Carbohydrate mimetic peptides were screened for inhibition of selectin-mediated hematogenous metastasis of cancer cells. One peptide, designated I-peptide, showed an affinity for selectin in vitro and suppressed lung metastasis of melanoma cells in a mouse model. However, subsequent studies revealed that the in vivo receptor of I-peptide was not selectin but serine/arginine-rich alternative mRNA splicing factor and annexin A1 (Anxa1). Anxa1 is expressed on the surface of vascular endothelial cells in various malignant tumors, including brain tumors. IF7 peptide, an analog of I-peptide, showed specificity to the N-terminal region of Anxa1. IF7 rapidly accumulated in cancer cells by crossing the vascular endothelial cells. An IF7-anticancer drug conjugate suppressed tumor growth in mouse models of subcutaneous and brain tumors. These results indicate that IF7 functions as an efficient drug delivery system.

Previous studies have shown that various glycolipids including neutral and acidic glycosphingolipids (GSLs) involve multiple biological events such as survival, neuronal development and differentiation processes. Moreover, recent reports have indicated that some neutral GSLs are involved in neuroinflammatory signaling and therefore involved in the occurrence of certain neurological diseases. Sphingolipids, cholesterol, and glycerophospholipids are essential constituents of neuronal membranes which function as a protective barrier of neuronal cells against the external environment and providing essential biochemical platform for proper neuronal actions and functions. At present, however, detailed molecular basis of how GSLs transmit the signals in neuroinflammatory reactions in vivo remains to be elucidated. Furthermore, we recently identified new type of autoantibodies against neutral GSLs, especially lactosylceramide in a neuroinflammatory disorder, encephalomyeloradiculoneuropathy (EMRN) and found these autoantibodies can be used as a surrogate marker for this disorder. These anti-neutral glycolipids antibodies strongly indicate that they can be a strong inducer for neuroinflammation of the brain and peripheral nervous system as well by involving innate immunity. In this review, I focused the biological and immunological activities and implications of GSLs and their autoantibodies, especially in terms of neuroinflammatory reactions in animals and human.

Chondroitin sulfate (CS) chains, a class of sulfated glycosaminoglycan (GAG) polysaccharides, are major extra/pericellular components that function as microenvironmental cues during neuronal development and the regeneration of injured neurons. Interestingly, CS chains exert both facilitatory and inhibitory effects on neurite outgrowth. Such bidirectional CS chain effects are ascribable to their own structural divergence that could be generated via distinct enzymatic modifications. CS chains have long been considered as passive structural scaffolds that often behave as co-receptors and/or reservoirs for various humoral factors. However, the recent identification of cell surface receptor molecules with binding preferences to distinct CS structures has provided new insight into a novel CS chain effector mechanism functioning as dynamic extra/pericellular signaling ligands that could directly control the corresponding receptor-mediated signaling pathways. This new concept might also support the functional complexity of CS chains in neurobiological events.

Carbohydrate mimetic peptides were screened for inhibition of selectin-mediated hematogenous metastasis of cancer cells. One peptide, designated I-peptide, showed an affinity for selectin in vitro and suppressed lung metastasis of melanoma cells in a mouse model. However, subsequent studies revealed that the in vivo receptor of I-peptide was not selectin but serine/arginine-rich alternative mRNA splicing factor and annexin A1 (Anxa1). Anxa1 is expressed on the surface of vascular endothelial cells in various malignant tumors, including brain tumors. IF7 peptide, an analog of I-peptide, showed specificity to the N-terminal region of Anxa1. IF7 rapidly accumulated in cancer cells by crossing the vascular endothelial cells. An IF7-anticancer drug conjugate suppressed tumor growth in mouse models of subcutaneous and brain tumors. These results indicate that IF7 functions as an efficient drug delivery system.

Previous studies have shown that various glycolipids including neutral and acidic glycosphingolipids (GSLs) involve multiple biological events such as survival, neuronal development and differentiation processes. Moreover, recent reports have indicated that some neutral GSLs are involved in neuroinflammatory signaling and therefore involved in the occurrence of certain neurological diseases. Sphingolipids, cholesterol, and glycerophospholipids are essential constituents of neuronal membranes which function as a protective barrier of neuronal cells against the external environment and providing essential biochemical platform for proper neuronal actions and functions. At present, however, detailed molecular basis of how GSLs transmit the signals in neuroinflammatory reactions in vivo remains to be elucidated. Furthermore, we recently identified new type of autoantibodies against neutral GSLs, especially lactosylceramide in a neuroinflammatory disorder, encephalomyeloradiculoneuropathy (EMRN) and found these autoantibodies can be used as a surrogate marker for this disorder. These anti-neutral glycolipids antibodies strongly indicate that they can be a strong inducer for neuroinflammation of the brain and peripheral nervous system as well by involving innate immunity. In this review, I focused the biological and immunological activities and implications of GSLs and their autoantibodies, especially in terms of neuroinflammatory reactions in animals and human.

Chondroitin sulfate (CS) chains, a class of sulfated glycosaminoglycan (GAG) polysaccharides, are major extra/pericellular components that function as microenvironmental cues during neuronal development and the regeneration of injured neurons. Interestingly, CS chains exert both facilitatory and inhibitory effects on neurite outgrowth. Such bidirectional CS chain effects are ascribable to their own structural divergence that could be generated via distinct enzymatic modifications. CS chains have long been considered as passive structural scaffolds that often behave as co-receptors and/or reservoirs for various humoral factors. However, the recent identification of cell surface receptor molecules with binding preferences to distinct CS structures has provided new insight into a novel CS chain effector mechanism functioning as dynamic extra/pericellular signaling ligands that could directly control the corresponding receptor-mediated signaling pathways. This new concept might also support the functional complexity of CS chains in neurobiological events.