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We previously identified a novel selective androgen receptor modulator, S42, that does not stimulate prostate growth but has a beneficial effect on lipid metabolism. S42 also increased muscle weight of the levator ani in orchiectomized Sprague–Dawley rats. These findings prompted us to investigate whether S42 has a direct effect on cultured C2C12 myotubes. S42 significantly lowered expression levels of the skeletal muscle ubiquitin ligase (muscle atrophy-related gene), atrogin1 and Muscle RING-Finger Protein 1(MuRF1) in C2C12 myotubes, as determined by real time PCR. Phosphorylation of p70 S6 kinase (p70S6K), an essential factor for promoting protein synthesis in skeletal muscle, was significantly increased by S42 to almost the same extent as by insulin, but this was significantly prevented by treatment with rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). However, phosphorylation of Akt, upstream regulator of mTORC1, was not changed by S42. S42 did not increase insulin-like growth factor 1 (Igf1) mRNA levels in C2C12 myotubes. These results suggest that S42 may have an anabolic effect through activation of mTORC1–p70S6K signaling, independent of IGF-1-Akt signaling and may exert an anti-catabolic effect through inhibition of the degradation pathway in cultured C2C12 myotubes.

Incretin therapies have received much attention because of their tissue-protective effects, which extend beyond those associated with glycemic control. Cancer is a primary cause of death in patients who have diabetes mellitus. We previously reported antiprostate cancer effects of the glucagonlike peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4). Breast cancer is one of the most common cancers in female patients who have type 2 diabetes mellitus and obesity. Thus, we examined whether GLP-1 action could attenuate breast cancer. GLP-1R was expressed in human breast cancer tissue and MCF-7, MDA-MB-231, and KPL-1 cell lines. We found that 0.1 to 10 nM Ex-4 significantly decreased the number of breast cancer cells in a dose-dependent manner. Although Ex-4 did not induce apoptosis, it attenuated breast cancer cell proliferation significantly and dose-dependently. However, the dipeptidyl peptidase-4 inhibitor linagliptin did not affect breast cancer cell proliferation. When MCF-7 cells were transplanted into athymic mice, Ex-4 decreased MCF-7 tumor size in vivo. Ki67 immunohistochemistry revealed that breast cancer cell proliferation was significantly reduced in tumors extracted from Ex-4-treated mice. In MCF-7 cells, Ex-4 significantly inhibited nuclear factor κB (NF-κB ) nuclear translocation and target gene expression. Furthermore, Ex-4 decreased both Akt and IκB phosphorylation. These results suggest that GLP-1 could attenuate breast cancer cell proliferation via activation of GLP-1R and subsequent inhibition of NF-κB activation.GLP-1R agonist exendin-4 attenuated breast cancer cell proliferation via activation of GLP-1R and subsequent inhibition of nuclear factor-κB activation both in vivoand in vitro.

The superimposition of male sex organs (penis and vas deferens) in a female gastropod, called imposex, is widely attributed to the exposure to tributyltin (TBT) compounds, used world-wide in antifouling paints for ships. It has been hypothesized that the TBT-induced imposex is mediated by an increasing androgen level relative to the estrogen level, namely a decreased conversion of androgens to estrogens (i.e., aromatization). In the present study, we tested this hypothesis by examining the effects of TBT or triphenyltin (TPT) on the aromatase activity in a cultured human granulosa-like tumor cell line, KGN, which was recently established by our group. Treatment with more than 1000 ng/ml TBT compounds was very toxic to the cells and caused immediate cell death within 24 h, while 200 ng/ml was found to cause apoptosis of the cells. Treatment of the KGN cells for more than 48 h with 20 ng/ml TBT or TPT, which is a concentration level reported to cause imposex in marine species, did not affect cell proliferation but significantly suppressed the aromatase activity determined by a [3H]H2O release assay. Treatment with 20 ng/ml TBT compounds for 7 days also resulted in a reduction of the E2 production from Δ4-androstenedione stimulated by db-cAMP. The changes in the aromatase activity by TBT compounds were associated with comparable changes in P450arom mRNA assessed by RT-PCR. The luciferase activity of the P450arom promoter II (1 kb) decreased after the addition of 20 ng/ml TBT compounds in transfected KGN cells either in a basic state or in states stimulated by db-cAMP. The Ad4BP-dependent increase in the luciferase activity of P450arom promoter II was also downregulated by such treatments. These results indicate that TBT compounds inhibited the aromatase activity and also decreased the P450arom mRNA level at the transcriptional level in KGN cells. The direct inhibitory effect of TBT compounds on the aromatase activity may therefore partly explain the induction of imposex by these compounds in female species.

AbstractThis study was carried out to establish which type of cholesteatoma is controllable by conservative treatment from the viewpoint of mastoid ventilation. We examined the area of the air cell system and airspace (aeration) in the mastoid cavity by computed tomography and eustachian tube (ET) function by inflation-deflation test in 20 ears (20 patients) with severe attic retraction for over 12 months (retraction pocket group), 16 ears (16 patients) with cholesteatoma which could be controlled only by conservative treatment for over 12 months (nonsurgical group) and 43 ears (43 patients) which required surgery within a year in spite of similar conservative treatment (surgical group). The size of the mastoid air cell system in the retraction pocket group, nonsurgical group and surgical group was 2.9 ± 1.3, 1.9 ± 0.7 and 1.5 ± 0.9 cm2on average, respectively, with no significant difference between both cholesteatoma groups (nonsurgical and surgical group). While aeration was observed in the mastoid in 17 of 20 ears (85.%) in the retraction pocket group and in 12 of 16 ears (75.0%) in the nonsurgical group, aeration was present only in 9 of 43 ears (26.5%) in the surgical group, being significantly less in the surgical group than in the nonsurgical group and the retraction pocket group. In all ears in the retraction pocket and nonsurgical groups, and 19 of 30 ears in the surgical group, ET function was poor, there being no significant difference among the three groups. The present clinical observations suggest that progressiveness of cholesteatoma could be related to the ventilatory conditions in the mastoid rather than ET function, and that conservative treatment may be effective when ears with cholesteatoma have aeration in the mastoid.Copyright © 2001 S. Karger AG, Basel

To investigate the influence of gas exchange function through the middle ear mucosa on the development of sniff‐induced middle ear diseases, the authors examined the mastoid pneumatization among patients with sniffing habit using computed tomography, and also examined the change of negative middle ear pressure induced by sniffing using tympanogram. In 20 ears with cholesteatoma or adhesive otitis media, the areas of mastoid cavity measured at the level of the lateral semicircular canal were significantly smaller than those in 26 ears with otitis media with effusion (OME) or attic retraction and in eight normal ears with sniffing habit (P< .01 and P< .0001, respectively). In 26 ears with OME or attic retraction, the areas of mastoid cavity were significantly smaller than those in eight normal ears with sniffing habit (P< .0001). By contrast, in the four ears with sniff‐induced middle ear disease, the recovery of negative middle ear pressure in 5 minutes without swallowing was less than 10 mm H2O, whereas in all seven ears with normal eardrum, negative middle ear pressure recovered by more than 20 mm H2O in 5 minutes. These findings suggested that impairment of gas exchange function through the middle ear mucosa, as well as eustachian tube dysfunction, might be closely related to the development of sniff‐induced middle ear diseases.

Gas exchange function through the mastoid mucosa was investigated in ears after surgery using nitrous oxide. Increase in the mastoid pressure was assessed by a micropressure sensor placed in the mastoid cavity during the second‐stage revision operation performed under general anesthesia using 67% nitrous oxide, 33% oxygen, and sevoflurane on 14 ears with chronic adhesive otitis media or cholesteatoma as well as on seven ears without inflammation as controls. All seven control ears showed pressure increase in the mastoid in various degrees. In the 14 postoperative ears, nine of the 10 ears on which the mastoid mucosa had previously been able to be preserved in various degrees showed pressure increase in the mastoid, but none of the remaining four ears, which had previously had mastoidectomy, showed any pressure increase. The presence or absence of the mastoid pressure increase of those ears was also found to be correlated well with the presence or absence of mastoid aeration on computed tomography examined just before the second‐stage operation. These results appear to indicate that, in ears after surgery, recovery of both the gas exchange function and aeration in the mastoid is expected only when the mastoid mucosa can be preserved even partially.

To clarify the influence of inflammation on tubal compliance in children with otitis media with effusion (OME), we investigated the change of compliance of the ET by upper respiratory tract infection (URTI) in]8 children (23 ears) with OME using the forced response test. The tubal compliance index (TCI), the ratio of passive tubal resistances at two different airflow rates, significantly increased during URTI represented by acute rhinitis or paranasal sinusitis in comparison with non-URTI periods (paired t-test: t = 4.14, p <0.001). In nine ears, the TCI could be followed for some months after that, during which the children had had URTI several times. A clear reproducible correlation was found between the presence or absence of URTI and the TCI values; the TCI values increased again during URTI and decreased after the URTI periods. These results seemed to support our hypothesis that compliance of the ET may depend not only on the property of the cartilaginous framework of the ET but also upon the mucosal condition.

Incretin therapy has emerged as one of the most popular medications for type 2 diabetes. We have previously reported that the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin attenuates neointima formation after vascular injury in non-diabetic mice. In the present study, we examined whether combined treatment with linagliptin and the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin attenuates neointima formation in diabetic mice after vascular injury. Diabetic db/dbmice were treated with 3 mg/kg/day linagliptin and/or 30 mg/kg/day empagliflozin from 5 to 10 weeks of age. Body weight was significantly decreased by empagliflozin and the combined treatment. Blood glucose levels and glucose tolerance test results were significantly improved by empagliflozin and the combined treatment, but not by linagliptin. An insulin tolerance test suggested that linagliptin and empagliflozin did not improve insulin sensitivity. In a model of guidewire-induced femoral artery injury in diabetic mice, neointima formation was significantly decreased in mice subjected to combined treatment. In an in vitroassay using rat aortic smooth muscle cells (RASMC), 100, 500, or 1000 nM empagliflozin significantly decreased the RASMC number in a dose-dependent manner. A further significant reduction in RASMC proliferation was observed after combined treatment with 10 nM linagliptin and 100 nM empagliflozin. These data suggest that combined treatment with the DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice in vivoand smooth muscle cell proliferation in vitro.