Long-acting genipin derivative protects retinal ganglion cells from oxidative stress models in vitro and in vivo through the Nrf2/antioxidant response element signaling pathway

金沢大学医薬保健研究域医学系金沢大学理工研究域電子情報学系Previously, we reported that genipin, a herbal iridoid, had neuritogenic and neuroprotective actions on PC12 cells. Although nitric oxide (NO)-activated signalings were proposed to be neuritogenic, the neuroprotective action of genipin remains to be elucidated. From the standpoint of NO activation, we tested a possible protective mechanism through the nitrosative Kelch-like ECH-associated protein (Keap1)/NF-E2-related factor 2 (Nrf2)-antioxidant response element pathway in rat retinal ganglion cells (RGC-5 cells) in culture, and in vivo, against hydrogen peroxide and optic nerve injury (ONI), respectively, using a long-acting (1R)-isoPropyloxygenipin (IPRG001). IPRG001 induced NO generation and the expressions of antioxidative enzymes, such as heme oxygenase-1 (HO-1), in RGC-5 cells. The protective action of IPRG001 depended on HO-1 and NO induction. We found that S-nitrosylation of Keap1 by IPRG001 may contribute to translocation of Nrf2 to the nucleus and triggered transcriptional activation of antioxidative enzymes. Furthermore, apoptotic cells were increased and 4-hydroxy-2-nonenal was accumulated in rat retina following ONI. Pre-treatment with IPRG001 almost completely suppressed apoptosis and accumulation of 4-hydroxy-2-nonenal in RGCs following ONI accompanied by HO-1 induction. These data demonstrate for the first time that IPRG001 exerts neuroprotective action in RGCs in vitro and in vivo, through the Nrf2/antioxidant response element pathway by S-nitrosylation against oxidative stress. © 2010 International Society for Neurochemistry

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD

シンキ ゴウセイ カゴウブツ E6201 オヨビ EP4 アンタゴニスト ニ ヨル メンエキ ハンノウ ノ チョウセツ ト ソノ ヤクリ コウカ

まず、E6201の発見の経緯及び薬効発現のメカニズムに関して論述する。その後、乾癬とアトピー性皮膚炎といった皮膚疾患を念頭においた、細胞系での薬理プロファイルを説明する。乾癬においては、前述したように外用剤として、ビタミンD3誘導体、レチノイド誘導体、ステロイドなどが主に使用される。ステロイドはマルチな活性を持っているが、乾癬における主なメカニズムは、抗炎症作用、免疫抑制作用と考えられる。ステロイドの白血球からのサイトカイン産生抑制作用は強力であり、これが乾癬やアトピー性皮膚炎における有用性の主なメカニズムと考えられる。一方、ビタミンD3誘導体やレチノイド誘導体は、その免疫抑制作用やケラチノサイトの増殖抑制作用などが報告されている。アトピー性皮膚炎においては、ステロイド剤に加えてプロトピック(FK506 製剤)が著効を示すが、このサイトカイン産生抑制作用はそのメカニズムと共に有名である。近年、抗TNFα製剤が乾癬で有効性を示しており、PhIIIで抗p40抗体が高い効果を示している。そこで、我々はTNFαの産生抑制物質をスクリーニングする目的で、TNFαのプロモーターを組み込んだレポーター系を作製し、天然物のランダムスクリーニングを行った。その中から強力な抑制物質であるf152A1を発見し、その後の合成展開の中から代謝的に安定なE6201を発見した。更に、我々は、各種in vitroの系において、E6201の免疫系における薬理活性の検討を行ったので報告する

Genetic Diversity and Structure of <em>Quercus hondae</em>, a Rare Evergreen Oak Species in Southwestern Japan

Conservation of rare species is essential for maintaining ecosystem function. Quercus hondae is a rare evergreen oak species (Cyclobalanopsis) endemic to Japan. This species is found in several locations in Southwestern Japan; small populations remain in the tutelary forests of the Japanese shrine. To evaluate the genetic diversity and phylogeographic structure of this rare species, 11 microsatellite loci and chloroplast DNA sequences are analyzed for 12 populations of Q. hondae and 8 populations of the more widespread congeneric species, Q. glauca. It is found that heterozygosity at both the population and species level is substantially lower in Q. hondae than in Q. glauca. Genetic differentiation among populations of Q. hondae was high, in contrast to Q. glauca, in which populations exhibit largely insignificant differentiation. STRUCTURE analysis shows that at K = 7, the clusters largely corresponded to major predefined populations. This study suggests that there is little gene flow among extant Q. hondae populations and that Q. hondae is genetically differentiated due to the greater effect of genetic drift in small populations. This pattern is in sharp contrast to that of a more common congeneric species, which will be an important consideration in the conservation of Q. hondae

High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin—but not with treatment of physician’s choice—in the EMBRACE study

Eribulina; Càncer de mama metastàsic; Supervivència globalEribulin; Cáncer de mama metastásico; Supervivencia globalEribulin; Metastatic breast cancer; Overall survivalBackground Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). Methods The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician’s choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. Results Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437–0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800–1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. Discussion This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures.This work was supported by Eisai Inc., Woodcliff Lake, NJ, USA. The sponsor (Eisai Inc.) participated in the design of this analysis, data analysis, data interpretation, manuscript review, manuscript approval, and decision to submit for publication. Medical writing assistance was provided by Jessica Pannu, PharmD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, with funding provided by Eisai Inc