Catalytic Asymmetric Hydrolysis: Asymmetric Hydrolytic Protonation of Enol Esters Catalyzed by Phase-Transfer Catalysts

理学研究院徳永教授らのグループは、人工触媒を使うことによる、加水分解反応での鏡像異性体の作り分け（不斉合成）に、初めて成功しました 。これまでは、微生物や酵素などの生体触媒を用いないと、この反応を行うことは不可能と言われていました。一方、人工的にエステル加水分解を行う方法として酸や塩基を使う方法が知られてきましたが、鏡像異性体を認識すること（不斉合成）は不可能でした。人工触媒は、生体触媒に比べ、コストや安定性産優れている利点があり、また今回、簡単な方法で塩基によるエステル加水分解を不斉反応に適用できることを明らかにしたことにより、今後の発展が期待されます。（九州大学プレスリリースより

Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Abstract Background Transforming growth factor-β (TGF-β)/Smad signaling is well known to play a critical role in the pathogenesis of systemic sclerosis (SSc). We previously developed an artificial molecule, the histidine-pyridine-histidine ligand derivative HPH-15, which may have an antifibrotic effect. The purpose of the present study was to clarify the effects of this drug in human skin fibroblasts and in a preclinical model of SSc. Methods The effects of HPH-15 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. The antifibrotic properties of HPH-15 and its mechanisms were also examined in a bleomycin-induced skin fibrosis mouse model. Results HPH-15 suppressed the TGF-β-induced phosphorylation of Smad3 and inhibited the expression of collagen I, fibronectin 1, connective tissue growth factor, and α-smooth muscle actin induced by TGF-β in cultured human skin fibroblasts. In the bleomycin-induced skin fibrosis model, oral administration of HPH-15 protected against the development of skin fibrosis and ameliorated established skin fibrosis. Additionally, HPH-15 suppressed the phosphorylation of Smad3 in various cells, including macrophages in the bleomycin-injected skin. Further, in the treated mice, dermal infiltration of proinflammatory macrophages (CD11b+Ly6Chi) and M2 profibrotic macrophages (CD11b+CD204+ or CD11b+CD206+) was significantly decreased during the early and late stages, respectively. HPH-15 treatment resulted in decreased messenger RNA (mRNA) expression of the M2 macrophage markers arginase 1 and Ym-1 in the skin, whereas it inversely augmented expression of Friend leukemia integration 1 and Krüppel-like factor 5 mRNAs, the transcription factors that repress collagen synthesis. No apparent adverse effects of HPH-15 were found during the treatment. Conclusions HPH-15 may inhibit skin fibrosis by inhibiting the phosphorylation of Smad3 in dermal fibroblasts and possibly in macrophages. Our results demonstrate several positive qualities of HPH-15, including oral bioavailability, a good safety profile, and therapeutic effectiveness. Thus, this TGF-β/Smad inhibitor is a potential candidate therapeutic for SSc clinical trials

Additional file 1: of Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Figure S1. The molecular structure of HPH-15. (PDF 7 kb

Additional file 4: of Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Figure S4. The inverse proportional change of Ly6Chi macrophages and CD206+ M2 macrophages from the inflammation stage (day 7) to the fibrotic stage (day 21). The single-cell suspension obtained from the back skin of bleomycin-injected C57BL/6 mice on day 7 and day 21 was stained with the mAbs against CD45, CD11b, Ly6C, and CD206. Stained samples were analyzed using the FACSCanto II system. Data were analyzed using FlowJo software version 7. All values represent mean ± SEM. n = 3 at each time point. ** p ≤ 0.01. (PDF 49 kb

Additional file 2: of Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Figure S2. HPH-15 treatment did not affect the growing of the mice. The body weight changes of mice treated with vehicle or HPH-15 were assessed every 3 days. All values represent mean Âą SEM; n = 5 in each group. (PDF 6 kb

Additional file 3: of Blockade of TGF-β/Smad signaling by the small compound HPH-15 ameliorates experimental skin fibrosis

Figure S3. Every-other-day injection of bleomycin for 2 weeks induced significant skin fibrosis. Back skin of NaCl- or bleomycin-injected mice was harvested on day 14 and stained with H&E. Scale bar = 100 Îźm. n = 3 in each group. (PDF 80 kb