Inner ear dysfunction secondary to chronic otitis media (OM), including high-frequency sensorineural hearing loss or vertigo, is not uncommon. Although chronic middle ear inflammation is believed to cause inner ear dysfunction by entry of OM pathogen components or cytokines from the middle ear into the inner ear, the underlying mechanisms are not well understood. Previously, we demonstrated that the spiral ligament fibrocyte (SLF) cell line up-regulates monocyte chemotactic protein 1 (MCP-1) expression after treatment with nontypeable Haemophilus influenzae (NTHI), one of the most common OM pathogens. We hypothesized that the SLF-derived MCP-1 plays a role in inner ear inflammation secondary to OM that is responsible for hearing loss and dizziness. Antibiotics have led to a dramatic decline in the incidence of life-threatening complications of otitis media (OM), such as meningitis or brain abscess (3). However, inner ear dysfunction secondary to chronic OM, including high-frequency sensorineural hearing loss or vertigo, is not uncommon (13,26,36,55,60). Although chronic middle ear inflammation is believed to cause inner ear dysfunction by entry of OM pathogen components or cytokines from the middle ear into the inner ear, the underlying mechanisms are not well understood (18,32,39,44,52,87).The inner ear is a sensory organ for hearing (cochlea) and equilibrium (vestibule). It consists of a variety of specialized cell types (50, 51), such as sensory hair cells, supporting cells, sulcus cells, and spiral ligament fibrocytes (SLFs), which are the most abundant cell types exposed to the perilymph. The type of inner ear cells that respond to proinflammatory signals entering the inner ear remain unknown. Considering that SLFs are one of the abundant cell types in the cochlea and that they secrete cytokines and chemokines after proinflammatory stimuli (72, 97), we hypothesized that the SLFs are major responders to such signals.Preliminary studies of human temporal bones with labyrinthitis showed the infiltration of lysozyme-positive round cells with a monomorphic nucleus into the spiral ligament (unpublished data). Also, SLF cell lines (96) showed an induction in monocyte chemotactic protein 1 (MCP-1) expression after treatment with lysate of nontypeable Haemophilus influenzae (NTHI), one of the most common OM pathogens (72). Moreover, it has previously been shown that monocytes can infiltrate cochlea exhibiting chronic middle ear inflammation or acoustic trauma (22,34,37). These results led us to focus on MCP-1 as an SLF-derived proinflammatory chemokine attracting effector cells and causing inner ear dysfunction.MCP-1, also known as the chemokine C-C motif ligand 2, is produced by various cells, including endothelial cells, smooth muscle cells, fibroblasts, and macrophages, in response to cytokines, growth factors, or bacterial components (9,46,78). It is encoded by an immediate-early gene (33) and is up-regulated by various stimuli such as bacterial lipopolysaccharide (LPS), interleukin-1 (IL-1), tumor necrosis fact...
Protein array analysis showed that in response to NTHi or S. pneumoniae, rat SLFs released monocyte chemotactic protein 1, macrophage inflammatory protein 3 alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant 2 and 3. Treatment with IL-1alpha, on the other hand, resulted in release of MCP-1 but not the other molecules. Tissue inhibitor of metalloproteinase 1 and vascular endothelial growth factor were released regardless of the inflammatory stimulus used.
Background : We recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae (NTHi) and that interleukin 1 alpha (IL-1 alpha) up-regulates the transcription of beta-defensin 2 (DEFB4 according to new nomenclature of the Human Genome Organization) in human middle ear epithelial cells via a Src-dependent Raf-MEK1/2-ERK signaling pathway. Based on these observations, we investigated if human middle ear epithelial cells could release IL-1 alpha upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components.
A series of flavonoids isolated from Scutellariae radix were evaluated for their effects on cytochrome P-450 (CYP) activities in human liver microsomes. All flavonoids did not substantially inhibit pentoxyresorufin O-deethylation (CYP2B 1), mephenytoin 4-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and chlorzoxazone 6-hydroxylation (CYP2E1) activities (IC50: >50 microM). Baicalein and 2',5,6',7-tetrahydroxyflavone inhibited hepatic testosterone 6beta-hydroxylation (CYP3A4) activity with a IC50 of 17.4 and 7.8 microM, respectively. Oroxylin A inhibited diclofenac 4-hydroxylation (CYP2C9) activity with a IC50 of 6.7 microM. In contrast, all flavonoids tested inhibited hepatic caffeine N'-demethylation (CYP1A2) with IC50 values ranging from 0.7 to 51.3 microM. Kinetic analysis revealed that the mechanism of inhibition varied according to the flavonoids. These results suggest that flavonoids tested are inhibitors of hepatic CYP1A2 and that the extracts of Scutellariae radix, widely used as a hepatoprotective agent, may protect the liver through the prevention of CYPIA2-induced metabolic activation of protoxicants.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.