Effect of genistein on the activities of cytochrome P450 3A and P-glycoprotein in Chinese healthy participants.

To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration. Co-administration of genistein decreased the area under the concentration-time curve from 0 to 36 h (AUC 0-36) (143.65 ± 55.40 ng h/mL versus 126.10 ± 40.14 ng h/mL, p < 0.05), and the area under the concentration-time curve from zero to infinity (AUC 0-∞) (209.18 ± 56.61 ng h/mL versus 180.59 ± 43.03 ng h/mL, p < 0.05), and also maximum concentration (Cmax) of midazolam (48.86 ± 20.21 ng/mL versus 36.25 ± 14.35 ng/mL p < 0.05). Similarly, AUC 0-36 (2490.282 ± 668.79 ng h/mL versus 2114.46 ± 861.11 ng h/mL, p < 0.05), AUC 0-∞ (2980.45 ± 921.09 ng h/mL versus 2626.92 ± 1003.78 ng h/mL, p < 0.05) and Cmax of talinolol (326.58 ± 197.67 ng/mL versus 293.42 ± 127.19 ng/mL, p < 0.05) were reduced by genistein co-administration. The oral clearance of midazolam (1.68 ± 0.85 h-1 versus 3.98 ± 0.59 h-1, p < 0.05) and talinolol (3.34 ± 1.24 h-1 versus 3.79 ± 1.55 h-1, p<0.05) were increased by genistien significantly. Administration of genistein can result in a modest induction of CYP3A and possibly P-gp activity in healthy volunteers.

Soluble CD86 protein in serum samples of patients with asthma.

BACKGROUND: Previous studies have reported that soluble (s) CD86 is involved in the initiation of the immune response. A study was undertaken to investigate the concentrations of sCD86 in serum samples from patients with bronchial asthma and to determine the cell origin of sCD86. METHODS: Serum sCD86 concentrations were measured in 52 asthmatic subjects and 25 non-atopic normal volunteers using an enzyme linked immunosorbent assay, and the relationship of serum sCD86 concentrations to asthma severity and to total and differential white cell counts was analysed. Each type of white blood cell was purified and cultured in vitro to determine the cell origin of serum sCD86. RESULTS: Serum samples from patients with an acute asthma exacerbation had much higher levels of sCD86 (585.4 (20.5) IU/ml) than those from stable asthmatics (479.6 (15.7) IU/ml, p<0.001) and healthy individuals (435.1 (13.8) IU/ml, p<0.001), and there was no difference between the latter two groups (p = 0.079). In asthmatic subjects the serum sCD86 level was inversely correlated with airway responsiveness, forced expiratory volume in 1 second, and with arterial carbon dioxide tension. In addition, the serum sCD86 level was positively correlated with numbers of lymphocytes, eosinophils, monocytes, but not neutrophils. The in vitro experiments indicated that sCD86 was produced by monocytes. CONCLUSIONS: The serum sCD86 protein level was significantly increased in asthmatic subjects during an exacerbation and correlated with the severity of asthma. sCD86 is most probably derived from monocytes in the peripheral blood.

Endobronchial eosinophils preferentially stimulate T helper cell type 2 responses.

BACKGROUND: Antigen-loaded eosinophils instilled intratracheally into mice were capable of migrating into local lymph nodes and localize to the T cell-rich paracortical zones where they stimulated antigen-specific proliferation of CD4+ T cells. The aim of the present study was to evaluate whether eosinophils within the tracheobronchial lumen can stimulate Th2 cell expansion by presenting antigen both in vitro and in vivo. METHODS: Airway eosinophils were recovered from ovalbumin-sensitized and -challenged BALB/c mice, these eosinophils were then co-cultured with sensitized CD4+ cells in the absence or presence of anti-CD80 or/and -CD86 monoclonal antibodies. Airway eosinophils were instilled into the trachea of sensitized mice. At 3 days thereafter, the draining paratracheal lymph nodes were removed and teased into cell suspensions for culture. Cell-free culture supernatants were collected for detection of cytokines. RESULTS: Our data showed that airway eosinophils functioned as CD80- and CD86-dependent antigen-presenting cells (APCs) to stimulate sensitized CD4+ lymphocytes to produce interleukin (IL)-4, IL-5, and IL-13, but not interferon (IFN)-gamma in in vitro assay. When instilled intratracheally in sensitized recipient mice, airway eosinophils migrated into draining paratracheal lymph nodes primed Th2 cells in vivo for IL-4, IL-5, and IL-13, but not IFN-gamma, production during the in vitro culture that was also CD80- and CD86-dependent. CONCLUSION: Eosinophils within the lumina of airways could process inhaled antigen function in vitro and in vivo as APCs to promote expansion of Th2 cells. This investigation highlights the potential of eosinophils to not only act as terminal effector cells but also to actively modulate immune responses by amplifying Th2 cell responses.

Effect of inhaled interleukin-4 on airway hyperreactivity in asthmatics.

lnterleukin-4 (IL-4) has been shown to play a crucial role in the pathogenesis of allergic disease including bronchial asthma. In order to investigate the role of IL-4 in airway hyperreactivity, we investigated the effect of inhaled recombinant human IL-4 on airway responsiveness to methacholine and eosinophil numbers in induced sputum in eight patients with allergic asthma using a placebo-controlled study design. Our results demonstrated that in the control experiments receiving vehicle inhalation, methacholine PC20 values did not change nor did the numbers of eosinophils in sputum change from baseline values. In contrast, after IL-4 inhalation, methacholine PC20 fell from baseline (0.43 +/- 1.81 mg/mI) to 0.22 +/- 1.73 mg/mI (p < 0.01) at 24 h, and to 0.21 +/- 1. 74 mg/ml (p < 0.01) at 48 h. Accompanying this increased airway sensitivity was a significant eosinophilia in sputum. Our data indicated that IL-4 increases airway responsiveness by recruiting eosinophils into the airway in patients with allergic bronchial asthma.

Effect of inhaled interleukin-5 on airway hyperreactivity and eosinophilia in asthmatics.

In order to investigate the role of interleukin-5 (IL-5) in airway hyperreactivity and eosinophilia, we observed the effect of inhaled recombinant human IL-5 on airway responsiveness to methacholine and cell populations in induced sputum in eight patients with allergic bronchial asthma using a placebo-controlled study design. Our results demonstrated that the inhalation of IL-5 did not alter lung function in allergic asthmatics. In the control experiments receiving either vehicle or 0.4 ng of endotoxin, methacholine PC20 values did not change nor did the numbers of eosinophils or eosinophil cationic protein (ECP) sputum values change from baseline. In contrast, after IL-5 inhalation, methacholine PC20 fell from baseline (0.90 +/- 166 mg/ml) to 0.32 +/- 1.63 mg/ml (p < 0.01) at 24 h, and to 0.55 +/- 1.49 mg/ml (p < 0.05) at 48 h. Accompanying this increased airway sensitivity was a significant eosinophilia and elevated concentrations of ECP in induced sputum. Our data provided direct evidence that IL-5 increases airway responsiveness and infiltration of activated eosinophils into the airway in patients with allergic bronchial asthma. It also could be concluded that the observed airway hyperreactivity and eosinophilia were not endotoxin related.

[Effect of ligustrazine on plasma lipid peroxidation, superoxide dismutase of the coronary heart disease].

A clinical study on 59 remote myocardial infarction cases were divided randomly into treated group (31 cases) and normal control group (28 cases). Treated group used intravenously injected Ligustrazine 160 mg a day for 10 days. The plasma lipid peroxidation (LPO), superoxide dismutase (SOD) and sulfhydryl group were measured before and after treatment in the treated group, in comparing with normal control group. The results showed the levels of LPO significantly reduced (P < 0.01), and SOD, sulfhydryl group was obviously increased after Ligustrazine administration (P < 0.05). Attack of angina pectoris was reduced. Between these two group, the difference was significant (P < 0.05). Mechanism of Ligustrazine in reducing LPO and increasing SOD could be the inhibiting of platelet aggregation, regulating the TXA2/PGI2 ratio in plasma, protecting myocardial cell membrane and improving the myocardial ischemia. Ligustrazine could reduce the production of LPO due to the accelerating clearance of oxygen free radical.