レセプトデータに基づく妊娠中の医薬品使用と児の先天奇形との関連に関する検討

第3回日本DOHaD研究会学術集会　抄録集　【ポスター発表

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

Impact of local vaccine subsidization programs on the prevention of mumps in Japan

In Japan, although a mumps vaccination is outside the national universal vaccination program, some local governments have implemented their own program. However, little is known regarding the implementation status and the impact of these programs. In this study, we investigated the impact on the prevention of mumps, after identification of the status of the local government subsidization programs. We identified the implementation status of the subsidization programs using the websites of local governments. We retrieved the number of reported mumps cases from designated sentinel sites through the Surveillance of Infectious Diseases System implemented according to the Infectious Disease Control Law. Using this data, the impact of the subsidization program on prevention of mumps was assessed by comparing the number of mumps cases per site during the 2015–2016 outbreak among the areas categorized by the subsidization status, using a Poisson regression model. As of 2019, 26.2% (456/1,739) of the local governments were considered as having subsidization programs. We retrieved 52,719 mumps cases from 2010 to 2019. The number of mumps cases per sentinel site tended to be low in areas implementing a subsidization program, compared with the no-implementation areas throughout the data collection period. The adjusted model confirmed that the subsidization program implemented between 2010 and 2015 impacted on the number of mumps cases during the 2015–2016 outbreak, with a decrease in the numbers. Further studies with detailed data including vaccination coverage should be conducted

Time-dependent uptake of PGE₃, PGF_3α, and TXB₃ transport by ABCC4.

<p>Membrane vesicles (25 µg) from HEK293/P.B. cells (circles) or HEK293/4.63 cells (diamonds) were incubated at 37°C with (A) 1 µM PGE₃, (B) 2.5 µM PGF_3α, and (C) 2.5 µM TXB₃ in the presence of ATP (filled symbols) or AMP (open symbols). Each point represents the mean ± S.E. (n = 3).</p

Transport of Eicosapentaenoic Acid-Derived PGE₃, PGF_3α, and TXB₃ by ABCC4

<div><p>Background</p><p>Eicosapentaenoic acid-derived prostaglandin (PG) E₃, PGF_3α, and thromboxane (TX) B₃ are bioactive lipid mediators which have anti-cancer and anti-inflammatory effects. To exert their effects, PGE₃, PGF_3α, and TXB₃ must be released to the extracellular space from cells, but the release mechanism has been unclear. We therefore investigated the contribution of ATP-binding cassette transporter C4 (ABCC4), which has been known as a prostanoids efflux transporter, to the release of PGE₃, PGF_3α, and TXB₃.</p><p>Materials and Methods</p><p>ATP-dependent transport of PGE₃, PGF_3α, and TXB₃ via ABCC4 was investigated by using inside-out membrane vesicles prepared from ABCC4-overexpressing HEK293 cells. To evaluate the contribution of ABCC4 to the release of PGE₃, PGF_3α, and TXB₃, we measured the extracellular and intracellular levels of PGE₃, PGF_3α, and TXB₃ in A549 cells when we used ABCC4 inhibitors (dipyridamole, MK571, and probenecid) or ABCC4 siRNAs. The quantification of PGE₃, PGF_3α, and TXB₃ was performed by using liquid chromatography-tandem mass spectrometry.</p><p>Results</p><p>The apparent <i>K_m</i> values for ABCC4-mediated transport were 2.9±0.1 µM for PGE₃, 12.1±1.3 µM for PGF_3α, and 11.9±1.4 µM for TXB₃ and the ATP-dependent accumulation of PGE₃, PGF_3α, and TXB₃ into vesicles was decreased by using typical substrates and inhibitors of ABCC4. ABCC4 inhibitors and ABCC4 knockdown showed the reduction of extracellular/intracellular ratio of PGE₃ (40–60% of control) and PGF_3α (60–80% of control) in A549 cells.</p><p>Conclusions</p><p>Our results suggest that PGE₃, PGF_3α, and TXB₃ are substrates of ABCC4 and ABCC4 partially contributes to the release of PGE₃ and PGF_3α.</p></div

Effects of ABCC4 inhibitors on the transport of 3-series prostanoids in A549 cells.

<p>A549 cells were treated with 100 µM EPA for 24 h then 10 µM A23187 in presence or absence of ABCC4 inhibitors (50 µM dipyridamole, 50 µM MK571, or 500 µM probenecid) for 5 min. The extracellular and intracellular levels of (A, D) PGE₃, (B, E) PGF_3α, and (C, F) TXB₃ were measured and (G–H) the ratio of extracellular to intracellular levels were calculated. Each column represents the mean with S.E. (n = 3). Representative experiments are shown. *; <i>p</i><0.05, **; <i>p</i><0.01.</p