Age-related changes in oxidative DNA damage and benzo(a)pyrene diolepoxide-I (BPDE-I)-DNA adduct levels in human stomach

This study was conducted in order to obtain information on the association between age and oxidative DNA damage and benzo[a]pyrene diolepoxide-I (BPDE-I)-DNA adduct levels in the stomach tissues of normal subjects (n = 113). Subjects ranged from 17 to 75 yr. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, were measured by high-performance liquid chromatography-electrochemical detector (HPLC-ECD). BPDE-I-DNA adduct levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA) using the monoclonal antibody 8E11. Increase in 8-OHdG levels was observed in subjects from 31 to 60 yr of age. Higher levels of 8-OHdG were observed in the stomach tissues of those in the 51-60 yr old group. Although Helicobacter. Pylori-positive group subjects had higher 8-OHdG levels than those in the H. pylori-negative group, no age-related changes in 8-OHdG levels were observed in these groups. The levels of BPDE-I-DNA adduct also markedly increased with age. Higher levels of BPDE-I-DNA adduct were observed in subjects aged 61-70 yr, but this difference was not significant from other age groups. These results provide evidence that there is a progressive age-dependent accumulation of oxidative DNA damage and of BPDE-I-DNA adducts in human stomach tissues. It is possible that such damage contributes to the known increased incidence of gastric tumor with aging.     

Chemopreventive effects of aloe against genotoxicity induced by benzo[a]pyrene

Chemopreventive effects of aloe against benzo[a]pyrene (BaP) mutagenicity were investigated in the Salmonella typhimurium bacterial mutation assay, the chromosome aberration assay using Chinese hamster ovary (CHO) cells, and the mouse micronuclei test using bone-marrow cells. In the bacterial assay, aloe produced a concentration-dependent decrease in the number of mutant colonies induced by BaP. The chromosome-damaging responses of BaP in CHO cells were abolished by treatment with aloe, approximately to the level seen in control. In the in vivo mouse bone-marrow micronuclei test, pretreatment of aloe 24 h prior to BaP treatment reduced the frequency of micronucleated polychromatic erythrocytes. In the cells of CHO and bone marrow treated with aloe, glutathione (GSH) levels were shown to be higher and extracellular discharge rate increased as incubation time with aloe rose. MDR1 and MRP2 gene were more expressed in Hepa c cells than in NTCC cells, but there was no change in BCRP gene expression. The antimutagenic effects of aloe were statistically significant and concentration dependent. These results demonstrated that aloe might exert chemopreventive effects against BaP-induced mutagenicity.     

Pharmacological action ofPanax Ginseng on the behavioral toxicities induced by psychotropic agents

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.     

Antidiabetic stilbene and anthraquinone derivatives fromRheum undulatum

The antidiabetic-activity-guided fractionation and isolation of the 80% EtOH extracts obtained from cultivated Korean Rhubarb rhizomes (Rheum undulatum, Polygonaceae) led to the isolation and characterization of one stilbene, desoxyrhapontigenin (1) and two anthraquinones, emodin (2) and chrysophanol (3). Their structures were established by chemical and spectroscopic methods. Compounds 1, 2, and 3 inhibited postprandial hyperglycemia by 35.8, 29.5, 42.3%, respectively.     

冠心病与雄性激素的相关性

目的 探讨老年男性冠心病与内生性血浆睾酮及其它相关因素的关系.方法 选择ACS男性患者28例、稳定型心绞痛（SAP）男性患者28例、男性健康体检者28例为对照组.分别对三组人员进行颈动脉多普勒检查,并检查外周血睾酮（T）浓度及血脂（TC、LDL-C）、血糖（Glu）、CRP等相关指标,计算BMI.结果 ACS组、SAP组外周血T、TC、LDL-C、Glu等均显著高于对照组（P＜0.05）,冠心病患者（包括ACS、SAP）较对照组颈动脉中内膜厚度（IMT）、斑块个数等差异有统计学意义（P＜0.05）.ACS组与SAP组比较：外周血T、Tc、LDL-C、CRP的浓度及BMI、IMT、不稳定斑块差异均有统计学意义（P＜0.05）.ACS组与SAP组比较外周血Glu及硬斑例数差异无统计学意义（P＞0.05）.结论 老年男性冠心病患者T浓度与动脉粥样硬化、不稳定斑块、Tc、LDL-C、BMI呈负相关.     

Effects of inflammatory cytokine gene polymorphisms on warfarin maintenance doses in Korean patients with mechanical cardiac valves

Cytokines that are involved in inflammation are related to blood coagulation, which could indirectly affect warfarin dose requirements. This study aimed to examine the effects of inflammatory cytokine gene polymorphisms on warfarin dose requirements for Korean patients with mechanical heart valves. In total, 191 patients with mechanical heart valves who were on warfarin anticoagulation therapy and maintained INR levels of 2–3 for three consecutive occasions were retrospectively followed up. In addition to vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 polymorphisms, the interferon-γ, interleukin-1β (IL1B), interleukin-6, interleukin-10, transforming growth factor-β1 (TGFB1), tumor necrosis factor-α, and C-reactive protein genotypes were determined. The predictive contribution of age, VKORC1, and CYP2C9 to variability was 46.0 %. The addition of IL1B and TGFB1 polymorphisms increased the R ² to 48.8 % for stable dose requirements, and significantly higher doses were found, especially when the TGFB1 CC genotype was combined with the IL1B TT genotype. Based on the results, it was concluded that inflammatory cytokine genes, such as TGFB1 and IL1B, can be predictive variables for stable warfarin doses in Korean patients.     

The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory

Rationale

The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.

Objectives

To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D₂ receptor occupancy and changes in working memory.

Methods

Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [¹¹C]raclopride and [¹⁸?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [¹⁸?F]FDG scan.

Results

The mean (±SD) D₂ receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D₂ receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.

Conclusions

Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D₂ receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects.     

曲美他嗪对大鼠心力衰竭模型心功能及神经激素的影响

目的 探讨盐酸曲美他嗪对慢性心力衰竭(CHF)大鼠模型心功能和神经激素的影响.方法 腹主动脉缩窄法制备SD大鼠心衰模型,心脏超声测定室间隔(IVS)及左室后壁(LVPW)厚度、左室舒张末期内径(LVD)和收缩末期内径(LVS)、左室射血分数(LVEF)和短轴缩短率(FS);观察心肌细胞病理变化;Real-Time PCR定量测定神经激素尿钠肽(BNP)、C型心钠肽受体(NPRC)、心钠肽(ANP)、肌球蛋白重链(β-MHC)、血管紧张素1(AT1);免疫组化测定超氧化物歧化酶(SOD).结果 曲美他嗪高剂量组和模型组比较,IVS、LVPW、LVS、LVD分别为(0.63 ±0.05)mm、(0.73 ±0.06) mm、(0.73±0.05) nn、(0.87±0.06) mm和(1.07 ±0.06)mm、(1.13±0.06)mm、(0.93±0.06) mm、(1.33 ±0.06)mm(P ＜0.05);LVEF、FS分别为(27.75±1.83)％、(11.44±0.76)％和(11.78±0.56)％、(4.27±0.22)％(P＜0.01);心肌细胞结构明显改善;B NP、ANP、NPRC、ATI、β-MHC表达下降,SOD表达升高.结论 曲美他嗪能改善大鼠心衰模型神经激素的分泌,改善心功能.     

Differential regulation of observational fear and neural oscillations by serotonin and dopamine in the mouse anterior cingulate cortex

Rationale

The aberrant regulation of serotonin (5-HT) and dopamine (DA) in the brain has been implicated in neuropsychiatric disorders associated with marked impairments in empathy, such as schizophrenia and autism. Many psychiatric drugs bind to both types of receptors, and the anterior cingulate cortex (ACC) is known to be centrally involved with empathy. However, the relationship between the 5-HT/DA system in the ACC and empathic behavior is not yet well known.

Objectives

We investigated the role of 5-HT/DA in empathy-like behavior and in the regulation of ACC neural activity.

Methods

An observational fear learning task was conducted following microinjections of 5-HT, DA, 5-HT and DA, methysergide (5-HT receptor antagonist), SCH-23390 (DA D₁ receptor antagonist), or haloperidol (DA D₂ receptor antagonist) into the mouse ACC. The ACC neural activity influenced by 5-HT and DA was electrophysiologically characterized in vitro and in vivo.

Results

The microinjection of haloperidol, but not methysergide or SCH-23390, decreased the fear response of observing mice. The administration of 5-HT and 5-HT and DA together, but not DA alone, reduced the freezing response of observing mice. 5-HT enhanced delta-band activity and reduced alpha- and gamma-band activities in the ACC, whereas DA reduced only alpha-band activity. Based on entropy, reduced complexity of ACC neural activity was observed with 5-HT treatment.

Conclusions

The current results demonstrated that DA D₂ receptors in the ACC are required for observational fear learning, whereas increased 5-HT levels disrupt observational fear and alter the regularity of ACC neural oscillations.