Forward genetics combined with unsupervised classifications identified zebrafish mutants affecting biliary system formation.

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes.

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment.

NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3-Kinase/Akt Serine/Threonine Kinase and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma.

Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation. Aerobic glycolysis and glutaminolysis are two of the most essential characteristics of cancer metabolic reprogramming. Hyperactivated phosphoinositide 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways play central roles in cancer cell metabolic adaptation given that their downstream effectors, such as Akt and c-Myc, control most of the glycolytic and glutaminolysis genes.

The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-α-glycoprotein (ZAG) induces WAT browning in mice.

Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish.

The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish.

Ligand and Structure Based Models for the Identification of Beta 2 Adrenergic Receptor Antagonists.

Ligand bound beta 2 adrenergic receptor (β2AR) crystal structures are in use for screening of compound libraries for identifying inducers and blockers. However, in case of G protein coupled receptors (GPCR), docking and binding energy (BE) calculations are not enough to discriminate agonist and antagonists. Absence of a reliable model for discriminating β2AR antagonist is still a major hurdle.

Prilocaine hydrochloride protects zebrafish from lethal effects of ionizing radiation: role of hematopoietic cell expansion.

Drug repositioning is an approach of significant translatability, and the present study was undertaken to screen a collection of FDA approved small-molecule clinical compounds for identification of novel radioprotective agents. Screening of JHCCL (Johns Hopkins Clinical Compound Library), a collection of 1,400 FDA approved small molecules, lead to identification of prilocaine hydrochloride, a local anesthetic used widely during dental procedures, as a potential radioprotector. Prilocaine, at a concentration of 20 µM, protected zebrafish from radiation induced (20 Gy) pericardial edema (PE), microphthalmia and rendered 60 % survival advantage over radiation exposed controls.

Todralazine protects zebrafish from lethal effects of ionizing radiation: role of hematopoietic cell expansion.

The Johns Hopkins Clinical Compound Library (JHCCL), a collection of Food and Drug Administration (FDA)-approved small molecules (1400), was screened in silico for identification of novel β2AR blockers and tested for hematopoietic stem cell (HSC) expansion and radioprotection in zebrafish embryos. Docking studies, followed by the capacity to hasten erythropoiesis, identified todralazine (Binding energy, -8.4 kcal/mol) as a potential HSC-modulating agent.

Cycloxygenase-2 (COX-2)--a potential target for screening of small molecules as radiation countermeasure agents: an in silico study.

Cyclooxygenase-2 (COX-2) is well established for its role in inflammation, cancer and has also been reported to play a significant role in radiation induced inflammation and bystander effect. It has already been reported to have a role in protection against radiation induced damage, suggesting it to be an important target for identifying novel radiation countermeasure agents. Present study aims at identifying novel small molecules from pharmacopeia using COX-2 as target in silico.