Synthesis,Anti‐MRSA,and Anti‐VRE Activity of Hemin Conjugates with Amino Acids and Branched Peptides

The increasing prevalence of antibiotic‐resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram‐positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides. Arginine‐containing hemin conjugates demonstrated high antibacterial activity against Gram‐positive bacteria including methicillin‐ and vancomycin‐resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes.     

血红素亚铁片的制备工艺优选

目的:优化血红素亚铁片的制备工艺条件。方法:以崩解时限和脆碎度为指标,采用单因素试验考察稀释剂、崩解剂;选取糊精蔗糖质量比、羧甲基淀粉钠及聚乙烯吡咯烷酮(PVP)质量分数为考察因素,通过单因素试验和正交试验优选血红素亚铁片的制备工艺。结果:最佳制备工艺条件为糊精-蔗糖0.6∶1,PVP质量分数15%,羧甲基淀粉钠质量分数3%。结论:优选的工艺合理可行,制备的血红素亚铁片具有良好的脆碎度和崩解时限。     

Expression of HO-1 in Chronic Renal Insufficiency Rat Kidney and Implication

Thehemeoxygenase (HO)isthestartingandrate limitingenzymeinhemedegradation HO 1isinducibletypeHOandcanbeinducedbyheme ,weightmetals ,hypoxia ,endotoxin ,inflammatorycytokinesandhormones[1- 3] InrecentyearsmanystudiesdemonstratedthatHO playedimportantpro tectiverolesinrenaldiseases ,especiallyinthetubularinjuryandtherenalvascularinjury Inthisstudy ,weusedthe 5 / 6nephrectomizedratstobuildclassicchronicrenalinsufficiency(CRI)modelsandtoob servetherenalfunction ,pathologicchangesofrenaltissue…     

谷胱甘肽抑制蒿甲醚的抗血吸虫作用

目的　观察还原型谷胱甘肽 (GSH)对蒿甲醚伍用氯化血红素抗日本血吸虫作用的影响。　方法　将蒿甲醚、氯化血红素、GSH及谷胱甘肽耗竭剂 2 ,4 -二硝基氯苯 (CDNB)单一或伍用加入含 5周龄血吸虫的培养液内 ,温育2 4 h后 ,测定虫体的丙二醛含量 ,并观察培养至 96 h虫体存活情况。感染小鼠经蒿甲醚 30 0 mg/kg治疗后 6、12或 2 4h,测定虫体的 GSH水平。　结果　体外 ,蒿甲醚伍用氯化血红素作用血吸虫 2 4 h后 ,虫丙二醛含量明显升高。培养时间延长 ,虫陆续死亡。GSH对蒿甲醚伍用氯化血红素诱导血吸虫脂质过氧化及杀虫作用具有拮抗作用 ,CDNB则有增强作用。体内 ,蒿甲醚作用血吸虫 6～ 2 4 h,虫体内 GSH水平先降低再明显升高。　结论　 GSH可能在血吸虫防御蒿甲醚衍生的毒性过氧化物和自由基攻击中起重要作用。     

Acute intermittent porphyria: A critical diagnosis for favorable outcome

Acute intermittent porphyria (AIP) is an inherited metabolic disorder characterized by the accumulation of toxic metabolites of the heme pathway. It rarely presents in the prepubertal age group. AIP often presents with nonspecific and nonlocalizing symptoms. Moreover, several commonly used medications and stress states are known to precipitate an attack. We present the case of a previously healthy 5 years female who was diagnosed as acute central nervous system infection/inflammation at admission. It was the presence of red flags that led to a correct diagnosis. Besides supportive management, a dedicated search for intravenous hemin (chemically heme arginate, aminolevulinic acid synthase inhibitor, and drug of choice) was attempted. Unexpected help was rendered by doctors from a medical college in Gujarat, and two ampoules could be obtained. The patient received three doses of intravenous hemin; however, she succumbed later. This case is presented for the diagnostic and therapeutic challenges faced in developing countries.     

Hemin modulates cytokine expressions in macrophage-derived foam cells via heme oxygenase-1 induction

Lipid-laden foam cells were considered to be targets for therapeutic intervention in atherosclerosis. Several studies proposed new approaches to alter both lipid accumulation and inflammatory responses in macrophages. Finding anti-inflammatory signals during foam cell formation would provide new valid targets for anti-atherosclerotic treatment. The aim of the present study was to see whether oxidized low-density lipoprotein (ox-LDL) can active heme oxygenase (HO)-1 expression level in a human monocyte line, U937 cells, associated with the increase of cytokine secretion. We used hemin (HO-1 activator) and zinc protoporphyrin IX (ZnPP IX, HO-1 inhibitor) to determine the effect of HO-1 on the regulation of cytokine expressions. The results showed that hemin can significantly decrease pro-inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha levels, while enhancing IL-10 production in a dose-dependent manner in U937 foam cells. ZnPP IX did not significantly affect cytokine levels in foam cells. Our present results suggested that HO-1 is an important anti-inflammatory therapeutic target through inhibiting pro-inflammatory cytokines and enhancing anti-inflammatory cytokines for the management of atherogenesis.     

经胃肠道给予氯化血红素对压力负荷性心衰大鼠氧化应激状态的影响

目的探讨经胃肠道给予氯化血红素后体内血红素氧合酶-1(HO-1)-CO-胆红素的反应和对大鼠慢性压力负荷性心力衰竭进程中氧化应激的影响。方法成年雄性SD大鼠63只,随机分为血红素组、心衰组和对照组,每组21只,各组再分为4、8、12周三个小组,每小组7只。心衰组、氯化血红素组行腹主动脉缩窄术,对照组行假手术。从术后3周开始血红素组以60mg/(kg·d)氯化血红素灌胃,对照组和心衰组同时间灌以同体积生理盐水。各小组在相应的时间点检测血清HO-1、碳氧血红蛋白(COHb)、丙二醛(MDA)、氧化低密度脂蛋白(ox-LDL)的含量,检测血清超氧化物歧化酶(SOD)的活性。结果 (1)氯化血红素组在给药后4、8、12周血清HO-1含量明显高于心衰组,分别是(6.80±0.92)μg/Lvs(2.5±0.22)μg/L;(10.70±0.69)μg/Lvs(4.50±0.28)μg/L;(13.30±0.99)μg/Lvs(6.07±0.71)μg/L(P0.01);COHb含量均明显高于心衰组,分别为(4.34±0.31)%vs(1.68±0.11)%;(6.32±0.44)%vs(2.46±0.20)%;(7.80±0.39)%vs(3.01±0.42)%(P0.01)。(2)氯化血红素组在给药4、8、12周血清MDA含量均低于心衰组,分别为(8.3±1.3)μmol/Lvs(14.2±2.3)μmol/L(P0.05);(9.6±0.5)μmol/Lvs(20.2±3.2)μmol/L(P0.01);(11.8±1.1)μmol/Lvs(26.1±3.7)μmol/L(P0.01);(3)氯化血红素组SOD活性在4、8、12周均高于心衰组,分别是(125±6)kU/Lvs(95±10)kU/L(P0.01);(109±9)kU/Lvs(67±5)kU/L(P0.01);(72±10)kU/Lvs(40±6)kU/L(P0.01)。(4)氯化血红素组ox-LDL含量在4、8、12周均低于心衰组,分别为(1.14±0.16)μmol/Lvs(1.80±0.22)μmol/L;(1.38±0.14)μmol/Lvs(2.34±0.25)μmol/L;(1.83±0.16)μmol/Lvs(3.17±0.31)μmol/L(均P0.01)。结论经胃肠道给予氯化血红素可以对体内的HO-1产生诱导作用;HO/CO-胆红素系统的诱导可改善压力负荷心衰大鼠的体内氧化/抗氧化失衡状态。     

Hemin, an iron-binding porphyrin, inhibits HIF-1α induction through its binding with heat shock protein 90

Hypoxia and growth factor stimulation induce hypoxia-inducible factor-1α (HIF-1α), conferring upon cancer cells the ability to adapt to microenvironments and enhance proliferation, angiogenesis and metastasis. Hemin, an iron-binding porphyrin, has been used to treat porphyria attacks, particularly in acute intermittent porphyria. Although the anti-inflammatory and antitumor effects of hemin were reported, no information is available regarding its effect on HIF-1α. Our study investigated whether hemin and other protoporphyrin compounds have the ability to inhibit HIF-1α activity, and if so, what is the molecular basis of inhibition. Hemin treatment prevented CoCl(2) -induced HIF-1α expression. HIF-1α inhibition by hemin resulted from an increase in its facilitated ubiquitination and degradation, as shown by the experimental results using cychloheximide treatment and ubiquitination assays. Consistently, hemin repressed HIF-1α-dependent gene transactivation. Intriguingly, hemin directly impeded the binding between heat shock protein 90 (HSP90) and HIF-1α, which was reversed by the addition of an excess amount of ATP required for HSP90 activity. In addition, hemin decreased the expression of client proteins of HSP90. Thus, the inhibition of HIF-1α activity by hemin might result from its interaction with HSP90. Moreover, treatment of protoporphyrin IX, ZnPP or Co(III)PP, but not Mn(III)PP, inhibited HIF-1α induction, indicating that protoporphyrin ring in association with the nature of binding metal leads to HSP90 inhibition. In an in vivo model, hemin treatment inhibited not only the formation of new vessels but also cancer cell proliferation and migration/invasion, supporting the notion that hemin may be applied to the prevention and/or treatment of angiogenesis and/or cancer metastasis.     

An Upregulation of Interleukin-2 Receptor, Transferrin Receptor Expression and Cytokine Production Mediated by Hemin in Human Peripheral Blood Mononuclear CelIs

Background: We previously reported that hemin-induced mitogenicity in mouse splenocytes was potentiated up to two-fold by interleukin (IL)-2, and the combination of hemin and IL-2 was also effective in inducing cytotoxicity for NK-resistant target cells. The purpose of this study was to investigate the effects of hemin both on expression of membrane surface receptors and on production of cytokine in human peripheral blood mononuclear cells (PBMC).
Methods: Human PBMC were obtained from 16 healthy volunteers. We analyzed hemin-mediated surface phenotypes of cells using flow cytometry, and levels of tumor necrosis factor (TNF)-α and interferon (1FN)-γ in the culture-supernatant of cells by ELSA system.
Results: Hemin induced increased expression of both transferring receptor and IL-2 receptor (CD25) on PBMC in a dose-dependent manner. When the combination of hemin (30μno//L) and IL-2 (100U/mL) was added to the culture of PBMC, the population of double positive cells was increased up to 70.4%. These effects of hemin were enhanced by the addition of catalase in the culture. Treatment with hemin plus IL-2 effectively enhanced the production of TNF-α and IFN-γ in PBMC.
Conclusion: Hemin upregulated both IL-2 receptor and transferrin receptor expression, and stimulated TNF-α: and IFN-γ production in PBMC. IL-2 cooperated with hemin in eliciting these effects.     

盐酸洛美沙星中空栓剂的制备及其稳定性

目的:制备盐酸洛美沙星中空栓剂并研究其稳定性.方法:用热熔法制备中空栓剂并采用加速实验、强光照射实验、留样观察3种方法对该制剂稳定性进行考察.结果:制剂符合设计要求,按稳定性重点考察性状、融变时限、含量、有关物质检测等项目,均合格.结论:本制剂工艺可行,质量稳定,可应用于临床.