Clin. Invest. 1993. 92:359-371.)

Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial/smooth muscular/connective tissue-cell and renal mesangial/endothelial/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE–RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE–RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of “metabolic memory”, the “French paradox”, and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.

Concentric eyewall formation can be idealized as the interaction of a tropical cyclone core with nearby weaker vorticity of various spatial scales. This paper considers barotropic aspects of concentric eyewall formation from modified Rankine vortices. In this framework, the following parameters are found to be important in concentric eyewall formation: vorticity strength ratio, separation distance, companion vortex size, and core vortex skirt parameter. A vorticity skirt on the core vortex affects the filamentation dynamics in two important ways. First, the vorticity skirt lengthens the filamentation time, and therefore slows moat formation in the region just outside the radius of maximum wind. Second, at large radii, a skirted core vortex induces higher strain rates than a corresponding Rankine vortex and is thus more capable of straining out the vorticity field far from the core. Calculations suggest that concentric structures result from binary interactions when the small vortex is at least 4-6 times as strong as the larger companion vortex. An additional requirement is that the separation distance between the edges of the two vortices be less than 6-7 times the smaller vortex radius. Broad moats form when the initial companion vortex is small, the vorticity skirt outside the radius of maximum wind is small, and the strength ratio is large. In concentric cases, an outer vorticity ring develops when the initial companion vortex is large, the vorticity skirt outside the radius of maximum wind is small, and the strength ratio is not too large. In general, when the companion vortex is 3 times as strong as the core vortex and the separation distance is 4-6 times the radius of the smaller vortex, a core vortex with a vorticity skirt produces concentric structures. In contrast, a Rankine vortex produces elastic interaction in this region of parameter space. Thus, a Rankine vortex of sufficient strength favors the formation of a concentric structure closer to the core vortex, while a skirted vortex of sufficient strength favors the formation of concentric structures farther from the core vortex. This may explain satellite microwave observations that suggest a wide range of radii for concentric eyewalls.

The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and PKC signaling. Defective membrane transfer from PMNs to MNCs in patients with active systemic lupus erythematous suppressed activated mononuclear IL-2 production.