作者: Petersen, Asbjørn Graver ; Andersen, Maja Worm ; Nie, Yaohui ; Oró, Denise ; Hansen, Henrik H. ; Simonsen, Ulf ; Feigh, Michael ; Madsen, Martin Rønn ; Butts, Jordan ; Korntner, Stefanie H. ; Arraut, Alba Manresa ; Bousamaki, Jamal ; Salinas, Casper Gravesen ; Roqueta‐Rivera, Manuel ; Pors, Susanne E.

AbstractThis study comprehensively validated the bleomycin (BLEO) induced mouse model of IPF for utility in preclinical drug discovery. To this end, the model was rigorously evaluated for reproducible phenotype and TGFβ‐directed treatment outcomes. Lung disease was profiled longitudinally in male C57BL6/JRJ mice receiving a single intratracheal instillation of BLEO (n = 10–12 per group). A TGFβR1/ALK5 inhibitor (ALK5i) was profiled in six independent studies in BLEO‐IPF mice, randomized/stratified to treatment according to baseline body weight and non‐invasive whole‐body plethysmography. ALK5i (60 mg/kg/day) or vehicle (n = 10–16 per study) was administered orally for 21 days, starting 7 days after intratracheal BLEO installation. BLEO‐IPF mice recapitulated functional, histological and biochemical hallmarks of IPF, including declining expiratory/inspiratory capacity and inflammatory and fibrotic lung injury accompanied by markedly elevated TGFβ levels in bronchoalveolar lavage fluid and lung tissue. Pulmonary transcriptome signatures of inflammation and fibrosis in BLEO‐IPF mice were comparable to reported data in IPF patients. ALK5i promoted reproducible and robust therapeutic outcomes on lung functional, biochemical and histological endpoints in BLEO‐IPF mice. The robust lung fibrotic disease phenotype, along with the consistent and reproducible lung protective effects of ALK5i treatment, makes the spirometry‐confirmed BLEO‐IPF mouse model highly applicable for profiling novel drug candidates for IPF.

2024-02-01·F&S Science

Oocyte-derived growth differentiation factor 9 suppresses the expression of CYP17A1 and androgen production in human theca cells

Article

作者: Wu, Rihan ; Liu, Yang ; Chen, Minghui ; Guo, Xi ; Huang, Ling ; Huang, Chuan ; Zhong, Yiping

OBJECTIVETo investigate the direct effect of growth differentiation factor 9 (GDF9) on androgen production in human theca cells.DESIGNExperimental study.SETTINGTertiary hospital-based research laboratory.PATIENT(S)Women who underwent in vitro fertilization and intracytoplasmic sperm injections at our clinic were included in this study.INTERVENTION(S)Primary cultured human theca cells from women undergoing in vitro fertilization and intracytoplasmic sperm injection treatment were treated with GDF9, an activin receptor-like kinase 5 (ALK5) inhibitor, and a SMAD4 agonist.MAIN OUTCOME MEASURE(S)The expression of androgen synthesis-related genes StAR, CYP17A1, and LHCGR, levels of androstenedione and testosterone, phosphorylation of SMAD2/3, and the interaction between bone morphogenic protein-activated type II receptor and ALK5 were evaluated using reverse transcription-quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assays, and coimmunoprecipitation assays, respectively.RESULT(S)Growth differentiation factor 9 decreased StAR, CYP17A1, and LHCGR expression levels in human theca cells, which was prevented by treatment with the ALK5 inhibitor, and suppressed production of androgen in human theca cells. Growth differentiation factor 9 increased SMAD2/3 phosphorylation, and the ALK5 inhibitor also suppressed this effect. Bone morphogenic protein-activated type II receptor and ALK5 bound to each other after GDF9 stimulation. The SMAD4 agonist kartogenin also decreased messenger RNA levels of StAR and CYP17A1 and protein levels of StAR in human theca cells.CONCLUSION(S)Growth differentiation factor 9 can activate the bone morphogenic protein-activated type II receptor-ALK5-SMAD2/3 signaling pathway, suppress CYP17A1 expression, and decrease androgen production in human theca cells.

2019-01-01·Folia Biologica

Reprogramming of Human Pancreatic Organoid Cells into Insulin-Producing β-Like Cells by Small Molecules and in Vitro Transcribed Modified mRNA Encoding Neurogenin 3 Transcription Factor

Article

作者: Leontovyc, I ; Saudek, F ; Koblas, T ; Loukotová, S

Reprogramming of non-endocrine pancreatic cells into insulin-producing cells represents a promising therapeutic approach for the restoration of endogenous insulin production in diabetic patients. In this paper, we report that human organoid cells derived from the pancreatic tissue can be reprogrammed into the insulin-producing cells (IPCs) by the combination of in vitro transcribed modified mRNA encoding transcription factor neurogenin 3 and small molecules modulating the epigenetic state and signalling pathways. Upon the reprogramming, IPCs formed 4.6 ± 1.2 % of the total cells and expressed typical markers (insulin, glucokinase, ABCC8, KCNJ11, SLC2A2, SLC30A8) and transcription factors (PDX1, NEUROD1, MAFA, NKX2.2, NKX6.1, PAX4, PAX6) needed for the proper function of pancreatic β-cells. Additionally, we have revealed a positive effect of ALK5 inhibitor RepSox on the overall reprogramming efficiency. However, the reprogrammed IPCs possessed only a partial insulin-secretory capacity, as they were not able to respond to the changes in the extracellular glucose concentration by increasing insulin secretion. Based on the achieved results we conclude that due to the incomplete reprogramming, the IPCs have immature character and only partial properties of native human β-cells.

100 项与 ALK5 inhibitor (Nankai University) 相关的药物交易

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