Nogueira-Machado Jose A, de Oliveira Volpe Caroline M
Núcleo de Pós Graduação e Pesquisa (NPGP), Hospital Santa Casa de Misericórdia de Belo Horizonte - Belo Horizonte-MG-Brazil.
Recent Pat Endocr Metab Immune Drug Discov. 2012 Sep;6(3):201-9. doi: 10.2174/187221412802481784.
In the present study, we evaluated recent patents that describe products or methods able to down-regulate the pro-inflammatory action of HMGB-1, also called as amphoterin. High Mobility Group Box-1 (HMGB-1) has been implicated in the pathogenesis of inflammatory diseases. HMGB-1 has been proposed to be a crucial mediator in the pathogenesis of many diseases including sepsis, arthritis, cancer, autoimmunity diseases and diabetes. It has been suggested that HMGB-1 itself can signal through RAGEs (receptor for advanced glycation end products) and through the Toll-Like Receptors TLR2 and TLR4. Activation of these receptors results ultimately in the activation of Nuclear Factor-kappaB (NFkappaB), inducing the up-regulation of leukocyte adhesion molecules, production of pro-inflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. There are several patents proposed for controlling the production, secretion and neutralization of HMGB-1 and consequently the inflammatory process. We have divided the patents in six groups based on mechanism of action. The group 1 is associated with inhibition of HMGB-1 using anti-HMGB-1 antibodies; group 2: inhibition of HMGB-1 releases from the nucleus into the extracellular space; group 3: HMGB-A box as a competitive antagonist of HMGB-1; group 4: blockage of RAGE-HMGB-1 signaling using RAGE antagonists; group 5: blockage of TLR-HMGB-1 signaling using anti-TLR2 antibodies and group 6: other molecules that modulate HMGB-1 activity using e.g. human soluble thrombomodulin. The mechanism of HMGB-1 action, its role and efficiency of each group of patents proposed for controlling inflammation are discussed.
在本研究中，我们评估了近期的一些专利，这些专利描述了能够下调高迁移率族蛋白B1（HMGB-1，也称为两性调节蛋白）促炎作用的产品或方法。高迁移率族蛋白B1（HMGB-1）与炎症性疾病的发病机制有关。HMGB-1被认为是包括败血症、关节炎、癌症、自身免疫性疾病和糖尿病在内的多种疾病发病机制中的关键介质。有人提出，HMGB-1自身可通过晚期糖基化终产物受体（RAGEs）以及Toll样受体TLR2和TLR4发出信号。这些受体的激活最终导致核因子κB（NFκB）的激活，从而诱导造血细胞和内皮细胞中白细胞粘附分子的上调、促炎细胞因子和血管生成因子的产生，进而促进炎症反应。有几项专利提出用于控制HMGB-1的产生、分泌和中和，从而控制炎症过程。我们根据作用机制将这些专利分为六组。第1组与使用抗HMGB-1抗体抑制HMGB-1有关；第2组：抑制HMGB-1从细胞核释放到细胞外空间；第3组：HMGB-A盒作为HMGB-1的竞争性拮抗剂；第4组：使用RAGE拮抗剂阻断RAGE-HMGB-1信号传导；第5组：使用抗TLR2抗体阻断TLR-HMGB-1信号传导；第6组：使用例如人可溶性血栓调节蛋白等调节HMGB-1活性的其他分子。本文讨论了HMGB-1的作用机制、其作用以及每组提出的用于控制炎症的专利的有效性。
