Functional involvement of rat organic anion transporter 2 (Slc22a7) in the hepatic uptake of the nonsteroidal anti-inflammatory drug ketoprofen.

Rat organic anion transporter 2 (rOat2, Slc22a7) is a sinusoidal multispecific organic anion transporter in the liver. The role of rOat2 in the hepatic uptake of drugs has not been thoroughly investigated yet. rOat2 substrates include nonsteroidal anti-inflammatory drugs, such as ketoprofen, indomethacin, and salicylate. In the present study, the uptake of ketoprofen, indomethacin, and salicylate by freshly isolated rat hepatocytes was characterized. The uptake of ketoprofen, indomethacin, and salicylate by hepatocytes was sodium-independent, and the rank order of their uptake activities was indomethacin > ketoprofen > salicylate. Kinetic analysis based on Akaike's Information Criterion suggested that the uptake of ketoprofen and indomethacin by hepatocytes consists of two saturable components and one nonsaturable one. The K(m) and V(max) values for the high- and low-affinity components for ketoprofen uptake were 0.84 and 97 microM and 35 and 1800 pmol/min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 microM and 130 and 16,000 pmol/min/mg protein, respectively. The K(m) values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 microM for ketoprofen and indomethacin, respectively). The uptake of ketoprofen by hepatocytes was significantly inhibited by probenecid and rOat2 inhibitors (indocyanine green, indomethacin, glibenclamide, and salicylate). Other inhibitors of rOatps (taurocholate and pravastatin) and rOat3 (pravastatin and p-aminohippurate) had a slight effect, but digoxin had no effect. These results suggest that rOat2 accounts partly for the hepatic uptake of ketoprofen and, presumably, indomethacin as a high-affinity site and that other transporters, such as rOatps, but not rOatp2, and rOat3, are also involved.     

Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese women.

BACKGROUND: Recent laboratory studies have suggested that cadmium is an estrogenic compound and may be a potential risk factor for breast cancer. METHODS: We investigated the relationship between urinary cadmium concentrations and serum concentrations of estrone, testosterone, and dehydroepiandrosterone sulfate in 164 postmenopausal Japanese women. RESULTS: There was a significant positive association between the urinary cadmium and serum testosterone levels after controlling for age and body mass index. The mean testosterone level was 28% higher in women with high urinary cadmium (> or = 3.00 microg/g creatinine) than in those with low urinary cadmium (< 2.00 microg/g creatinine). Urinary cadmium was not significantly associated with serum estrone and dehydroepiandrosterone sulfate levels. Additional adjustment for smoking, alcohol and reproductive factors including known risk factors for breast cancer did not substantially alter the results. CONCLUSION: Data suggested that cadmium exposure is associated with increased testosterone levels. As high testosterone levels have been associated with the risk of breast cancer, the involvement of cadmium exposure in breast cancer risk should be evaluated in future studies.     

A new membrane-attack complex/perforin (MACPF) domain lethal toxin from the nematocyst venom of the Okinawan sea anemone Actineria villosa.

The Okinawan sea anemone Actineria villosa causes severe cases of stinging. We isolated the 60 kDa A. villosa toxin (AvTX-60A) as the major toxin from the isolated nematocysts of this species. AvTX-60A showed fatal toxicity to mice with intraperitoneal injection at a minimum lethal dose of less than 250 microg/kg. The N-terminal amino acid sequence was determined and the corresponding cDNA encoding AvTX-60A was sequenced. The deduced amino acid sequence of AvTX-60A showed high similarity with PsTX-60A, which had been isolated as one of the major toxins from the venomous sea anemone Phyllodiscus semoni. These sea anemone toxins are new members of the family of proteins containing membrane-attack complex/perforin (MACPF) domains, best known in pore forming proteins such as perforin. These are the first examples of MACPF domain proteins as toxins for prey acquisition or repelling predators in nature.     

The effect of denture installation at mandibular rest position on unsteady motion of the centre of pressure in postural sway

Wearing dentures has been believed to decrease the instability of the postural sway using the total length of centre of pressure (CoP) trajectory or the magnitude of its variability. However, the physical aspects of the postural sway have not been taken into account while evaluating the CoP in patients who wear dentures. The CoP fluctuations are found to show a random walk process. Therefore, changes in the random movement of CoP caused by wearing dentures should be examined by nonlinear dynamics that enables analysis of the characteristics found in the random movement. We evaluated the effect of complete denture installation on CoP sway for twenty‐six edentulous patients by performing the following steps. First, we excluded subjects who did not show crossover in spectral analyses. Then, we evaluated the spectral characteristics and phase shifts of the velocities of CoP sway for the subjects who showed crossover. We found that wearing complete dentures decreased the fluctuations in the high‐frequency part of the power spectral density (PSD) and the phase shift in the mediolateral direction. On the other hand, we also found that the use of complete dentures decreased the fluctuations of PSD amplitude in the anteroposterior direction. From the point of view of the kinetic energy of the musculoskeletal system, we suggested that the use of complete dentures could reduce the energy consumption for the standing posture.     

Congenital Cytomegalovirus Infection in Children with Autism Spectrum Disorder: Systematic Review and Meta-Analysis

Association of congenital cytomegalovirus (CMV) infection with autism spectral disorder (ASD) has been suggested since 1980s. Despite the observed association, its role as a risk factor for ASD remains to be defined. In the present review, we systematically evaluated the available evidence associating congenital CMV infection with ASD using PubMed, Web of Science, Cochrane Library, and Embase databases. Any studies on children with CMV infection and ASD were evaluated for eligibility and three observational studies were included in meta-analysis. Although a high prevalence of congenital CMV infection in ASD cases (OR 11.31, 95% CI 3.07–41.66) was indicated, too few events (0–2 events) in all included studies imposed serious limitations. There is urgent need for further studies to clarify this issue.     

Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix

The lateral habenula (LHb) attracts a growing interest as a regulator of monoaminergic activity which were frequently reported to be defective in depression. Here we found that chronic social defeat stress (CSDS) increased production of pro-inflammatory cytokines in LHb associated with mobilization of monocytes and remodeling of extracellular matrix by increased matrix metalloproteinase (MMP) activity. RNA-seq analysis identified proprotein convertase Pcsk5 as an upstream regulator of MMP activation, with upregulation in LHb neurons of mice with susceptibility to CSDS. PCSK5 facilitated motility of microglia in vitro by converting inactive pro-MMP14 and pro-MMP2 to their active forms, highlighting its role in mobilization of microglia and monocytes in neuroinflammation. Suppression of Pcsk5 expression via small interfering RNA (siRNA) ameliorated depressive-like behaviors and pathological mobilization of monocytes in mice with susceptibility to CSDS. PCSK5-MMPs signaling pathway could be a target for development of the antidepressants targeting the inflammatory response in specific brain regions implicated in depression.Subject terms: Cellular neuroscience, Gene expression analysis