Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH.

Apratoxin A Shows Novel Pancreas-Targeting Activity through the Binding of Sec 61.

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown.

Brunner's gland lesions in rats induced by a vascular endothelial growth factor receptor inhibitor.

Vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitors are reported to cause reversible mucosal hyperplasia (adenosis) in the duodenum of rats; however, the pathogenesis is not fully elucidated. Using lenvatinib, a VEGF RTK inhibitor, we characterized the histologic time course of this duodenal change in rats. At 4 weeks, there was degeneration and necrosis of Brunner's gland epithelium accompanied by neutrophil infiltration around the affected glands.

Assessment of the translational value of mouse lupus models using clinically relevant biomarkers.

Lupus is an autoimmune disease with a poorly understood etiology that manifests with a diverse pathology. This heterogeneity has been a challenge to clinical drug development efforts. A related difficulty is the uncertain translational power of animal models used for evaluating potential drug targets and candidate therapeutics, because it is unlikely that any 1 preclinical model will recapitulate the spectrum of human disease.

Evaluation of a candidate anti-arthritic drug using the mouse collagen antibody induced arthritis model and clinically relevant biomarkers.

The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel EP4 receptor antagonist (ER-886046) for its anti-arthritic potential.

Docosahexaenoic acid supplementation fully restores fertility and spermatogenesis in male delta-6 desaturase-null mice.

Delta-6 desaturase-null mice ((-/-)) are unable to synthesize highly unsaturated fatty acids (HUFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), and n6-docosapentaenoic acid (DPAn6). The (-/-) males exhibit infertility and arrest of spermatogenesis at late spermiogenesis. To determine which HUFA is essential for spermiogenesis, a diet supplemented with either 0.

Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence.

Agents that can modulate colonic environment and control dysregulated signaling are being evaluated for their chemopreventive potential in colon cancer. Ursodeoxycholate (UDCA) has shown chemopreventive potential in preclinical and animal models of colon cancer, but the mechanism behind it remains unknown. Here biological effects of UDCA were examined to understand mechanism behind its chemoprevention in colon cancer.

Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity.

Background: There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA), a putative chemopreventive agent, exhibited distinct biological effects, yet appeared to act on some of the same signaling molecules. The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA.

Deoxycholic acid induces intracellular signaling through membrane perturbations.

Secondary bile acids have long been postulated to be tumor promoters in the colon; however, their mechanism of action remains unclear. In this study, we examined the actions of bile acids at the cell membrane and found that they can perturb membrane structure by alteration of membrane microdomains. Depletion of membrane cholesterol by treating with methyl-beta-cyclodextrin suppressed deoxycholic acid (DCA)-induced apoptosis, and staining for cholesterol with filipin showed that DCA caused a marked rearrangement of this lipid in the membrane.

Bile acid induces hydrophobicity-dependent membrane alterations.

Elevated concentrations of fecal bile acids are a known risk factor for colon cancer, owing to alterations in cellular signaling. In colonic cells, where bile acid uptake is minimal, the hydrophobicity-induced membrane perturbation and alterations have been proposed, but these membrane alterations are largely uncharacterized. In this study, we examined the determinants and characteristics of bile acid-induced membrane alterations, utilizing PKCalpha activation and cholesterol up-regulation as model indicators.

Ursodeoxycholic acid can suppress deoxycholic acid-induced apoptosis by stimulating Akt/PKB-dependent survival signaling.

The nontoxic bile acid ursodeoxycholic acid (UDCA) is reported to be an anti-apoptotic agent with efficacy against a variety of death stimuli including the cytotoxic bile acid deoxycholic acid (DCA). To gain insight into this anti-apoptotic property, we tested UDCA for its ability to protect the colon carcinoma-derived cell line HCT116 against DCA-induced apoptosis. We found that UDCA could suppress DCA-induced apoptosis in a time- and dose-dependent manner and that this effect correlated with Akt phosphorylation.