SCY-078 demonstrated in vivo efficacy against infections caused by both WT and echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against echinocandin-resistant C. glabrata infections.
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from hepatic steatosis (excessive accumulation of triglycerides [TG]) to nonalcoholic steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The molecular pathogenesis of steatosis and progression to more severe NAFLD remains unclear. Obesity and aging, two principal risk factors for NAFLD, are associated with a hyperadrenergic state. β-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of β2-adrenergic receptors (β2-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of β2-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective β2-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying β2-AR mediated steatosis by investigating changes in hepatic expression and cellular localization of enzymes, transcription factors and coactivators involved in processes of lipid accrual and disposition-and also functional aspects thereof-in livers of formoterol treated animals. Our results suggest that β2-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete β-oxidation of fatty acids with accumulation of potentially toxic long-chain acylcarnitine intermediates, and reduced TG secretion-all previously invoked as contributors to fatty liver disease. Experiments are ongoing to determine whether sustained activation of hepatic β2-AR signaling by formoterol might be utilized to model fatty liver changes occurring in hyperadrenergic states of obesity and aging, and thereby identify novel molecular targets for the prevention or treatment of NAFLD.
We investigated whether increased signaling by beta2-adrenergic receptors (β2-ARs), which mediate the action of catecholamines, enhances the progression of hepatocellular carcinoma (HCC). Mean age of patients with HCC, the most prolific form of liver cancer, has progressively increased over the last decade. Beta2-AR-mediated signaling in liver increases with age. We also observed increased β2-AR levels in liver tissues of patients with HCC compared to control subjects. We, therefore, hypothesized that increased β2-AR signaling enhances HCC progression while inhibition of β2-AR signaling by treatment with beta blockers suppresses its progression. To test this hypothesis, we used N-nitrosodiethylamine (DEN) to induce HCC in liver-specific β2-AR knockout (LKO) and control mice in the absence or presence of beta blocker propranolol. At the end of 25 weeks, we observed increased numbers of visible tumors, disarray of liver architecture, and mortality in DEN-induced control mice which was reduced by propranolol treatment. We also observed that DEN-treated LKO mice demonstrated reduced mortality, disarray of architecture, and phosphorylation of oncogene Src compared to DEN-treated control mice. Taken together, these results indicate that decreased β2-AR signaling because of a lack of receptors in the liver or inhibition of receptor action with propranolol reduces HCC progression. Studies are in progress to determine the β2-AR-mediated mechanisms involved in HCC progression. Our studies suggest that beta blocker propranolol, used to treat cardiovascular diseases, may be repurposed as a potential therapeutic option for treatment of HCC.
Substantial synthetic biology efforts have been made to engineer biosensors to detect intestinal inflammation, however none target the most clinically accepted biomarker, calprotectin. To develop an in situ biosensor for calprotectin, we optimized a zinc uptake regulator (Zur) regulated promoter coupled with a memory circuit that can detect and record intestinal inflammation in vivo. The level of activation strongly correlates with calprotectin levels in the colon of two independent mouse models of colitis. Coupling of the biosensor with the production of the anti-inflammatory cytokine IL10 allowed for the resolution of chemically induced colitis, demonstrating the ability of the biosensor to sense and respond to disease. This work highlights the utility of developing synthetic organisms for the diagnosis and treatment of intestinal disease using clinically validated biomarkers.
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