Production and Treatment Strategies of Molecular Targeting Anti-Metastatic Agent

α - α抑制剂（inter- α inhibitor, IaI）家族的生物学功能有了新的研究进展。IaI家族的抗蛋白水解活性来源于比库宁（又称尿胰蛋白酶抑制剂）。越来越多的证据表明，比库宁不仅是一种抗蛋白水解剂，而且被认为是一种抗炎剂，可以抑制脂多糖（LPS）诱导的细胞因子合成。Bikunin的功能是通过LPS受体和/或尚未识别的Bikunin信号受体抑制钙内流和细胞外信号调节激酶（ERE）信号传导。LPS通过LPS信号受体，增加钙内流，磷酸化ERK，激活多种转录因子，如核因子κ b （NFκB）或早期生长反应-1 (Egr-1)，从而促进细胞因子的表达。据预测，游离比库宁或细胞结合比库宁在信号级联中的缺陷会下调细胞因子的表达，使巨噬细胞/中性粒细胞更多地失活，并损害炎症过程。这篇综述主要集中在我们目前对比库宁的明显功能、它的配体、与之相互作用的效应分子及其调控的理解上。基于几种工作模型，bikunin（包括KTI）的具体作用被提出：1)LPS增加巨噬细胞对bikunin的结合能力并使其融入巨噬细胞；2)比库宁首先与包括LPS在内的细菌毒素直接相互作用，增强细菌毒素的捕获；3)比库宁降低LPS与巨噬细胞的结合；4)比库宁通过cd44结合的Link蛋白和/或未知成分与活化的炎症细胞表面相互作用，并使一些膜结合的蛋白酶失活；5)比库尼抑制脂多糖诱导的钙内流增加，钙内流触发信号使丝裂原活化蛋白激酶(MAPKK [MEK]) /ERK1/2和NFkB失活，导致脂多糖诱导的细胞因子合成受到抑制；6)ERK1/2也磷酸化特定的核转录因子。然而，有一个相互矛盾的数据，比库宁不抑制NFkB的激活，尽管它抑制ERK1/2激活依赖性Egr-1在LPS刺激的单核细胞中的表达；最后，7)利用bikunin-deficient （Knockout）小鼠和相应的野生型小鼠，证实了bikunin对LPS诱导的急性器官损伤或炎症反应的保护作用，提示内源性bikunin对LPS诱导的急性器官损伤或炎症反应具有保护作用。因此，越来越多的证据表明，比库宁会损害lps诱导的炎症基因和细胞因子的表达，从而促进器官损伤。比库宁确实通过抑制钙内流的增加来抑制lps诱导的ERK1/2激活，从而抑制ERK1/2诱导的转录因子的激活，包括Egr-1。所有的影响都可以解释为比库宁直接与LPS相互作用，使LPS受体系统失活，或阻止钙流入。因此，比库宁不仅是一种抗蛋白水解剂，而且被认为是一种抑制lps诱导的细胞因子合成的抗炎剂。少

There have been new developments in biological functions of the inter-alpha inhibitor (IaI) family. The anti-proteolytic activity of IaI family originates from bikunin (also known as urinary trypsin inhibitor). There is growing evidence that bikunin is not just an anti-proteolytic agent but is considered to be an anti-inflammatory agent which suppresses the lipopolysaccharide (LPS) -induced cytokine synthesis. Bikunin functions to inhibit calcium influx and extracellular signal-regulated kinase (ERE) signaling via LPS receptors and/or as yet unidentified bikunin signaling receptors. Through LPS signaling receptor, LPS increases calcium influx and phosphorylates ERK, which activates multiple transcription factors, nuclear factor kappaB (NFκB) or early growth response-1 (Egr-1), all leading to promote cytokine expression. Deficits in signaling cascades by free bikunin or cell-bound bikunin are predicted to down-regulate cytokine expression, render macrophages/neutrophils more inactivatio … More n, and impair inflammatory process. This review largely focuses on our current understanding of the apparent functions of bikunin, its ligands, the effector molecules with which it interacts, and its regulation.Based on several working models, specific roles of bikunin, including KTI, have been proposed: 1) LPS increases the binding capacity of the macrophages for bikunin and its incorporation into them; 2) bikunin first directly interacts with bacterial toxins including LPS, which enhances trapping of bacterial toxins; 3) bikunin causes a decrease in the binding of LPS to macrophages; 4) bikunin interacts with activated inflammatory cell surface via CD44-bound Link protein and/or unknown components as well as inactivates some membrane-bound proteinases; 5) bikunin inhibits the LPS-induced increase in calcium influx, which triggers a signal that inactivates mitogen-activated protein kinase kinase (MAPKK [MEK]) /ERK1/2 and NFkB, leading to suppression of LPS-induced cytokine synthesis; 6)ERK1/2 also phosphorylates specific nuclear transcription factors. However, there is a conflicting data in which bikunin does not inhibit the activation of NFkB, although it inhibited ERK1/2 activation-dependent Egr-1 expression in monocytes stimulated with LPS; and finally, 7) the protective role of bikunin against acute inflammatory organ injury induced by LPS was confirmed using bikunin-deficient (Knockout) mice and corresponding wild-type mice, suggesting that endogenous bikunin is protective against acute organ injury or inflammatory reaction induced by LPS. Thus, a growing body of evidence has accumulated that bikunin impairs LPS-induced inflammatory genes and cytokine expression that promote organ injury. Bikunin does inhibit LPS-induced ERK1/2 activation by suppressing an increase in calcium influx, leading to suppression of ERK1/2-induced activation of transcription factors, including Egr-1. All effects could be explained by which bikunin directly interacts with LPS, inactivates the LPS receptor system, or blocks calcium influx. Therefore, bikunin is not just an anti proteolytic agent but is considered to be an anti-inflammatory agent which suppresses the LPS-induced cytokine synthesis. Less