Author: Liu, Jingyu ; Jiang, Yue ; Sun, Haixiang ; Ding, Lijun ; Liu, Yang ; Zhang, Yang ; Hu, Yali ; Wang, Zhilong ; Kong, Na ; Li, Chaojun ; Yan, Guijun ; Yuan, Qiong

AbstractAlthough adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of pregnancies affected by neural tube defects (NTDs), the mechanisms underlying FA-resistant NTDs are poorly understood, and thus NTDs still remain a global public health concern. A high level of Krüppel-like factor 12 (KLF12) exerts deleterious effects on heath in most cases, but evidence for its roles in development has not been published. We observed KLF12-overexpressing mice showed disturbed neural tube development. KLF12-overexpressing fetuses died in utero at approximately 10.5 days post-coitus, with 100% presenting cranial NTDs. Neither FA nor formate promoted normal neural tube closure in mutant fetuses. The RNA-seq results showed that a high level of KLF12 caused NTDs in mice via overactivating the sonic hedgehog (Shh) signaling pathway, leading to the upregulation of patched 1, GLI-Krüppel family member GLI1, hedgehog-interacting protein, etc., whereas FA metabolism-related enzymes did not express differently. PF-5274857, an antagonist of the Shh signaling pathway, significantly promoted dorsolateral hinge point formation and partially rescued the NTDs. The regulatory hierarchy between a high level of KLF12 and FA-resistant NTDs might provide new insights into the diagnosis and treatment of unexplained NTDs in the future.

01 Jul 2016·Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition

[Inhibition of Cigarettes Smoke-induced Epithelial to Mesenchymal Transition by the SMO Inhibitor PF-5274857 in Beas-2b Epithelial Cells].

Article

Author: Zhang, Ping ; Fan, Ya-Ping ; Feng, Yun ; Zhou, Wen-Jie ; Fu, Jian ; Li, Qian ; Chen, Jiao

OBJECTIVESTo explore the effects of the Smoothened (Smo) inhibitor PF-5274857 on cigarette smoke (CS)-induced epithelial-mesenchymal transition (EMT) and apply a new idea fororal squamous cell carcinoma (OSCC) treatment.METHODSBeas-2b cells were used to investigate the CS-induced EMT. Both pretreat and post-treat were performed in the study. In pretreat group, after being pretreated with 3 μmol/L PF-5274857 for 2 h, cells were cultured with CS for 8 d; In post-treat group, cells were treated by 3 μmol/L PF-5274857 for 4 d after CS cultrue. Western blot and immunofluorescence were applied to examine the EMT markers E-cadherin, vimentin, and smooth muscle actin α (α-SMA) in Beas-2b epithelial cells. The transwell culture system was used in migration assays.RESULTSPretreat Beas-2b cells with PF-5274857 for 2 h can prevent the CS-induced EMT for epithelial and mesenchymal markers, as well as migration capacity. Up regulated E-cadherin and down regulated vimentin and α-SMA were observed by Western blot. Furthermore Beas-2b cells induced by CS that underwent EMT showed increased E-cadherin and decreased vimentin and α-SMA after treatment with PF-5274857 for 4 d. Importantly, the elevated migration capacity level was also decreased.CONCLUSIONSThe Smo inhibitor PF-5274857 has both preventive effect and therapeutic potential against CS-induced EMT.

01 Apr 2016·Pharmacology Research & PerspectivesQ4 · MEDICINE

Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model

Q4 · MEDICINE

ArticleOA

Author: Denais‐Laliève, Delphine ; Calmettes, Marie‐Thérèse ; Lestienne, Fabrice ; Degryse, Anne‐Dominique ; Tourette, Amélie ; Cathala, Claudie ; Rauly‐Lestienne, Isabelle ; Ailhaud, Marie‐Christine ; Lauressergues, Emilie ; Cussac, Didier ; Troulier, David ; Tardif, Stéphanie ; De Vries, Luc ; Dumoulin, Antoine ; Heusler, Peter

AbstractThe Hedgehog (HH) pathway has been linked to the formation of basal cell carcinoma (BCC), medulloblastoma, and other cancers. The recently approved orally active drugs vismodegib (GDC‐0449) and sonidegib (LDE–225) were not only efficacious for the treatment of advanced or metastatic BCC by antagonizing the smoothened (SMO) receptor, but also produced important side effects, limiting their use for less invasive BCC. Herein, we compared a large series of SMO antagonists, including GDC‐0449 and LDE‐225, the clinically tested BMS‐833923, CUR‐61414, cyclopamine, IPI‐926 (saridegib), itraconazole, LEQ‐506, LY‐2940680 (taladegib), PF‐04449913 (glasdegib), and TAK‐441 as well as preclinical candidates (PF‐5274857, MRT‐83) in two SMO‐dependent cellular assays and for G‐protein activation. We report marked differences in inhibitor potencies between compounds as well as a notable disparity between the G‐protein assay and the cellular tests, suggesting that classification of drugs is assay dependent. Furthermore, we explored topical efficacies of SMO antagonists on depilated mice using Gli1 and Ptch1 mRNA quantification in skin as biomarkers of the HH signaling inhibition. This topical model rapidly discriminated drugs in terms of efficacies and potencies for inhibition of both biomarkers. SMO antagonists showed also a large variation in their blood and skin partition, suggesting that some drugs are more favorable for topical application. Overall, our data suggested that in vitro and in vivo efficacious drugs such as LEQ‐506 and TAK‐441 may be of interest for topical treatment of less invasive BCC with minimal side effects.

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