Immune-mediated inner ear disorder has been well established as a clinical entity; however, the innate immune system of the inner ear is a poorly understood area of research with high clinical and immunological importance. Although the presence of resident tissue macrophages in the inner ear has been suggested, there has been some controversy. In this study, we analyzed the origin of cochlear resident macrophages and the contribution of hematopoietic bone marrow (BM) to the recruitment of macrophages in the cochlea. To visualize the localization of BM-derived cells, BM chimeric mice were made by transplantation of hematopoietic stem cells, which were genetically labeled with enhanced green fluorescent protein, into lethally irradiated C57BL/6 mice. The distribution and characteristics of BM-derived cells in the mouse cochlea were studied immunohistochemically. We successfully identified the constitutive presence of tissue resident macrophages in the spiral ligament and spiral ganglion that are derived from BM in larger numbers than previously reported. Moreover, cochlear resident macrophages gradually turn over for several months during steady-state replacement by BM-derived cells, and the number of cochlear macrophages immediately increased in response to local surgical stress. The present findings demonstrate the hematopoietic origin of cochlear resident and infiltrating macrophages. Our study provides a novel anatomical and immunological basis for the inner ear and indicates that the cochlear resident macrophages would be a therapeutic target in inner ear disorders.

The rhizome of turmeric, Curcuma longa, has been used as a food additive, especially as a spice in curry, as a coloring agent, and in cosmetics (1, 2). In addition to its aromatic, stimulant, and coloring properties, the powdered rhizome of turmeric possesses anti-inflammatory, antioxidant, and antitumor activities and has been taken orally to treat dyspepsia, flatulence, and liver and urinary tract diseases (3-6). Most of these pharmaceutical properties of turmeric depend on the curcuminoids, including curcumin (3e), demethoxycurcumin (4e), and bisdemethoxycurcumin (2e) (see Fig. 1A). The amounts (wild type t%) of these curcuminoids were ϳ2, 0.7, and 0.6% in powdered turmeric (7).Type III polyketide synthases (PKSs), 4 consisting of a homodimer of ketosynthase, play an important role in the biosynthesis of most plant polyketides (8). Chalcone synthase (CHS), a typical type III PKS, catalyzes the formation of naringenin chalcone by the following mechanism (see Fig. 1B) (9, 10). The reaction of CHS is primed by a transfer of the acyl moiety of p-coumaroyl-CoA, which is called a starter substrate, to the catalytic cysteine of CHS. Subsequent iterative decarboxylative condensation of three malonyl-CoAs, which are called extender substrates, yields a tetraketide intermediate. These iterative condensations are catalyzed by a Cys-Asn-His catalytic triad (8, 9). The resultant tetraketide intermediate is then cyclized by Claisen condensation, followed by aromatization resulting in naringenin chalcone formation. Like CHS, most type III PKSs catalyze condensation of one starter substrate and several extender substrates.Due to the pharmaceutically important properties of curcuminoids, the biosynthetic pathway has been the subject of much attention, and radio tracer studies were performed decades ago (11). Based on those results, Schröder (12) proposed that curcuminoids are derived from the phenylpropanoid pathway and that one or more type III PKSs were responsible for the formation of its scaffold. Curcuminoids, consisting of two phenylpropanoid units, are chemically derived from phenylalanine connected by a central carbon unit derived from malonyl-CoA. The 13 C feeding experiment carried out by Kita et al. (13) showed that the curcuminoid scaffolds originate from two phenylalanines. One possible pathway from phenylalanine to curcumin is presented in Fig. 1A. However, it is not known when the methyl ethers at the 3Ј position of curcumin are incorporated, i.e. before or after curcumin scaffold formation, or how the curcumin scaffold is synthesized, i.e. by a single type III PKS enzyme or a multiple enzyme system.On the basis of these findings, several groups attempted to identify one or more type III PKSs responsible for the formation of the curcuminoid scaffold. Brand et al. (14) characterized a type III PKS in Wachendorfia thyrsiflora, a plant that produces phenylphenalenones derived from a curcuminoid scaffold. This type III PKS, named WtPKS1, synthesizes a benzalacetone scaffold and triketide pyrones from various star...

The anti-H pylori effect of dual treatment is highly efficient for CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as a first line of therapy for this type of patients. Genotyping can provide a choice for the optimal regimen based on individual CYP2C19 genotype.

Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down-regulation of the prosensory domain markers, p27Kip1, Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea.

Cell-based tissue engineering using BSCs may improve the quality of the healing process in vocal fold injuries.