Study on development of anti-septic zinc(II) complex with immune-enhancing activity

内毒素是革兰氏阴性细菌高度保守的外膜复合体，可引起感染性休克、发热甚至死亡。小鼠和人巨噬细胞对内毒素的反应特别强烈，内毒素诱导产生多种炎症调节因子，如一氧化氮(NO)、活性氧(ROS)、多种细胞因子(IL-1β、肿瘤坏死因子-α、IL-6、干扰素-γ)和前列腺素。它有四个配位键，在许多蛋白质和酶中发挥结构作用。据报道，在体外和体内实验中，它也显示出类似胰岛素的活性。在胰岛素类药物的开发中，合成的低分子量锌配合物，如双麦芽糖基锌(II)、锌(MAL)_2及其衍生物，比离子锌具有更好的类胰岛素活性。而锌则为Exhi…所知更多的BIT抗氧化作用，并抑制内毒素诱导的NO和ROS的产生。因此，锌具有广泛的药理活性，可能通过抑制炎症刺激来保护机体对抗内毒素诱导的感染性休克。在本研究中，我们研究了麦芽糖酸锌衍生物作为一种潜在的护肝药物，对脂多糖诱导的大鼠原代肝细胞体外毒性和体内内毒素休克的抑制作用，这是一个人类败血症模型。结果表明，腹腔注射脂多糖(30 mg/kg)和注射锌(甲基)2(10 mg/kg)前后，大鼠在注射后96h内的存活率分别接近100%和70%。而低剂量和高剂量锌(5 mg/kg和20 mg/kg)均可降低小鼠的存活率。此外，药代动力学分析表明，具有S_2O_2配位模式的锌配合物具有比麦芽糖酸锌衍生物更强的抗菌活性，这主要是由于锌(S_2O_2)络合物具有较高的胃肠道生物利用度和分布于器官。较少

Septic shock with fever and even death is induced as one of the biological responses, which are triggered by LPS (lipopolysaccharide, endotoxin), a highly conserved outer membrane compound of gram-negative bacteria. Murine and human macrophages exhibit a particularly vigorous response to endotoxin, which induces production of a variety of inflammatory modulators such as nitric oxide (NO), reactive oxygen species (ROS), several cytokines (IL-1β, TNF-α, IL-6, INF-γ), and prostaglandins.Zinc (Zn) is an essential trace element in all-living systems. It has four coordinating bonds and plays a structural role in many proteins and enzymes. It has been also reported to exhibit insulinomimetic activity in both in vitro and in vivo experiments. In the development of insulinomimetic agents, synthetic low-molecular weight Zn complexes such as bis(maltolato)zinc(II), Zn(mal)_2, and its derivatives exhibited more promise in insulinomimetic activity than ionic zinc species. While, Zn is known to exhi … More bit antioxidative effects and inhibit LPS-induced NO and ROS production. Then, Zn has extensive pharmacological activity and may protect the body against the LPS-induced septic shock with suppressing inflammatory stimulation.In the present study, we examined the suppressive effect of zinc-maltolate derivatives as a potential liver-protecting agent on the LPS-induced in vitro hepatotoxicity in isolated rat primary hepatocytes and in vivo endotoxin shock in rats, which is a model of human septicemia. The results indicated that the survival rate of rats, who were intraperitoneally (ip) administered with LPS (30 mg/kg) and ip pre- or post-treated with Zn(mal)_2 injection at a dose of 10 mg Zn/kg, was almost 100% or approximately 70% within 96 hours after LPS injection, respectively. While, the survival rates was decreased in both cases at lower and higher doses of 5 and 20 mg Zn/kg. In addition, pharmacokinetic analysis suggested that Zn complexes with S_2O_2 coordination mode may exhibit more potent anti-septic activity than zinc-maltolate derivatives after oral administration, mainly due to the higher bioavailability from the gastrointestine and distribution to organs of Zn(S_2O_2) complexes. Less