adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.

We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.

Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.

Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis.

Transcriptional determinants of lipid mobilization in human adipocytes.

Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins.

Α Humanized RANKL Transgenic Mouse Model of Progestin-Induced Mammary Carcinogenesis for Evaluation of Novel Therapeutics.

Receptor activator of nuclear factor-κB ligand (RANKL) is critically involved in mammary gland pathophysiology, while its pharmaceutical inhibition is being currently investigated in breast cancer. Herein, we investigated whether the overexpression of human RANKL in transgenic mice affects hormone-induced mammary carcinogenesis, and evaluated the efficacy of anti-RANKL treatments, such as OPG-Fc targeting both human and mouse RANKL or Denosumab against human RANKL. We established novel MPA/DMBA-driven mammary carcinogenesis models in TgRANKL mice that express both human and mouse RANKL, as well as in humanized humTgRANKL mice expressing only human RANKL, and compared them to MPA/DMBA-treated wild-type (WT) mice.

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 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 approach screened 20'000 compounds, while complementary and proteomic assays were developed to test the efficacy of the 46 predictions.

A facile consensus ranking approach enhances virtual screening robustness and identifies a cell-active DYRK1α inhibitor.

Background: Virtual screening is vital for contemporary drug discovery but striking performance fluctuations are commonly encountered, thus hampering error-free use. Results and Methodology: A conceptual framework is suggested for combining screening algorithms characterized by orthogonality (docking-scoring calculations, 3D shape similarity, 2D fingerprint similarity) into a simple, efficient and expansible python-based consensus ranking scheme. An original experimental dataset is created for comparing individual screening methods versus the novel approach.

Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance.

A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated tumor suppressor p53 was demonstrated in cancer cell lines.