

Neurological complications of scrub typhus are reported to be rare. Peripheral nervous system involvement has been reported in only one case. We present two cases of Guillan–Barré syndrome (GBS) associated with scrub typhus. In both cases, the findings of an elevated indirect immunofluorescent antibody titer for Orientia tsutsugamushi and nerve conduction study showing sensory-motor polyneuropathy, have led us to believe that scrub typhus could be one of the antecedent illnesses associated with GBS.

Genetic susceptibility to ischemic cerebrovascular disease in Koreans

Ischemic cerebrovascular disease (ICVD) is a multifactorial disease caused by the interactions of several genetic and environmental factors. Tobacco smoke is a major cause of both cancer and vascular disease. Although its carcinogenic role via induction of DNA damage and mutation is well established, the mechanisms involved in vascular disease remain unclear. One possibility is that DNA damage causes smooth muscle cell proliferation in the intima of arteries, thereby contributing to atherothrombotic processes. The binding of chemicals to DNA is modulated by detoxification enzymes, including glutathione S-transferase (GST). We examined whether polymorphisms in this gene, as well as the angiotensin-converting enzyme (ACE) gene influence the risk of ICVD on smoking status. DNA was analyzed for deletions in the GST M1, T1, and ACE genes by polymerase chain reaction (PCR). No significant association was observed between GST null genotype and ICVD, even in smokers. However, a significant association between ACE and ICVD was observed only in smokers (X2=0.023, p<0.05). We conclude that GST polymorphism is not a risk factor for the development of ICVD through smoking and suggest a high probability that ACE polymorphism may contribute to the odds of ICVD in smokers.

Regulation of TH1/TH2 Cytokine Production by Chungsim-Yeunja-Tang in Patients with Cerebral Infarction

Chungsim-Yeunja-Tang is a prescription for the Taeumin cerebral infarction (CI) patients according to Sasang constitutional philosophy. Taeumin patients with CI were treated with CY-Tang during the acute stage. Clinical signs of CI disappeared markedly in about 2 weeks after oral administration of CY-Tang in all patients. The mean interleukin (IL)-2 plasma levels were slightly lower in the patients with CI than in the normal groups, whereas the mean TNF-α, IL-4, IL-6, and IgE levels were significantly higher in the patients with CI. There were no significant differences in interferon-γ (IFN-γ) levels between the groups. Serum IFN-γ and IL-2 levels derived from T helper (Th) 1 cells were significantly elevated in the patients with CI by CY-Tang administration. Significant reduced plasma levels of IL-4 and IL-6 derived from Th2 cells and IgE were observed in the patients treated with CY-Tang. Plasma levels of TNF-α derived from Th1 significantly increased in the patients treated with CY-Tang. During the period of CY-Tang administration, there were no other adverse effects. The data indicate that CY-Tang has a good CI treatment effect, and that its action may be due to the regulation of cytokine production.

GLUTATHIONE S-TRANSFERASE GENE POLYMORPHISM AND ISCHEMIC CEREBROVASCULAR DISEASE

Glutathione S-transferase polymorphisms (GST) were examined in 142 cases with ischemic cerebrovascular disease (ICVD) to explore whether the GST polymorphisms confer a risk to an individual to develop ICVD. Tobacco smoke is a major cause of both cancer and vascular disease. The subjects were therefore stratified with ICVD for smoking status, and then the authors examined whether polymorphisms in this detoxification enzyme gene, GST, influence risk of ICVD. The GST genotype was analyzed by the polymerase chain reaction. Neither GSTM1 nor GSTT1 genotypes in the ICVD group was significantly different from the control group (n = 344), even in smokers. The authors attempted the combined analysis for GSTM1 and GSTT1 genotypes in ICVD for smoking status. No significant association was observed among the combined genotypes and ICVD. The observations do not confirm the effect of the GSTM1 and GSTT1 genotypes as a risk factor for ICVD, even in smokers. However, this approach provides a way of addressing the hypothesis that environmental genotoxins could play a role in the etiopathogenesis of ICVD.

Novel effects of On-Chung-Eum, the traditional plant medicine, on cytokine production in human mononuclear cells from Behçet's.

Plant medications have been used as treatment in various kinds of systemic inflammatory disorder such as Behçets disease (BD). We investigated the roles of On-Chung-Eum (OCE), a traditional plant medicine, in cytokine regulation of BD. The effects of OCE on cytokine production from phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) of Behçets patients and control subjects were measured by ELISA. PBMC from patients with active BD produced higher levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) compared to control. OCE significantly inhibited the production of TNF-α, IL-1β and interferon-γ (INF-γ) compared to absence of OCE. The inhibitory effects of OCE showed in a dose-dependent manner, and OCE had better effects than immunosuppressive drug, cyclosporin A. OCE is able to effectively inhibit proinflammatory cytokines and immunoregulatory Th1 cytokine. OCE treatment for BD patients may help the improvement of symptoms through cytokine modulation.

Antiinflammatory effect of Daesiho, a Korean traditional prescription for cerebral infarct patients

Daesiho, a prescription composed of eight herbal mixtures, has been widely used in the treatment of cerebral infarct in Oriental medicine. However, the mechanisms by which the formula affects the production of pro‐inflammatory cytokines in cerebral infarct patients remains unknown. The levels of secretory protein pro‐inflammatory cytokines, including tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β and IL‐6, were significantly increased in both lipopolysaccharide (LPS) and phytohemagglutinin (PHA)‐stimulated peripheral blood mononuclear cells (PBMCs) from cerebral infarct patients and LPS‐stimulated THP‐1 differentiated macrophage‐like cells (THP‐1/M). However, pretreatment with Daesiho significantly inhibited the secretion of pro‐inflammatory cytokines, including TNF‐α, IL‐1β, and IL‐6, in stimulated PBMCs and THP‐1/M cells. In addition, Daesiho significantly suppressed mRNA expression of pro‐inflammatory cytokines. Therefore, these data indicate that Daesiho may be beneficial in the cessation of inflammatory processes of cerebral infarction through suppression of the production of pro‐inflammatory cytokines via inhibition of mRNA expression. Copyright

The Effect of SHJKS on Cytokines Production and NF-κB Activation in the Peripheral Blood Mononuclear Cells of Patients with Cerebral Infarction

The Korean genuine medicine “Seonghyangjeongkisan” (SHJKS) has long been used for various cerebrovascular diseases. However, very little scientific investigation has been carried out. Cytokines involved in the regulation of inflammatory reactions and immune responses may play a role in the pathogenesis of cerebral infarction (CI). The aim of the present study is to elucidate how SHJKS modulates the inflammatory reaction in lipopolysaccaride (LPS) plus phytohaemagglutinin (PHA)-stimulated peripheral mononuclear cells (PBMCs) from CI patients. The amount of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in PBMC culture supernatant was significantly increased in the LPS plus PHA treated cells compared to unstimulated cells. SHJKS inhibited the TNF-α, IL-1β, IL-6, and IL-8 production in dose dependent manner. Maximal inhibition rate of the TNF-α, IL-1β, IL-6, and IL-8 by SHJGS (1.0 mg/ml) was 68.01 ± 0.28% (P < 0.01), 52.11 ± 0.56 % (P < 0.01), 53.42 ± 0.46 % (P < 0.01), and 46.70 ± 0.37% (P < 0.05), respectively. In addition, we show that SHJKS suppressed nuclear factor (NF)-κB activation induced by LPS plus PHA, leading to suppression of IκB-α phosphorylation and degradation. These results suggest that SHJKS might have regulatory effects on LPS plus PHA-induced cytokine production and NF-κB activation, which might explain its beneficial effect in the treatment of CI.