Peptide PD29 treats bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß/smad signaling pathway.

Pulmonary fibrosis (PF) is an end-stage change in lung disease characterized by fibroblast proliferation, massive extracellular matrix (ECM) aggregation with inflammatory damage, and severe structural deterioration. PD29 is a 29-amino acid peptide which has the potential to alleviate PF pathogenesis via three mechanisms: anti-angiogenesis, inhibition of matrix metalloproteinase activities, and inhibition of integrins. In this study, fibrotic lung injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administered 7.5, 5, or 2.5 mg/kg PD29 daily for 30 days. BLM induced-syndromes including structure distortion, excessive deposition of ECM, excessive inflammatory infiltration, and pro-inflammatory cytokine release were used to evaluate the protective effect of PD-29. Oxidative stress damage in lung tissues was attenuated by PD29 in a dose-dependent manner. The expression of TGF-ß1 and the phosphorylation of Smad-2/-3-its downstream targets-were enhanced by BLM and weakened by PD29. In vitro, PD29 inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and transformation in A549 cells and mouse primary fibroblasts into myofibroblasts. In summary, PD29 reversed EMT and transformation of fibroblasts into myofibroblasts in vitro and prevented PF in vivo possibly by suppressing the TGF-ß1/Smad pathway.

Facile Synthesis and Cytotoxicity of Phenazine-Chromene Hybrid Molecules Derived from Phenazine Natural Product.

AIM AND OBJECTIVE: Small molecule targeted drugs can effectively reduce the toxicity and side effects of drugs, and improve the efficacy of drugs by their specific antitumor activity. Hence, the development of small molecular targeted drugs for cancer has important significance. This study was undertaken to design and synthesize novel phenazine-chromene hybrid molecules in order to optimize the structure and improve the efficacy of this kind of hybrids. MATERIALS AND METHODS: O-diaminobenzene was used as starting material to synthesize twentyfour heterocyclic compounds designed as hybrid molecules of phenazine and 4H-chromene pharmacophores by facile methods. The structures of the compound were confirmed by 1H NMR, 13C NMR and HRMS. Furthermore, the synthesized compounds were evaluated for in vitro activity against four human cancer cell lines and two non-cancer cell lines by MTT test. RESULTS: Some compounds showed strong cytotoxic activities against HepG2 and A549 cancer lines (IC50 = 5-10 µM). Comparing 2i with 2l, the introduction of hydrophilic groups on the phenazine core could not improve the antiproliferative activity significantly. Except 2d and 3c, compounds owning chlorine substituent on the 4H-chromene pharmacophore seemingly contribute to enhance the compounds' antiproliferative activity. Specially, compound 3c showed highest cytotoxicity against A549 cells with IC50 values of 3.3±0.4 µM. Furthermore, all compounds showed low or no cytotoxicity against HUVEC and L02 non-cancer cells in vitro. CONCLUSION: Compound 3c may be used as potential lead molecule against A549 cancer cells.