Upregulation of Histidine Decarboxylase Immunoreactivity in Neointimal Smooth Muscle Cells of Balloon-injured Porcine Coronary Arteries

粥状動脈硬化により狭窄した冠動脈にバルーンを挿入して拡張する経皮的冠動脈形成術(PTCA)はステントと併用して広く行われているが、術後の再狭窄が問題となっている。再狭窄の主な原因は、血管中膜平滑筋細胞の内膜への遊走と増殖による内膜肥厚である。この過程には、血小板由来増殖因子など種々のペプチド性増殖因子の関与が示唆されているが、非ペプチド性因子の関与については明らかでない。我々は、ブタ冠動脈バルーン障害モデルの内膜肥厚部位に、著しいヒスタミン含量の増加を見出し報告して来た。一般に、組織中のヒスタミンは、肥満細胞中に貯蔵され遊離されるか、ヒスチジン脱炭酸酵素(HDC)により新規に合成分泌される。そこで、本研究では、ブタ冠動脈バルーン障害モデルにおけるHDCの分布を免疫組織化学的に検討し、内膜肥厚部位に著しいHDCの発現を明らかにした。また、ウェスタンブロット解析の結果、内膜肥厚部位を含む血管に63kDaのHDC陽性バンドを検出した。このことからヒスタミンは、内膜肥厚部位の平滑筋細胞から合成分泌されていることが示唆された。(著者抄録

Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity

Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity

GSK3 inhibitor enhances gemtuzumab ozogamicin‐induced apoptosis in primary human leukemia cells by overcoming multiple mechanisms of resistance

Abstract In acute myeloid leukemia (AML), the heterogeneity of genetic and epigenetic characteristics makes treatment difficult. The prognosis for AML is therefore poor, and there is an urgent need for new treatments for this condition. Gemtuzumab ozogamicin (GO), the first antibody‐drug conjugate (ADC), targets the CD33 antigen expressed in over 90% of AML cases. GO therefore has the potential to counter the heterogeneity of AML patients. However, a major clinical problem is that drug resistance to GO diminishes its effect over time. Here, we report that the inhibition of glycogen synthase kinase 3 (GSK3) alone overcomes several forms of GO resistance at concentrations without antileukemic effects. The GSK3 inhibitors tested significantly enhanced the cytotoxic effect of GO in AML cell lines. We elucidated four mechanisms of enhancement: (1) increased expression of CD33, the target antigen of GO; (2) activation of a lysosomal function essential for hydrolysis of the GO linker; (3) reduced expression of MDR1 that eliminates calicheamicin, the payload of GO; and (4) reduced expression of the anti‐apoptotic factor Bcl‐2. A similar combination effect was observed against patient‐derived primary AML cells. Combining GO with GSK3 inhibitors may be efficacious in treating heterogeneous AML