ABSTRACT
The immunoproteasome (iP) is a variant of the constitutive proteasome (cP) that is abundantly expressed in immune cells which can also be induced in somatic cells by cytokines such as TNF-α or IFN-γ. Accumulating evidence support that the iP is closely linked to multiple facets of inflammatory response, eventually leading to the development of several iP inhibitors as potential therapeutic agents for autoimmune diseases. Recent studies also found that the iP is upregulated in reactive glial cells surrounding amyloid ß (Aß) deposits in brains of Alzheimer's disease (AD) patients, but the role it plays in the pathogenesis of AD remains unclear. In this study, we investigated the effects of several proteasome inhibitors on cognitive function in AD mouse models and found that YU102, a dual inhibitor of the iP catalytic subunit LMP2 and the cP catalytic subunit Y, ameliorates cognitive impairments in AD mouse models without affecting Aß deposition. The data obtained from our investigation revealed that YU102 suppresses the secretion of inflammatory cytokines from microglial cells. Overall, this study indicates that there may exist a potential link between LMP2/Y and microglia-mediated neuroinflammation and that inhibition of these subunits may offer a new therapeutic strategy for AD.
Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Cognitive Dysfunction/drug therapy , Cysteine Endopeptidases/genetics , Neuroglia/drug effects , Proteasome Inhibitors/pharmacology , Alzheimer Disease/enzymology , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Brain/enzymology , Brain/pathology , Cell Line , Cognitive Dysfunction/enzymology , Cognitive Dysfunction/genetics , Cognitive Dysfunction/pathology , Cysteine Endopeptidases/metabolism , Disease Models, Animal , Gene Expression Regulation , Humans , Interleukin-1alpha/genetics , Interleukin-1alpha/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Liver/drug effects , Liver/enzymology , Liver/pathology , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Mice, Transgenic , Monocyte Chemoattractant Proteins/genetics , Monocyte Chemoattractant Proteins/metabolism , Neuroglia/enzymology , Neuroglia/pathology , Protein Subunits/antagonists & inhibitors , Protein Subunits/genetics , Protein Subunits/metabolism , Spleen/drug effects , Spleen/enzymology , Spleen/pathologyABSTRACT
A novel and efficient asymmetric synthesis of 2,4-diaryl-1-benzopyrans via enantioselective decarboxylative alkylation of ß-keto acids to o-QM intermediates, followed by sequential cyclization and dehydration, has been developed. The synthetically useful chiral 2,4-diaryl-1-benzopyran derivatives were obtained in moderate to high yields and high enantioselectivities through a one-pot, two-step sequence. This approach offers a facile way to prepare chiral 2,4-diaryl-1-benzopyran derivatives with a wide range of functional group tolerance.
ABSTRACT
Toll-like receptor 4 (TLR4) recognizes LPS and triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter, inducing interferon-ß (TRIF)-dependent major downstream signaling pathways. Previously, we presented biochemical evidence that 1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), which was synthesized in our laboratory, inhibits NF-κB activation induced by LPS. Here, we investigated whether FPP modulates the TLR4 downstream signaling pathways and what anti-inflammatory target in TLR4 signaling is regulated by FPP. FPP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization. These results suggest that FPP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression.
Subject(s)
Lipopolysaccharides/pharmacology , Protein Multimerization/drug effects , Pyrrolidines/pharmacology , Toll-Like Receptor 4/metabolism , Vinyl Compounds/pharmacology , Animals , Cells, Cultured , HEK293 Cells , Humans , Mice , Molecular Structure , NF-kappa B/metabolism , Protein Binding/drug effects , Toll-Like Receptor 4/chemistryABSTRACT
When various pathogens invade a host, toll-like receptors (TLRs) play a significant role in recognizing the pathogen-associated molecular patterns carried by the pathogens to induce innate immune reaction, followed by acquired immunity reaction. TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. To evaluate the therapeutic potential of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. FPP inhibited the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) induced by TLR agonists, as well as inhibited the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. FPP also inhibited the activation of NF-κB and IRF3 when induced by the overexpression of downstream signaling components of the TLRs. As a result, FPP has potential to become a new therapeutic drug for many inflammatory diseases.
