To investigate which phosphodiesterase (PDE) isoforms are expressed in fibroblasts isolated from the tunica albuginea (TA) of patients with Peyronie's disease (PD), and to measure the potency of PDE inhibitors in preventing transformation of these fibroblasts to profibrotic myofibroblasts.

Materials and Methods:

Fibroblasts isolated from the TA of men undergoing surgery for correction of PD curvature were transformed to myofibroblasts using transforming growth factor beta‐1. The expression of 21 PDE isoforms was investigated using quantitative reverse transcriptase‐polymerase chain reaction and protein analysis, as were the effects of various PDE inhibitors on prevention of myofibroblast transformation. Intracellular cAMP and cGMP in the presence of PDE inhibitors were quantified using cGMP/cAMP enzyme‐linked immunosorbant assay assays.

Results:

We found that PDE1A, 1C, 4, 5A, 7B and 8B were expressed at mRNA and protein levels. Selective inhibitors of these enzymes prevented myofibroblast transformation in a concentration‐dependent manner, with PDE1 inhibitor ITI‐214 and PDE4 inhibitors roflumilast and roflumilast N‐oxide showing greatest potency. ITI‐214 and roflumilast N‐oxide increased intracellular cAMP, but not cGMP, in a concentration‐dependent manner.

Conclusions:

This is the first demonstration of the expression of PDE1, 7 and 8 isoforms, and the function of PDE1 and PDE4 in human TA fibroblasts. The ability of inhibitors of these enzymes to prevent myofibroblast transformation suggests that such inhibitors can be developed to treat acute PD.

2025-04-01·ADVANCED MATERIALS

Engineered Stem Cell Booster Breaks Pathological Barriers to Treat Chronic Pancreatitis

Article

作者: Chen, Bi‐Te ; Cheng, Xian‐Wu ; Zhou, Fang ; Li, Ling ; Wang, Guang‐Ji ; Xing, Lei ; Qi, Liang ; Yu, Ping ; Liu, Yang ; Wang, Hui ; Wang, Jing ; Zhao, Min ; Zhang, Chen ; Wei, Ning ; Huang, Zhang‐Jian ; Jiang, Hu‐Lin ; Han, Han

Abstract:

Chronic pancreatitis (CP) is a long‐standing progressive fibrosis and has long been considered incurable, which remains a heavy health burden worldwide. Mesenchymal stem cells (MSCs) with anti‐fibrosis properties are currently used in the treatment of fibroinflammatory diseases. However, its therapeutic effect is limited mainly due to two main types of pathological barriers in CP: 1) Fibrotic collagen hinders cell delivery, and 2) Malignant microenvironment attacks cell inactivation. Here, a MSCs‐based exogenous nitric oxide (NO) delivery system (MSCs‐Lip@RNO) is constructed. In the MSCs‐Lip@RNO, NO not only can be a cell booster to regulate collagen fibers, relieve the vascular compression and enhance the accumulation of MSCs in the whole pancreas, but also can form a protective gas layer on the cell surface, which enhances the therapeutic effect of MSCs. In the CP rat model, the pancreatic injury and fibrosis are reduced with 7 days after a single dose administration of this long‐acting MSCs. Collectively, this study offers a promising strategy for enhancing the delivery and therapeutic efficacy of MSCs to break pathological barriers in CP treatment.

2025-01-05·JOURNAL OF COMPUTATIONAL CHEMISTRY

Development of a machine learning‐based target‐specific scoring function for structure‐based binding affinity prediction for human dihydroorotate dehydrogenase inhibitors

Article

作者: He, Zhe ; Bao, Wenzhuo ; Liu, Hongsheng ; Zhang, Li ; Hu, Mengfeng ; Tian, Qifeng ; Meng, Jinhui ; Feng, Huawei ; Liu, Jinhan

Abstract:

Human dihydroorotate dehydrogenase (hDHODH) is a flavin mononucleotide‐dependent enzyme that can limit de novo pyrimidine synthesis, making it a therapeutic target for diseases such as autoimmune disorders and cancer. In this study, using the docking structures of complexes generated by AutoDock Vina, we integrate interaction features and ligand features, and employ support vector regression to develop a target‐specific scoring function for hDHODH (TSSF‐hDHODH). The Pearson correlation coefficient values of TSSF‐hDHODH in the cross‐validation and external validation are 0.86 and 0.74, respectively, both of which are far superior to those of classic scoring function AutoDock Vina and random forest (RF) based generic scoring function RF‐Score. TSSF‐hDHODH is further used for the virtual screening of potential inhibitors in the FDA‐Approved & Pharmacopeia Drug Library. In conjunction with the results from molecular dynamics simulations, crizotinib is identified as a candidate for subsequent structural optimization. This study can be useful for the discovery of hDHODH inhibitors and the development of scoring functions for additional targets.

100 项与 Roflumilast N-oxide 相关的药物交易

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