A network-based computational and experimental framework for repurposing compounds toward the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver pathologies, however, none approved condition-specific therapy yet exists. The present study introduces a drug repositioning (DR) approach that combines in vitro steatosis models with a network-based computational platform, constructed upon genomic data from diseased liver biopsies and compound-treated cell lines, to propose effectively repositioned therapeutic compounds. The introduced in silico approach screened 20'000 compounds, while complementary in vitro and proteomic assays were developed to test the efficacy of the 46 in silico predictions. This approach successfully identified six compounds, including the known anti-steatogenic drugs resveratrol and sirolimus. In short, gallamine triethiotide, diflorasone, fenoterol, and pralidoxime ameliorate steatosis similarly to resveratrol/sirolimus. The implementation holds great potential in reducing screening time in the early drug discovery stages and in delivering promising compounds for in vivo testing.

Tissue Engineering with Mechanically Induced Solid-Fluid Transitions.

Epithelia are contiguous sheets of cells that stabilize the shape of internal organs and support their structure by covering their surfaces. They acquire diverse morphological forms appropriate for their specific functions during embryonic development, such as the kidney tubules and the complex branching structures found in the lung. The maintenance of epithelial morphogenesis and homeostasis is controlled by their remarkable mechanics-epithelia can become elastic, plastic, and viscous by actively remodeling cell-cell junctions and modulating the distribution of local stresses. Microfabrication, finite element modelling, light-sheet microscopy, and robotic micromanipulation are used to show that collagen gels covered with an epithelial skin serve as shape-programmable soft matter. The process involves solid to fluid transitions induced by mechanical perturbations, generates spatially distributed surface stresses at tissue interfaces, and is amenable to both additive and subtractive manufacturing techniques. The robustness and versatility of this strategy for engineering designer tissues is demonstrated by directing the morphogenesis of a variety of molded, carved, and assembled forms from the base material. The results provide insight into the active mechanical properties of the epithelia and establish methods for engineering tissues with sustainable architectures.