Fig. 1. Schematic presentation of the effects of AGE–RAGE interaction. Interaction of circulatory AGE in bloodstream with RAGE at the cell surface induces the generation of reactive oxygen species (ROS) that in turn activates transcription factor NF-κB. NF-κB subsequently activates several proinflammatory genes including tissue factor (TF), ERK 1/2, Ras, vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1) and receptor for advanced glycation end products (RAGE) causing cellular inflammation. ↑ Indicates gene activation.

Fig. 2. Schematic presentation of the effects of TNFα on RAGE expression. Stimulation of cells with TNFα induces the generation of reactive oxygen species (ROS) through the activation of mitochondrial respiratory chain and NADPH oxidase. ROS in turn activates the proinflammatory transcription factor NF-κB that further activates RAGE promoter and induces cell surface RAGE expression. The ROS generation by NADPH oxidase and mitochondria activates each other by positive feedback. ↕ Indicates bi-directional activation.

Fig. 3. Schematic presentation of the possible effects of estrogens on AGE–RAGE and nitric oxide signaling (NO) in cellular homeostasis. In homeostasis estrogens activate eNOS and inhibit iNOS that causes basal level of NO generation leading to anti-inflammatory and cellular protective actions. Estrogens might decrease AGE level and increases the basal level of RAGE in cells in homeostatic condition. The high basal level of RAGE in turn might maintain the homeostasis of cell proliferation, signaling and cell survival. ↑ Indicates activation and ↓ indicates inhibition, respectively, ? indicates undefined.

Fig. 4. Schematic presentation of the possible effects of estrogen on AGE–RAGE and nitric oxide signaling (NO) in diabetes. Diabetic vascular tissues are characterized by high level of both NO and ROS generation. In diabetes, estrogen might inhibit eNOS and activate iNOS that causes high level of NO generation in the cell. Estrogens might increase the AGE–RAGE level and activate AGE–RAGE interaction causing a high level of ROS generation in diabetic condition. High level of NO and ROS together causes proinflammation, cellular toxicity and damage. ↑ Indicates activation and ↓ indicates inhibition, respectively, ? indicates undefined.