Kyung-Yo Kim

Reduced IL-2 but elevated IL-4, IL-6, and IgE serum levels in patients with cerebral infarction during the acute stage

Cytokines in the central nervous system (CNS) may play an important role in functioning as intercellular signals that orchestrate the response to injury. Whether this is a cause or result of the brain disease process is uncertain. We investigated IFN-γ, IL-2, IL-4, IL-6, and IgE in the sera of 38 patients with cerebral infarction during the acute stage and 10 normal controls using an originally devised sensitive sandwich enzyme-linked immunosorbent assay (ELISA). We found that serum levels of IL-2 derived from T helper 1 (Th1) cells were slightly reduced in patients with cerebral infarction, whereas serum levels of IL-4 and IL-6 derived from Th2 cells were elevated significantly. IL-4 induces synthesis of IgE in human B cells. Endogenous IL-6 plays an obligatory role in IL-4-dependent human IgE synthesis. We observed that serum IgE levels were elevated significantly in patients with cerebral infarction. However, serum IFN-γ levels were not elevated significantly in cerebral infarction patients. These findings suggest that elevated IL-4, IL-6, and IgE levels in the human serum may be an important factor in cerebral infarction during the acute stage. Decrease of IL-2 levels in the serum of patients with cerebral infarction may be a regulatory mechanism.

Cytokine production regulation in human astrocytes by a herbal combination (Yuldahansotang)

ABSTRACT Yuldahansotang (YH-Tang), a Sasang Constitutional prescription composed of seven herbal mixtures, has been developed as a formula to prevent and treat cerebral infarction (CI) of Taeumins. However, the mechanisms by which this formula affects CI remain unknown. Previously, regulation of serum cytokine levels by YH-Tang has been observed in individuals at the acute stage of CI disease. It is uncertain whether this is a cause or a result of the disease process. In this study, we investigated whether YH-Tang inhibited secretion of inflammatory cytokines from human astrocytes. YH-Tang regulated the cytokine secretions in astrocytes stimulated with substance P (SP) and lipopolysaccharide (LPS). YH-Tang significantly inhibited interleukin (IL)-1, IL-4, IL-6 and tumor necrosis factor-α (TNF-α) secretion in astrocytes stimulated with SP and LPS, but did not inhibit interferon-γ (IFN-γ) and IL-2 secretion significantly. IL-1 has been shown to elevate TNF-α secretion from LPS-stimulated astrocytes while having no effect on astrocytes in the absence of LPS. Therefore, we investigated whether IL-1 mediated inhibition of TNF-α secretion from astrocytes by YH-Tang. Incubation of human astrocytes with IL-1 antibody abolished the synergistic cooperative effect of LPS and SP. These results suggest that YH-Tang may indirectly inhibit TNF-α secretion by inhibiting IL-1 secretion. Moreover, these findings indicate that YH-Tang has regulatory effects on cytokine secretion in an acute CI patient.

Yangkyuk-Sanhwa-Tang induces changes in serum cytokines and improves outcome in focal stroke patients

Yangkyuk-Sanhwa-Tang (YS-Tang), a specific prescription composed of nine herbal mixtures, has been developed as a formula for the Soyangin cerebral infarction (CI) patients according to Sasang constitutional philosophy. However, the mechanisms by which this formula affects CI remain unknown. This study revealed changes in cytokine production in the acute stage of Soyangin constitution CI patients after YS-Tang administration. Clinical signs (vertigo, headache and slurred speech) of CI disappeared significantly in about 2 weeks after oral administration of YS-Tang (P < .05). The mean interleukin (IL)-2 plasma levels were lower by 15% in the patients with CI than in the normal groups, whereas the mean TNF-alpha, IL-4, IL-6 and IgE levels were significantly higher in the patients (P < .01). There were no significant differences in interferon-gamma (IFN-gamma) levels between the groups. Serum IFN-gamma and IL-2 levels were elevated significantly (P < .01) in the patients with CI by YS-Tang administration. Significant reduced plasma levels (P < .01) of TNF-alpha, IL-4, IL-6 and IgE were observed in the patients treated with YS-Tang. During the period of YS-Tang administration, there were no other adverse effects. The data indicate that YS-Tang has an enhancing effect on antiinflammatory cytokines and an inhibitory effect on inflammatory cytokines. These results may implicate a good CI treatment effect of YS-tang and that its action may be due to regulation of cytokine production.

Association Between Tumor Necrosis Factor-α Gene Polymorphism and Sasang Constitution in Cerebral Infarction

During the last decade, a growing corpus of evidence has indicated an important role of cytokines in the development of brain damage following cerebral ischemia. Tumor necrosis factor-alpha (TNF-alpha), a potent immunomodulator and pro-inflammatory cytokine, has been implicated in many pathological processes. In this study, we examined whether promoter region polymorphism in the TNF-alpha gene at position -308 affects the odds of cerebral infarction (CI) and whether genetic risk is enhanced by Sasang constitutional classification. Two hundred and twelve CI patients and 610 healthy controls were genotyped and determined according to Sasang constitutional classification. A significant decrease was found for the TNF-alpha A allele in CI patients compared with controls (p = 0.033, odds ratio, OR: 0.622). However, there was no significant association between TNF-alpha polymorphism and Sasang constitution in CI patients. Our finding suggests that TNF-alpha promoter region polymorphism is responsible for susceptibility to CI in Koreans.

Candidate genes of cerebral infarction and traditional classification in Koreans with cerebral infarction

Sasang constitutional medicine is a major branch of Korean traditional Oriental medicine. The differences of disease susceptibility to be shown in Sasang constitution may be due to genetic factors. Therefore, the authors examined relationship between candidate genes of cerebral infarction (CI) and Sasang constitution. The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the ϵ4 allele of the apolipoprotein E gene (ApoE/ϵ4) are reported to be associated with ischemic heart disease. CI is another atherosclerotic disease; and the effects of these polymorphisms on CI have been confusing. This study investigated whether ACE/DD, AGN/TT, and ApoE/ϵ4 genotypes are associated with CI and whether genetic risk is enhanced by Sasang constitutional classification. The authors ascertained these genotypes in patients with CI (N=211), diagnosed by brain computed tomography. Control subjects for the infarction group were randomly selected from 319 subjects matched for age, sex, and history of hypertension with patients. The ACE/DD genotype was not associated with CI. However, there was significant association between ApoE polymorphism and CI (χ2=15.089, p<.05). Furthermore, frequency of AGN/TT genotype was higher in the patients with CI than in the controls (χ2=20.072, p<.05). The frequency of T allele was 0.91 in patients and 0.82 in controls (χ2=17.237, p<.05). However, Sasang constitutional classification did not increase the relative risk for CI in the subjects with ApoE/ϵ4 or AGN/T allele. These results suggest that ApoE and AGN polymorphism predict CI, but Sasang constitutional classification does not enhance the risk for CI associated with ApoE/ϵ4 or AGN/TT in a Korean population.

Production of Hydrogen Peroxide by Serum and its Involvement in Cell Proliferation in ROS 17/2.8 Osteoblasts

Abstract The effects of hydrogen peroxide, which fetal bovine serum (FBS) releases, on proliferation have been studied in ROS 17/2.8 osteoblasts. Cell proliferation, when activated by FBS, was inhibited by catalase in ROS 17/2.8 osteoblasts, but did not in primary osteoblast-like cells. Serum-induced extracellular signal-regulated kinase (ERK) activity was reduced by the pretreated catalase in ROS 17/2.8 osteoblasts. In addition, the present studies demonstrate that addition of FBS led to an increase of fluorescene of dihydrorhodamine 123, indicating formation of free radicals including hydrogen peroxide in ROS 17/2.8 osteoblasts, but not in primary osteoblast-like cells. These phenomena may account for the generation of reactive oxygen species during cellular proliferation in ROS 17/2.8 osteoblasts.

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.

Comparative Study on the Pulse Wave Variables and Sasang Constitution in Cerebral Infarction Patients and Healthy Subjects

This study was performed to determine whether a pulse analyzer was useful 1) to characterize the variables of pulse wave of cerebral infarction patieno (CI), compared with those of healthy subjects, as well as 2) to determine Sasang Constitution in CI and healthy subjects. 1. Calibrated in Gwan, the amount of energy(Energy), height of main peak(H1), height of aorticvalley(H2), height of aortic peak(H3), total area of pulse wave(At), and area of main peak width(Aw) of the CI group were higher than those of the healthy group. 2. Calibrated in Cheek, Energy, H1, H2, H3, height of valve valley(H4), At, Aw, and main peak angle(MPA) of the CI group were higher than those of the healthy group. 3. Among the healthy (subjects) group, Taeumin showed the highest contact pressure(CP) and height of valve peak(H5) calibrated in Chon. The main peak width divided by whole time of pulse wave(MPW/T) calibrated in Gwan and Cheok, was highest in Soyangin and was lowest in Taeumin. The H3 divided by H1(H3/H1) and the time to valve valley minus the time to main peak and divided by T[(T4-T1)/T] calibrated in Cheek were highest in Soyangin. The time to main peak(T1) was longest in Soumin. 4. Among the CI group, At calibrated in Chon was widest in Taeumin and was narrowest in Soumin The time to aortic peak(T3) calibrated in Cheek was longest in Soumin and was shortest in Soyangin. The time to valve peak(T5) was shortest in Soyangin. 5. There were main effects of cerebral infarction in the area of systolic period(As) and area of diastolic period(Ad) calibrated in Chon, Energy calibrated in Cwan, and Energy, H1, H2, H3, (H4+H5)/Hl, and MPA calibrated in Cheek. 6. There were main effects of Sasang Constitution in (T4-T1)/T, area of systolic period(As), and Ad calibrated in Chon. 7. The interactions between the cerebral infarction and Sasang Constitution were observed in H5/H1 , T, At, As, Ad, and MPA calibrated in Chon, H4, T4, (T4-T1)/T, As, and Ad calibrated in Cwan, and 74,75, and MPW calibrated in Cheok. Therefore, we concluded that pulse analyzer was useful to determine the risk degree of cerebral infarction and Sasang Constitution.

Gene-gene interaction in cerebral infarction patients: Relationship between apolipopreotein E gene polymorphism and Sasang-constitution

Sasang Constitutional Medicine is a major branch of Korean Traditional Oriental Medicine. The differences of disease susceptibility to be shown in Sasang constitution may be due to genetic factors. Therefore, we examined interrelationship among cerebral infarction (CI), apolipoprotein E (apoE) gene polymorphism, and Sasang constitutional classification. ApoE is a key protein modulating the highly atherogenic apoB containing lipoproteins and is a candidate gene for the development of coronary artery disease (CAD). The alleles were the first to be implicated in premature CAD, which resulted in this polymorphism being extensively studied. We investigated the association between apoE genotype and CI by case-control study in a Korean population. We also classified CI patients and control group into groups according to Sasang Constitutional Medicine. 196 CI patients and 379 controls without CI were examined. ApoE genotype was determined by 8% polyacrylamide gel separation after DNA amplification. A significant difference in the apoE genotype distribution was observed in the CI patients compared with that in controls (=14.920, df=4, P=0.005). Also, the frequency of Taeumin constitution in patients with CI was significantly higher than that in controls (58.0% vs. 36.9%; P alleles. No differences in the apoE genotypes frequencies were observed in the Taeumin compared with that in the other constitutions. In addition, we investigated whether the DD genotype of angiotensin converting enzyme (ACE) gene, a candidate gene for CI, was associated with CI, Taeumin constitution, and apoE polymorphism. As a result, the frequency of Taeumin constitution was significantly higher in CI patients with both apoE and ACE ID/DD genotypes than in the remaining Sasang constitutions (14.5% vs. 8.3% and 0%) (=13.521, df=6, P=0.035). In summary, we concluded that the apoE polymorphism is a major risk factor for CI in Koreans and the ACE ID/DD genotype enhanced the relative risk for CI in the subjects with apoE genotype and Taeumin constitution.

Glutathione S-transferase polymorphisms and traditional classification in Korean population with cerebrovascular disease

Glutathione S-transferase polymorphisms (GST) were examined in 98 cases with cerebrovascular disease (CVD) to test the hypothesis that GST polymorphisms confer a risk to an individual to develop CVD. Tobacco smoke is a major cause of both cancer and vascular disease. We therefore were stratified the subjects with CVD for smoking status, and then examined whether polymorphisms in this detoxification enzyme gene, GST, influence risk of CVD. Neither GSTM1 nor GSTT1 genotypes in the CVD group was significantly different from the control group (n=230), even in smokers. We attempted the combined analyses for GSTM1 and GSTT1 genotypes in CVD for smoking status. No significant association observed between the combined genotypes and CVD. We also classified the subjects and control group into four types according to Sasang Constitutional Medicine, Korean Traditional Oriental Medicine, and investigated the association among GST genotypes, CVD, and Sasang constitutional classification. Our observations do not confirm the effect of the GSTM1 and GSTT1 genotypes as a risk factor for CVD, even in smokers. Furthermore, we first attempted to evaluate the efficacy of Sasang Constitutional Medicine, and to find an association with CVD.