Self-Organization of Sinusoidal Vessels in Pluripotent Stem Cell-derived Human Liver Bud Organoids.

The induction of tissue-specific vessels in living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b putative liver sinusoidal progenitors (iLSEP) by dictating developmental pathways. By devising an inverted multilayered air-liquid interface (IMALI) culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organized to generate and sustain hepatocyte-like cells neighbored by divergent endothelial subsets composed of CD32bCD31, LYVE1STAB1CD32bCD31THBDvWF, and LYVE1THBDvWF cells.

Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19.

COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular organoid from pluripotent stem cells for modeling endotheliopathy.

The promise of human organoids in the digestive system.

The advent of organoid technology has enabled scientists and clinicians to utilize cells from primary tissues or pluripotent stem cells (PSCs) to grow self-organizing tissue systems, thus attaining cellular diversity, spatial organization, and functionality as found within digestive tracts. The development of human gastrointestinal (GI) and hepato-biliary-pancreatic organoids as an in-a-dish model present novel opportunities to study humanistic mechanisms of organogenesis, regeneration and pathogenesis. Herein, we review the recent portfolios of primary tissue-derived and PSC-derived organoids in the digestive systems.

Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration.

Dysfunctional mitochondria accumulate in many human diseases. Accordingly, mitophagy, which removes these mitochondria through lysosomal degradation, is attracting broad attention. Due to uncertainties in the operational principles of conventional mitophagy probes, however, the specificity and quantitativeness of their readouts are disputable.

Bombesin receptor subtype-3-expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus.

Objectives: Bombesin receptor subtype-3 (BRS-3) has been suggested to play a potential role in energy homeostasis. However, the physiological mechanism of BRS-3 on energy homeostasis remains unknown. Thus, we investigated the BRS-3-mediated neuronal pathway involved in food intake and energy expenditure.

A potent neuromedin U receptor 2-selective alkylated peptide.

Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable.

A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced-Obese Rats With Circadian Rhythm Change.

Bombesin receptor subtype 3 (BRS-3) is an orphan G protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects.

Cancer with low cathepsin D levels is susceptible to vacuolar (H )-ATPase inhibition.

Vacuolar (H )-ATPases (V-ATPases) have important roles in the supply of nutrients to tumors by mediating autophagy and the endocytic uptake of extracellular fluids. Accordingly, V-ATPases are attractive therapeutic targets for cancer. However, the clinical use of V-ATPase inhibitors as anticancer drugs has not been realized, possibly owing to their high toxicity in humans.

Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition.

Lysosomal protein degradation via autophagy strictly regulates cellular protein homoeostasis. Herein we performed high-content screening to identify compounds that inhibit autophagy pathways. We obtained 11 hit compounds and performed cluster analysis using cellular morphological information.

Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors.

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats.

Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors.

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety.

Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.

Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes.

Construction of a regulatable cancer-specific adenoviral expression system using human telomerase reverse transcriptase gene promoter.

We constructed a novel cancer-specific regulatable adenoviral expression system comprising two vectors: one expressing rtTA, a reverse tetracycline transactivator regulated by the human telomerase reverse transcriptase (hTERT) gene promoter, the other expressing the target gene regulated by the tetracycline response element (TRE). rtTA transactivates target gene expression in the presence of doxycycline. Using these vectors, we constructed an adenoviral expression system, the Tel-On system, which enables highly efficient target gene transduction.