Low Dose of Emodin Inhibits Hypercholesterolemia in a Rat Model of High Cholesterol.

BACKGROUND Emodin has been widely used in traditional Chinese medicine, but few studies have tried to understand the mechanism of its anti-hypercholesterolemic effect. MATERIAL AND METHODS To delineate the underlying pathways, high-cholesterol diet (HCD)-fed Sprague-Dawley rats were orally administrated emodin or the lipid-lowering medicine simvastatin. Emodin was administered at 10, 30, or 100 mg/kg, while simvastatin was administered at 10 mg/kg. Parameters measured included lipid profiles (serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, aorta endothelium-dependent vasorelaxation in response to acetylcholine, and nitric oxide (NO) production. RT-qPCR and western blotting were performed to evaluate aortic endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), and hepatic LDL receptor (LDLR). Indices of liver and serum oxidation were also measured. RESULTS The atherogenic index was increased by the HCD but significantly reduced in all treatment groups. The HCD-fed experimental group treated with emodin at 10 mg/kg had significantly lower serum total-C and LDL-C and improved aorta vasorelaxation and enhanced NO production. Also, emodin significantly attenuated the lipid profiles and restored endothelial function, as reflected by upregulated expression of hepatic LDLR and p-eNOS, respectively. Furthermore, emodin at 10 mg/kg significantly enhanced superoxide dismutase activity, lowered the malondialdehyde level in both liver and serum, and enhanced catalase activity in serum. CONCLUSIONS The ability of emodin to inhibit hypercholesterolemia in HCD-fed rats was associated with lower serum total-C and LDL-C, restoration of aortic endothelial function, and improved antioxidant capacity. Low-dose emodin showed better protection of aortic endothelium and better antioxidant activity than did higher doses.

Association between Polymorphisms of the AKT1 Gene Promoter and Risk of the Alzheimer's Disease in a Chinese Han Population with Type 2 Diabetes.

AIMS: Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with type 2 diabetes (T2D) where the v-akt murine thymoma viral oncogene homolog 1 (AKT1) plays an important role in the protein synthesis pathways and cell apoptosis processes. Evidence has been shown that AKT1 protein may be related to AD risk among patients with T2D. The aim of this study was to analyze the potential association between single nucleotide polymorphisms of AKT1 promoter and the risk of AD among patients with T2D. METHODS: The association between AKT1 polymorphisms and AD risk in patients with T2D was assessed among 574 consecutive unrelated subjects including 112 AD patients with T2D, 231 patients with AD, and 231 healthy controls in a case-control study. The cognitive function of all subjects was assessed using MMSE. Six single nucleotide polymorphisms with minor allele frequency >0.2 (rs2498786, rs74090038, rs2494750, rs2494751, rs5811155, and rs2494752) in AKT1 promoter were analyzed by polymerase chain reaction (PCR), and the concentration of AKT1 protein in serum was tested using enzyme-linked immunosorbent assay (ELISA). RESULTS: Overall, there was statistically significant difference in AKT1 rs2498786 polymorphism. The CC frequency of AKT1 rs2498786 polymorphism in AD with T2D group and AD control group was significantly higher than that in healthy control group (PAD+T2D vs. health < 0.0001, PAD vs. health < 0.0001). However, the difference was not found between AD with T2D group and AD control group. Compared with healthy control group, the plasma levels of AKT1 protein in AD with T2D group (PAD+T2D vs. health < 0.0001) and AD control group (PAD vs. health = 0.0003) decreased significantly. Among genotypes of AKT1 rs2498786 polymorphism, the AKT1 protein level in GG genotype was significantly higher than that in GC genotype (PGG vs. GC < 0.0001) and CC genotype (PGG vs. CC < 0.0001). CONCLUSION: The study suggests that AKT1 rs2498786 polymorphism in insulin signaling pathway may be associated with AD risk and different genotypes may affects levels of protein expression. However, the polymorphism is not shown to be exclusive in AD patients with T2D.

Spatio-temporal analysis of female breast cancer incidence in Shenzhen, 2007-2012.

INTRODUCTION: Breast cancer is a leading tumor with a high mortality in women. This study examined the spatio-temporal distribution of the incidence of female breast cancer in Shenzhen between 2007 and 2012. METHODS: The data on breast cancer incidence were obtained from the Shenzhen Cancer Registry System. To describe the temporal trend, the average annual percentage change (AAPC) was analyzed using a joinpoint regression model. Spatial autocorrelation and a retrospective spatio-temporal scan approach were used to detect the spatio-temporal cluster distribution of breast cancer cases. RESULTS: Breast cancer ranked first among different types of cancer in women in Shenzhen between 2007 and 2012 with a crude incidence of 20.0/100,000 population. The age-standardized rate according to the world standard population was 21.1/100,000 in 2012, with an AAPC of 11.3%. The spatial autocorrelation analysis showed a spatial correlation characterized by the presence of a hotspot in south-central Shenzhen, which included the eastern part of Luohu District (Donghu and Liantang Streets) and Yantian District (Shatoujiao, Haishan, and Yantian Streets). Five spatio-temporal cluster areas were detected between 2010 and 2012, one of which was a Class 1 cluster located in southwestern Shenzhen in 2010, which included Yuehai, Nantou, Shahe, Shekou, and Nanshan Streets in Nanshan District with an incidence of 54.1/100,000 and a relative risk of 2.41; the other four were Class 2 clusters located in Yantian, Luohu, Futian, and Longhua Districts with a relative risk ranging from 1.70 to 3.25. CONCLUSIONS: This study revealed the spatio-temporal cluster pattern for the incidence of female breast cancer in Shenzhen, which will be useful for a better allocation of health resources in Shenzhen.

Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients.

BACKGROUND: Accumulating data suggest that hyperhomocysteinemia is associated with the risk of ischemic stroke (IS) and coronary heart disease (CHD) in the general population, but the relationship remains unclear in hypertensive patients. We examined the association of total homocysteine (tHcy) with IS and CHD in hypertensive patients. METHODS: A total of 5935 Chinese hypertensive patients were recruited in a community-based cross-sectional study from 60 communities in Shenzhen, China. Plasma tHcy was quantitatively measured using the enzyme cycle method. Conventional risk factors for IS and CHD were obtained through questionnaire interviews and physical examinations. We included cerebral infarction, embolism and small-vessel disease as IS; and myocardial infarction, angina pectoris, coronary revascularization, and cardiac arrest as CHD. IS and CHD were retrospectively adjudicated by specialists via interviews, hospital records or relevant tests. RESULTS: Significantly higher values of tHcy were observed in IS patients than in non-IS controls among both men and women. Greater tHcy level was dose dependently associated with an increased risk of IS presence in women, men and them combined (p-trend: 0.002, 3.8×10(-4) and 0.001). The odds ratios (95% CI) of IS for tHcy ≥30 (vs. <15) µmol/L were 2.84 (1.73-4.34) in men, 4.41 (1.62-9.15) in women, and 2.86 (1.72-4.75) in their combination after adjusting for other main risk factors of IS. We did not find any significant association between tHcy and presence of CHD after the adjustment for covariates. CONCLUSIONS: Plasma homocysteine level is positively associated with the presence of IS, but not CHD, in Chinese hypertensive patients.

Vascular endothelial growth factor gene promoter polymorphisms and Alzheimer's disease risk: a meta-analysis.

AIM: Conclusions on the association between polymorphisms in the vascular endothelial growth factor (VEGF) gene promoter and risk of Alzheimer's disease (AD) are ambiguous, and sufficient evaluation of the association is lacking. Therefore, we performed a meta-analysis of observational studies to explore the association between polymorphisms in the VEGF gene promoter and AD risk. METHODS: Bibliographical searches were performed in the MEDLINE, EMBASE, and China National Knowledge Infrastructure (CNKI) databases without any language limitations. Three investigators independently assessed abstracts for relevant studies and independently reviewed all eligible studies. A meta-analysis was conducted using a fixed- or random-effects model. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of association. All statistical analyses were performed using Stata 11.0 software. RESULTS: The meta-analysis of 2787 AD cases and 2841 controls from eight published case-control studies on the -2578C/A polymorphism and 1422 AD cases and 1063 controls from four studies on the -1154G/A polymorphism did not show any significant associations. However, in a subgroup analysis stratified by the presence of APOE є4, associations were observed with APOE ε4 (-) for -2578C/A (A vs. C: OR = 1.22, 95% CI = 1.04-1.43, P = 0.014; A/A vs. C/C: OR = 1.59, 95% CI = 1.11-2.27, P = 0.011 and A/A vs. A/C + C/C: OR = 1.46, 95% CI = 1.08-1.99, P = 0.015) and -1154G/A (A vs. G: OR = 0.74, 95% CI = 0.62-0.89, P = 0.001; A/A vs. G/G: OR = 0.57, 95% CI = 0.37-0.87, P = 0.009; A/G vs. G/G: OR = 0.69, 95% CI = 0.53-0.89, P = 0.004 and A/A + A/G vs. G/G: OR = 0.66, 95% CI = 0.52-0.85, P = 0.001). CONCLUSION: This meta-analysis showed the risk role of the -2578 polymorphism and the protective role of the -1154 polymorphism when the APOE є4 status was negative, suggesting that the two polymorphisms in the VEGF promoter may have opposing effects on AD risk in an APOE є4-independent manner.

Polymorphism -116C/G of human X-box-binding protein 1 promoter is associated with risk of Alzheimer's disease.

AIM: Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with endoplasmic reticulum (ER) stress response. In the response, the regulator factor human X-box-binding protein 1 (XBP1) has been shown to facilitate the refolding and degradation of misfolded proteins, prevent neurotoxicity of amyloid-beta (Aß) and tau, and play an important role in the survival of neurons. The aim in the study was to analyze the potential association between the -116C/G polymorphism of XBP1 and the risk of AD. METHODS: The association between -116C/G polymorphism of XBP1 promoter and possible risk of AD was assessed among 276 patients with AD and 254 matched healthy individuals in a case-control study. RESULTS: Overall, there was a significantly statistical difference in genotype (P = 0.0354) and allele frequencies (P = 0.0150, OR = 1.3642, 95% CI = 1.0618-1.7528) between the AD subjects and control subjects, showing that the -116C/G polymorphism of XBP1 might lead to increased susceptibility for AD in a Chinese Han population. In addition, the -116CG and -116GG genotypes were significantly associated with increased AD risk in female (P = 0.0217) and in subjects with APOE є4 (-) (P = 0.0070) in stratified analyses, and the -116CC genotype was significantly associated with fast cognitive deterioration in the AD patients (P = 0.0270). CONCLUSION: The study supports a role for the -116C/G polymorphism of XBP1 gene in the pathogenesis of AD, and further studies with a larger sample size and detailed data should be performed in other populations.

Analysis of human immunodeficiency virus type 1 Vif gene sequences among men who have sex with men in Heilongjiang province of China.

To identify the current prevalent subtypes and to study the genetic variation of HIV-1 strains in men who have sex with men (MSM) residing in Heilongjiang province, China. We analyzed the characteristics of the nucleotide sequences and the corresponding deduced protein of Vif of HIV-1 strains isolated from 17 drug-naive HIV-1-seropositive MSM. Subtypes B (7.65%) and B' (Thailand B) (11.76%), CRF07_BC (47.06%), and CRF01_AE (23.53%) were identified. Phylogenetic analysis showed that there was a close relationship between our strains and those from the same MSM population in Hebei province, which is geographically close to Heilongjiang. Most of the documented Vif functional motifs are well conserved in the majority of our analyzed sequences. Taken together, our results suggest that there might be multiple introductions of HIV in Heilongjiang MSM and frequent sexual communications with other geographically nearby MSM populations.

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, I(2) = 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 hyperuricemia.

[Relationship between maximum body mass index and type 2 diabetes mellitus among adults in Heilongjiang province.].

OBJECTIVE: To determine the prevalence and distribution of type 2 diabetes mellitus (T2DM) and the relationship between maximum body mass index (MAXBMI) and T2DM. METHODS: From June to August, 2005, a stratified cluster sampling of 1071 permanent residents in communities, over 20 years old, from 4 districts and 1 county of Mudanjiang was chosen. The prevalence of T2DM, and the association between T2DM and different levels of the MAXBMI, current BMI were studied. RESULTS: The prevalence in the communities was 7.09% and in those with past maximum BMI >/= 28 kg/m(2), it was 12.10%. With the increase of past MAXBMI levels, the risk of T2DM patients also increased significantly (trend chi(2) = 17.387 23, P < 0.0001). Data from multifactor analysis showed that MAXBMI in the past was positively related to T2DM (OR = 3.06, P = 0.0013). In T2DM patients, the group with MAXBMI >/= 27.4 kg/m(2) had higher 2-hour postprandial blood glucose than those with lower MAXBMI (P = 0.0408). When compared with low maximum BMI group in normal blood glucose population, the group with higher MAXBMI (>/= 25.4 kg/m(2)) had higher blood glucose and greater change of BMI. CONCLUSION: In both groups that patients with T2DM and with normal glucose, in order to control blood glucose better, researchers should not only concern about the influence of the MAXBMI in the past, but also pay attention to constantly keep BMI at the normal range.

Genetic polymorphisms of glutathione S-transferase T1 and bladder cancer risk: a meta-analysis.

In recent years, there have been numerous papers emphasizing the relationship between Glutathione S-transferases polymorphisms and bladder cancer risk, but the findings have not reached a consensus. The relationship between glutathione S-transferase T 1 null genotype and bladder cancer susceptibility is now even more disputable. Therefore, we present a meta-analysis of (nested) case-controlled, genotype-based studies (including 37 studies, 6,986 cases and 9,166 controls) examining this association. Using a fixed-effect model, statistically significant increase was observed between glutathione S-transferase T 1 deletion and bladder cancer risk for the overall studies (OR = 1.12; 95% confidence interval (CI): 1.04-1.21; P = 0.004 for Z test; I (2) = 47.43 for heterogeneity). After adjusting the result using trim-and-fill method, the outcome still had significant difference with little downgrade (OR = 1.10, 95% CI = 1.02-1.18). Three potential sources of heterogeneity including ethnicity, source of control and smoking status were also assessed. Minor increased correlation was found only in population-based studies (OR = 1.16; 95% CI = 1.03-1.30; I (2) = 47.16). Our analysis suggests that glutathione S-transferase T 1 null status is associated with a modest increase in the risk of bladder cancer and the difference exiting in source of control has been confirmed. Due to limited sample size, various confounding variables as well as discrepancy in study design, a valid conclusion still cannot be confirmed.

Analysis of human immunodeficiency virus type 1 nef gene sequences among inmates from prisons in China.

To provide the hard-won information on HIV-1 polymorphism from inmates in prison and to study the genetic variation of HIV-1 strains, we analyzed the characterization of the nucleotide and corresponding protein sequences of naturally occurring nef sequences derived from 16 HIV-1-positive inmates from prisons in China. Nested PCR and DNA sequencing were used to determine nef sequences in peripheral blood mononuclear cells. Phylogenetic analysis revealed a distribution of the viral sequences among subtype B, CRF_BC, and CRF_AE, with subtype B accounting for more than half of the genotypes. When compared with the consensus sequence, a certain amino acid sequence variability was observed. However, most of the described nef functional motifs were relatively well conserved in the majority of the sequences analyzed. Our results indicate that HIV-1 strains found in our study subjects may have a common origin and the description of motifs will produce important information for further studies of nef function.

Cigarette smoke extract activates PKC isoforms and down-regulates the expressions of potassium channels BK(Ca) and Kv1.5 in rat bronchial smooth muscle cells.

Large-conductance calcium-activated potassium channel (BK(Ca)) and voltage-gated potassium channel Kv1.5 play an important role in the pathogenesis of bronchial hyperresponsiveness (BHR). It is known that cigarette smoke can induce BHR, however, the role of BK(Ca) and Kv1.5 expression in it remains to be further elucidated. The purpose of the present study was to investigate the direct effects of cigarette smoke extract (CSE) on BK(Ca) and Kv1.5 expression, and the role of protein kinase C (PKC) isoforms activation in primary cultured rat bronchial smooth muscle cells (BSMCs). Primarily cultured rat BSMCs were treated with 5% CSE, the expression and translocation of PKC isoforms were measured by Western blot, and the mRNA and protein levels of BK(Ca) and Kv1.5 alpha-subunits were determined by semi-quantitative RT-PCR and Western blot, respectively. The results showed that 5% CSE induced the translocation of PKCepsilon, PKCeta, PKCtheta from soluble fraction to particulate fraction, and reduced mRNA and protein expressions of BK(Ca) and Kv1.5 alpha-subunits. The decreased expression of potassium channels was partly restored by PKC inhibitor, BIM or Goe6983. In summary, CSE may activate PKC isoforms epsilon, eta, theta, thereby down-regulate the expressions of BK(Ca) and Kv1.5 in BSMCs.

Involvement of ATP-sensitive potassium channels in proliferation and differentiation of rat preadipocytes.

This paper was aimed to investigate the effects of ATP-sensitive potassium channels on the proliferation and differentiation of rat preadipocytes. We examined the expression of sulphonylurea receptor 2 (SUR2) mRNA in preadipocytes and adipocytes obtained by inducing for 5 d and the effects of the inhibitor (glibenclamide) and opener (diazoxide) of ATP-sensitive potassium channels on the expression of SUR2 mRNA in preadipocytes by real-time PCR. Preadipocyte proliferation and cell cycle were measured by MTT spectrophotometry and flow cytometer. The content of intracellular lipid was measured by oil red O staining, cell diameter was determined by Image-Pro Plus 5.0 software and the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA was estimated by RT-PCR. SUR2 mRNA was expressed in both preadipocytes and adipocytes obtained by inducing for 5 d, and the expression in adipocytes was obviously higher than that in preadipocytes. Glibenclamide inhibited the expression of SUR2 mRNA in preadipocyte, promoted preadipocyte proliferation in a dose-dependent manner, increased the cell percentages in G(2)/M + S phase, increased lipid content, augmented adipocyte diameter, and promoted the expression of PPAR-gamma mRNA. But the actions of diazoxide were contrary to those of glibenclamide. These results suggest that ATP-sensitive potassium channels regulate the proliferation and differentiation of preadipocytes, and PPAR-gamma is probably involved in the effect of ATP-sensitive potassium channels.

[Study on the distribution and risk factors of hypertension among children: a cohort study].

OBJECTIVE: To explore the association between hypertension and the tendency of change among children,so as to lay a foundation for the prevention and control of hypertension. METHODS: Based on findings from the prevalence survey that carried out in September 1999 in Daqing of Heilongjiang province. New admission children were selected as subjects to conduct a five-year cohort study. All the subjects were interviewed with questionnaires and their blood specimens were collected for biochemical analysis. All data were analyzed using SPSS 10.0 software. Results The prevalence of hypertension among 447 children was found 2.01% at the baseline study but increased to 5.37% in the fifth year. During a five year period, the systolic pressure level among children increased from (100.65 +/- 11.62)mmHg (1 mm Hg = 0.133 kPa) to (106.67 +/- 9.29) mm Hg,while the diastolic pressure level was from (66.27 +/- 11.31) mm Hg to (70.28 +/- 7.98) mm Hg and showed significant difference between boys and girls. There were association between hypertension and family history, body mass index (BMI), triglyceride, insulin, insulin resistance index while insulin sensitivity index and family history, BMI and insulin sensitivity index appeared to be the important factors. Children under this study were divided to 'with family history or without' and then every group was divided to 'with over weight-obesity or normal'. Obesity and insulin sensitivity seemed the key risk factors on hypertension. Descent of insulin sensitivity was an independent risk factor. CONCLUSION: The level of blood tension among children in Daqing city was higher than that from the national data. The present study confirmed that over-weight,obesity, heredity and insulin resistance were the risk factors of hypertension while insulin resistance was related to hypertension. The interaction of these risk factors was independent or correlated to each other.

[Awareness on SARS and public health emergencies among general publics].

OBJECTIVE: To explore the awareness on sever acute respiratory syndrome (SARS) and public health emergencies among general publics. METHODS: A cluster sampling method was implemented in Harbin and Jiagedaqi district of Daxinanling of Heilongjiang province. Research subjects were divided into three groups as city, township and rural areas and were given questionnaires to fill in. Data was analyzed with Epi-data and SPSS. RESULTS: 2003 available questionnaires were collected. The general publics well understood the knowledge on public health emergencies and the SARS with the whole recognition rate more than 60 percent. During the epidemics, people in city, town and countryside were calm (71.7%). The rates of attitude towards the government were significantly different among the subjects living with the city, town or rural areas. The city group expressed the highest favor to the government and media, 71.8% of them gave the credit on the control of SARS to the effective method taken by the government and 65.0% of them showed that they had enough confidence on the governmental ability of dealing with crises while the countryside group trusted the hospitals and relative specialists the most. CONCLUSION: It is essential for the government to interact and communicate with the publics through media, medical and related institutions when confronting with the public health emergencies. Publicity on health knowledge and coping system on emergency should play key roles in the development of an effective public health system while the government should lead the battle.

[Effect of exercise stress on cigarette smoking induced downregulation of BKca and Kv1.5 expression in pulmonary arterial smooth muscle cells of rats].

OBJECTIVE: To investigate the effect of exercise stress on chronic cigarette smoking induced downregulation of large conductance calcium-activated potassium channel (BKca) and voltage-dependent delayed rectifier potassium channel (Kv1.5) expression in pulmonary arterial smooth muscle cells of rats. METHODS: Rats were divided into three groups: the normal control group, the smoking control group and the smoking + exercise group. The plasma cortisol level, the potassium channel expression and the pathological changes in lung tissue were determined with HE staining, the immunohistochemistry and the in-situ hybridization. RESULTS: (1) In the smoking + exercise group, the plasma cortisol level was determined immediately after exercise [(1528.7 +/- 469.7) ng/L] and was higher than that determined before exercise [(672.4 +/- 235.7) ng/L] (P < 0.01); (2) The HE staining showed that the chronic pulmonary inflammatory response in the smoking control group was severe while it was mild in the smoking + exercise group; (3) The mRNA and protein expression (OD value) of BKca in the smoking control group (mRNA: 0.2206 +/- 0.0415 for big artery and 0.3935 +/- 0.1378 for small artery; protein: 0.2634 +/- 0.1219 for big artery and 0.0995 +/- 0.0851 for small artery) were less than those in the normal control group. The mRNA expression of BKca in the smoking + exercise group (OD value) (0.5022 +/- 0.1134 for big artery and 0.6408 +/- 0.2135 for small artery) was higher than that in the smoking control group; (4) The mRNA and protein expression of Kv1.5 in the smoking control group (OD value) (mRNA: 0.9354 +/- 0.3290 for big artery and 0.5012 +/- 0.1170 for small artery; protein: 1.1112 +/- 0.3310 for big artery and 0.4736 +/- 0.1250 for small artery) were less than those in the normal control group. The protein expression of Kv1.5 in the smoking + exercise group (0.7445 +/- 0.2690) in small artery was higher than that in the smoking control group. CONCLUSION: Proper exercise stress can decrease inhibition effect of the chronic smoking on the expression of potassium channel BKca and Kv1.5, which perhaps partly results from exercise induced increase of cortisol secretion.

Passive sensitization increases histamine-stimulated calcium signaling and NF-kappaB transcription activity in bronchial epithelial cells.

AIM: To find out if the two aspects of asthma (chronic airway inflammation and bronchial hyperresponsiveness) are related to hypersensitivity of calcium signaling in bronchial epithelial cells. METHODS: Porcine bronchial epithelial cells (PBEC) were divided into sensitized (S) and non-sensitized (N) groups. In group S, the cells were preincubated with serum from ovalbumin sensitized guinea pigs. In group N, the cells were preincubated with serum from nonsensitized guinea pigs. Single cell calcium imaging and ELISA-based NF-kappaB activity were used to evaluate the histamine-stimulated intracellular free calcium level and NF-kappaB activity, respectively. RESULTS: First, 0.1 micromol/L histamine could induce [Ca(2+)](i) oscillations in PBEC of group S, but not in group N. Second, 1 micromol/L histamine could induce [Ca(2+)](i) oscillations of PBEC in both group S and group N. The [Ca(2+)](i) oscillation frequency of PBEC was significantly higher in group S than in group N, though the [Ca(2+)](i) oscillation amplitude showed no difference between the two groups. Finally, when 10 micromol/L histamine was used to stimulate PBEC, a transient initial increase followed by a sustained elevation (FSE) of [Ca(2+)](i) was observed in PBEC in both groups. The amplitude of the FSE of [Ca(2+)](i) in PBEC was significantly higher in group S than in group N. The subsequent NF-kappaB activity was in accordance to the calcium oscillation frequency evoked by histamine, but not to the amplitude. CONCLUSION: It was suggested that the increased sensitivity of calcium signaling in bronchial epithelial cells might contribute to the exorbitant inflammation or increased susceptibility in asthmatic airway epithelial cells.

Role of histamine in airway remodeling of asthmatic guinea pig.

To investigate the role of histamine in airway remodeling, 50 healthy guinea pigs were divided into 5 groups: control group: nebulized inhalation of distilled water for 8 weeks; asthma model group: nebulized inhalation of ovalbumin (OVA) for 8 weeks after sensitization; continued asthma model group: nebulized inhalation of OVA for 14 weeks after sensitization; histamine group: nebulized inhalation of OVA for 14 weeks after sensitization and histamine was added in the last 6 weeks; antagonist group: nebulized inhalation of OVA for 14 weeks after sensitization and histamine receptor antagonists were added in the last 6 weeks. For each group, the concentration of histamine, sodium ion (Na(+)), chlorine ion (Cl(-)), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), pH, actual bicarbonate (AB), standard bicarbonate (SB) in serum, and thickness of airway mucosa, base membrane and smooth muscle were measured and compared with each other. The results showed that: (1) the concentration of histamine in serum and the thickness of airway increased, the following order was, the control group, the asthma model group, the continued asthma model group and histamine group (P<0.01); and the concentration of histamine in serum and the thickness of airway of antagonist group was lower than that of the continued asthma model group (P<0.05, 0.01). (2) PaO2 of the asthma model group was lower than that of the normal control group (P<0.01); PaO2, pH, AB, SB decreased, the following order was, the asthma model group, the continued asthma model group and the histamine group (P<0.01); and PaO2, pH, AB, SB of the antagonist group was higher than that of the continued asthma model group (P<0.01); but for PaCO2, the order was converse (P<0.01); For the concentration of Na(+) and Cl(-) in serum, there was no difference among these groups. It is concluded that: (1) Histamine is one of the mediators in the airway remodeling of asthma. (2) Histamine receptor antagonists may play a role in preventing and treating airway remodeling. (3) There is a negative correlation between the PaO2, pH and the wall thickness of the airway (P<0.01), while a positive correlation between the PaCO2, anion gap (AG) and the wall thickness of the airway (P<0.01).

Effect of chronic cigarette smoking on large-conductance calcium-activated potassium channel and Kv1.5 expression in bronchial smooth muscle cells of rats.

To investigate the role of potassium channels in the pathogenesis of airway hyperresponsiveness induced by cigarette smoking, the alteration in expression of large-conductance calcium-activated potassium channel (BKca) and voltage-dependent delayed rectifier potassium channel (Kv1.5) in bronchial smooth muscle cells were investigated in chronic cigarette smoking rats. Airway responsiveness was determined, hematoxylin and eosin staining, immuno-histochemistry, in-situ hybridization and western blot techniques were used. The results showed: (1) Chronic cigarette smoking down-regulated the protein synthesis and mRNA expression of BKca and Kv1.5 in bronchial and bronchiolar smooth muscles. (2) BKca decreased more markedly than Kv1.5 in bronchi, but there was no difference between them in bronchioli. (3) No changes in the expression of these two potassium channel proteins were found in extracted cell membrane protein from lung tissue. The results suggest that chronic cigarette smoking can down-regulate the levels of BKca and Kv1.5 in rat bronchial smooth muscle cells in vivo, which might contribute to the mechanism of airway hyperresponsiveness induced by cigarette smoking.