Effect of antibiotic-administration period on hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver,kidney, and brain capillaries

Antibiotic administration affects pharmacokinetics through changes in the intestinal microbiota, and bile acids are involved in this regulation. The purpose of the present study was to clarify the effect of different periods of antibiotic administration on the hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries. Vancomycin and polymyxin B were orally administered to mice for either 5- or 25-days. The hepatic bile acid profile of the 25-day treatment group was distinct. In the liver, the protein expression of cytochrome P450 (Cyp)3a11 showed the greatest reduction to 11.4% after the 5-day treatment and further reduced to 7.01% after the 25-day treatment. Similar reductions were observed for sulfotransferase 1d1, Cyp2b10, carboxylesterase 2e, UDP-glucuronosyltransferase (Ugt)1a5, and Ugt1a9. In the kidney and brain capillaries, no drug-metabolizing enzymes or drug transporters were changed with >1.5-fold or <0.66-fold statistical significance in either period. These results suggest that bile acids and metabolizing enzymes in the liver are affected in a period-dependent manner by antibiotic treatment, while the blood-brain barrier and kidneys are less affected. Drug-drug interactions of antibiotics via the intestinal microbiota should be considered by changing drug metabolism in the liver.     

Influence of circadian rhythm on mortality after myocardial infarction: data from a prospective cohort of emergency calls

Myocardial infarction (MI) occurs more frequently in the morning as a result of the concomitant unfavorable timing of several physiological parameters and/or biochemical conditions. However, little is known about the possible influence of this circadian pattern on prognosis. To evaluate whether the time of symptom onset could potentially influence mortality from acute MI, this prospective study considered all consecutive MIs admitted to the ED of Ferrara, Italy, after a call to the Emergency Coordinating Unit from January 1, 1998, to December 31, 2001. The total sample consisted of 442 MIs (mean age, 68.7 years; males, 72%). Eighty patients (males, 82.5%) died in the ED; the remaining 362 were admitted to the hospital. Of these, 50 (males, 60%) died during their hospital stay. Based on the timing of their symptom onset, cases were categorized both into 24 1-hour intervals and four 6-hour intervals (midnight to 5:59 am, 6:00 am to 11:59 am, noon to 5:59 pm, and 6:00 pm to 11:59 pm), and the circadian distributions of fatal versus nonfatal MIs were compared. The circadian variation of MI peaked between 6:00 am and noon (P < .001), and in this period, there was a trend toward a higher frequency of fatal cases (41.5% vs. 35.2%; chi(2) = 1.911, P = .167). To verify whether this higher frequency of fatal events in the morning hours could be related to possible higher severity of cases observed in that hours, a further separate analysis considering age, infarct site, and peak levels of MB was made. Again, no significant temporal differences among the four 6-hour intervals were found between fatal and nonfatal Mis, although a trend toward older age was observed in morning MIs. Not only the frequency, but also the mortality, of acute MI could be increased in the morning hours. This could be of practical interest for emergency doctors and could have significant implications for acute treatment, because several studies have reported a lowered efficacy of thrombolytic drugs in the morning hours.     

炎琥宁注射液联合双歧三联活菌胶囊对小儿轮状病毒性肠炎心肌酶谱的影响

目的：探讨炎琥宁注射液联合双歧三联活菌胶囊对小儿轮状病毒性肠炎(rotavirus enteritis, RVE)患儿心肌酶谱的影响。方法将符合入选标准的146例RVE患儿采用随机数字表法分为2组,每组73例。对照组在常规治疗基础上服用双歧杆菌三联活菌胶囊;观察组在对照组基础上加用炎琥宁注射液。2组均治疗5 d。采用ELISA法检测血清IL-17、IL-6、TNF-?、LDH、肌酸激酶(creatine kinase, CK)和CKMB,评价临床疗效。结果治疗后,观察组血清IL-17[(22.35±4.21)ng/ml比(30.24±6.07)ng/ml, t＝2.395]、IL-6[(31.26±6.14)ng/ml 比(43.72±8.22)ng/ml,t＝2.347]、TNF-?[(35.62±6.24)ng/ml 比(49.18±8.72)ng/ml,t＝2.421]水平,以及血清 LDH[(135.16±31.25)U/L 比(174.08±40.22)U/L,t＝2.373]、CK[(37.82±7.39)U/L 比(50.21±11.16)U/L , t＝2.385]、CKMB[(90.14±11.63)U/L 比(113.22±18.35)U/L , t＝2.392]水平均低于对照组(P＜0.05)。观察组总有效率为94.5%(69/73)、对照组为83.6%(61/73),2组比较差异有统计学意义(χ2＝2.352,P＝0.047)。结论炎琥宁注射液联合双歧三联活菌胶囊可降低RVE患儿炎症因子水平,减轻心肌损伤,提高临床疗效。     

lncRNA-MALAT1/miRNA-145在舒芬太尼预处理减轻大鼠心肌缺血-再灌注损伤中的作用

目的探讨长链非编码RNA(lncRNA)肺腺癌转录子1(MALAT1)在舒芬太尼预处理减轻大鼠心肌缺血-再灌注损伤(MIRI)中的作用。方法 SPF级大鼠36只,体重180~200 g,随机分为三组:假手术组(Sham组),缺血-再灌注损伤组(IR组),缺血-再灌注损伤+舒芬太尼组(SUF组),每组12只。IR组和SUF组建立大鼠心肌缺血-再灌注损伤模型,SUF组于再灌注前10 min尾静脉注射舒芬太尼1μg/kg,Sham组和IR组注射等体积生理盐水。再灌注后2 h检测大鼠血清中肌酸激酶同工酶MB(CK-MB)、心肌肌钙蛋白T(cTnT)和乳酸脱氢酶(LDH)活性,同时检测大鼠心肌梗死面积;检测心肌细胞凋亡相关蛋白Bcl-2、Bax、Cleaved-caspase-3和Caspase-3含量;检测大鼠心肌组织中lncRNA-MALAT1和miRNA-145的相对表达量。结果与Sham组比较,IR组和SUF组CK-MB和cTnT浓度明显升高,LDH活性明显增强,心肌梗死面积明显增大,心肌组织中Bax/Bcl-2比值明显降低,Cleaved-caspase-3蛋白含量明显升高,lncRNA-MALAT1相对表达量明显升高,而miRNA-145相对表达量明显降低(P<0.05)。与IR组比较,SUF组CK-MB和cTnT浓度明显降低,LDH活性明显减弱,心肌梗死面积明显减小,Bax/Bcl-2比值明显升高,Cleaved-caspase-3蛋白含量明显降低,lncRNA-MALAT1相对表达量明显降低,miRNA-145相对表达量明显增加(P<0.05)。结论舒芬太尼预处理能减轻大鼠心肌缺血-再灌注损伤程度,其机制可能与抑制lncRNA-MALAT1、升高miRNA-145表达有关。     

Identification of phenolic constituents and antioxidant activity of Aloe barbadensis flower extracts

Aloe vera (Aloe barbadensis Miller) has been used as topical and oral therapeutic. This research highlights the phenolic constituents’ profile and antioxidant activity of 70% ethanol extracts of Aloe vera flower for the first time. The ethanol-based extracts showed the inhibition for linoleic acid oxidation and free radical-induced DNA damage. Among about 11 phenolic constituents of the extract, identified by using high performance liquid chromatography (HPLC), the content of vanillic acid was highest, corresponding to strong antioxidant activities of the extract. The extracts elevated superoxide dismutase, catalase, and glutathione peroxidase enzymes activities in the liver tissue of hydrogen peroxide-treated BALB/c mice. The radical-scavenging activities of the extracts were well-correlated to the total phenolic content. Therefore, Aloe bardadensis flower might be an effective source of natural antioxidant.     

bFGF通过促进心脏血管新生改善心肌梗死后小鼠心脏重构

目的:探讨碱性成纤维细胞生长因子(basic fibroblast growth factor,b FGF)对心肌梗死小鼠心脏的保护作用及机制。方法:采用异氟烷麻醉C57/B6小鼠(8~12周龄)后,侧开胸结扎冠状动脉左前降支,建立小鼠心肌梗死模型;设立假手术组为对照,心肌梗死模型小鼠随机分为心梗组和bFGF给药组,其中bFGF组小鼠心梗7d后给予5μg b FGF隔天腹腔注射给药;在小鼠心梗第28天时采用心脏多普勒超声检测心功能,以左室舒张末期内径、左室收缩末期内径、左心室射血分数和左心室短轴缩短分数评价心脏功能改变;28 d后处死小鼠,行病理切片观察心肌纤维化程度和心肌梗死区内血管新生的情况;Western blot检测血管新生指标。结果:bFGF给药组小鼠心肌纤维化程度较心梗模型组明显减少;第28天行超声心动图检查结果示,心梗组小鼠心功能较假手术组差,而bFGF给药组小鼠心功能与心梗组比较有明显的改善;小鼠心肌病理切片免疫荧光观察结果发现,bFGF给药组心肌梗死区的新生血管比心梗组明显增多;Western blot实验表明,bFGF能够激活AKT/HIF-1α/VEGF通路。结论:隔天腹腔注射bFGF能够减少心肌梗死小鼠心肌纤维化,改善心功能。bFGF可能通过AKT/HIF-1α/VEGF信号通路促进血管新生,从而保护心脏。     

Zacopride对血管紧张素Ⅱ诱发的心肌纤维化的影响

目的:研究内向整流钾通道(IK1)激动剂扎考必利(zacopride,Zac)对血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)诱导的心脏成纤维细胞(cardiac fibroblasts,CFb)细胞活力和凋亡的影响,探讨其抑制心肌纤维化的机制。方法:以组织块消化和差速贴壁法原代分离培养SD乳鼠心室成纤维细胞,用AngⅡ诱导细胞建立细胞活化模型。将分离培养的CFb随机分为空白对照组、AngⅡ模型组、Zac干预组、Zac+Ba Cl2干预组、Zac+氯喹干预组和AngⅡ+卡托普利阳性对照组。CCK-8法检测Zac对CFb活力的影响;ELISA法测定CFb上清液中Ⅰ、Ⅲ型胶原含量;流式细胞术检测细胞凋亡率;Western blot检测心肌内向整流钾通道蛋白Kir2.1表达的变化。结果:与空白对照组比较,AngⅡ模型组CFb活力及胶原合成显著增加,Kir2.1的表达降低(P0.05);与AngⅡ模型组比较,Zac干预组CFb活力及胶原合成显著降低,凋亡率显著升高,Kir2.1的表达明显上调(P0.05);IK1阻断剂Ba Cl2和氯喹可阻断Zac对IK1通道的激动效应,明显逆转Zac的抗心肌纤维化作用。结论:Zac可明显抑制AngⅡ诱发的心肌纤维化,其机制可能与激动心肌内向整流钾通道,进而抑制成纤维细胞活力并诱导其凋亡有关。     

右侧颈交感干离断对大鼠心肌梗死后炎症反应的抑制作用及对HMGB1/TLR4/NF-κB通路的影响

目的:观察右侧颈交感干离断(TCST)对大鼠心肌梗死后炎症反应的抑制作用及高迁移率族蛋白B1(HMGB1)的表达和TLR4/NF-κB信号通路的影响。方法:结扎左冠状动脉前降支制备急性心肌梗死(acute myocardial infarction,AMI)模型,将造模成功的大鼠随机分为心肌梗死(MI)组和心肌梗死+右侧颈交感干离断(MI+TCST)组,MI+TCST组在左冠状动脉前降支结扎后立即离断右侧颈交感神经干。MI组和MI+TCST组分别按模型制备及干预后1、3、7、14和28 d分为5个亚组,另设假手术(sham)组,只穿线不结扎,每组8只。建模后4周,超声心动图检测大鼠心脏功能,然后处死大鼠,取心脏计算心脏肥厚指数,并取梗死周围心肌组织采用HE染色观察心肌病理形态改变。Real-time PCR法检测不同时点梗死边缘区HMGB1、肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)的m RNA表达。Western blot分析MI后不同时点梗死边缘区HMGB1和TLR4蛋白的表达变化,并进一步分析右侧TCST对HMGB1和TLR4/NF-κB信号通路蛋白表达的影响。结果:与MI组比较,MI+TCST组左心室射血分数(LVEF)和左心室短轴缩短分数(LVFS)显著升高(P0.05),左心室舒张末期内径(LVEDd)、左心室收缩末期内径(LVESd)和心脏肥厚指数显著降低(P0.05),梗死边缘区各时点HMGB1、TNF-α和IL-6的m RNA表达水平显著降低(P0.05)。Western blot检测结果显示,与sham组比较,HMGB1蛋白的表达在MI后3 d开始升高,并于7 d达到高峰,之后逐渐下降,28 d时仍明显高于假手术组(P0.05);TLR4蛋白的表达变化与HMGB1一致。进一步研究发现右侧TCST可显著降低心肌组织HMGB1和TLR4/NF-κB信号通路蛋白的表达(P0.05)。结论:右侧颈交感干离断可改善MI后心室重构,发挥保护心功能的作用,其机制可能与其抑制HMGB1/TLR4/NF-κB信号通路,减轻炎症反应有关。     

Human phagocytic cell response to histamine derived from potential probiotic strains of Lactobacillus reuteri

Histamine derived from lactobacilli isolates is considered to be a potential immunomodulator able to interact with the host immune system. We tested the effect of pure histamine (0.413?mM) together with the effect of cell-culture supernatants (CCS) containing different concentration of histamine produced by two of Lactobacillus reuteri isolates on the activities of antioxidant enzyme, as well as on the phagocytic activity of human leucocytes (HL). Phagocytic activity represents the non-specific immune response of HL homogenate, in vitro. Analysed histamine-producers were represented by a goatling isolate named L. reuteri KO5 and a lamb isolate named L. reuteri E and histamine production was determined using HPLC method connected with UV detection. Concretely, the samples contained the mixture of isolated HL and the addition of lactobacilli CCS at three different final concentrations of histamine ～ 0.1, 1.8 and 5.4?mM. It was found that pure histamine (0.413?mM) did not significantly influence the oxidant-antioxidant balance in HL demonstrated by unchanged degree of HL lipid peroxidation. However, at the same time, the final activity of catalase and superoxide dismutase were significantly changed (p?≤?0.001).Moreover, the phagocytic index (p?≤?0.01), lysozyme (p?≤?0.05) and peroxidase activity (p?≤?0.001), and production of IL-1β significantly decreased. CCS containing different concentration of produced histamine were also able to modulate the host non-specific immune response together with the enzymatic activity of SOD and catalase too. However, our findings indicated that the impact of lactobacilli histamine is strictly strain-dependent and concentration dependent. Moreover, it seems that histamine is not the only one lactobacilli metabolite, which may play an important role in overall immunomodulatory and antioxidant potential of tested lactobacilli.     

着丝粒蛋白A在大鼠心脏的表达及增龄变化

目的 探讨着丝粒蛋白A（CENP-A）在大鼠心脏中的表达部位及增龄变化。方法 取新生1 d、1周龄、2周龄、3周龄、4周龄、3月龄、6月龄大鼠各10只,采用免疫组织化学、免疫荧光、Western blotting、Real-time PCR技术,观察心脏不同部位CENP-A的分布和增龄变化;利用图像分析系统对CENP-A进行定量分析,并对不同年龄组心脏CENP-A含量进行对比。结果 大鼠心脏中CENP-A的表达主要分布在血管壁、心外膜及外膜下组织。随着年龄增长血管壁中CENP-A表达基本稳定,心外膜及外膜下组织中CENP-A表达逐渐减少,新生1 d表达最多,3月龄、6月龄明显减少。血管壁中CENP-A主要是在平滑肌细胞表达,且各年龄段表达基本不变。在靠近心外膜的组织中也有少量心肌细胞表达,且随增龄变化而减少。结论 大鼠心脏CENP-A的表达随增龄变化逐渐减少,血管壁CENP-A的表达稳定不变。