Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis.

BACKGROUND & AIMS: ß-Catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of ß-catenin signaling and activation of FXR in a mouse model of cholestasis will reduce injury and biliary fibrosis through inhibition of bile acid synthesis. METHODS: To induce cholestasis, we performed bile duct ligation (BDL) on wild-type male mice. Eight hours after surgery, mice received FXR agonists obeticholic acid, tropifexor, or GW-4064 or Wnt inhibitor Wnt-C59. Severity of cholestatic liver disease and expression of target genes were evaluated after either 5 days or 12 days of treatment. RESULTS: We found that although the FXR agonists worsened BDL-induced injury and necrosis after 5 days, Wnt-C59 did not. After 12 days of BDL, Wnt-C59 treatment, but not GW-4064 treatment, reduced both the number of infarcts and the number of inflammatory cells in liver. RNA sequencing analysis of whole livers revealed a notable suppression of nuclear factor kappa B signaling when Wnt signaling is inhibited. We then analyzed transcriptomic data to identify a cholangiocyte-specific signature in our model and demonstrated that Wnt-C59-treated livers were enriched for genes expressed in quiescent cholangiocytes, whereas genes expressed in activated cholangiocytes were enriched in BDL alone. A similar decrease in biliary injury and inflammation occurred in Mdr2 KO mice treated with Wnt-C59. CONCLUSIONS: Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the nuclear factor kappa B-dependent inflammatory axis, reducing cholestatic-induced injury.

Women with fibromyalgia's experience with three motion-controlled video game consoles and indicators of symptom severity and performance of activities of daily living.

PURPOSE: Little is known of Motion-Controlled Video Games (MCVGs) as an intervention for people with chronic pain. The aim of this study was to explore the experience women with fibromyalgia syndrome (FMS) had, using commercially available MCVGs; and to investigate indicators of symptom severity and performance of activities of daily living (ADL). METHOD: Of 15 female participants diagnosed with FMS, 7 completed a program of five sessions with Nintendo Wii (Wii), five sessions with PlayStation 3 Move (PS3 Move) and five sessions with Microsoft Xbox Kinect (Xbox Kinect). Interviews were conducted at baseline and post-intervention and were supported by data from observation and self-reported assessment. RESULTS: Participants experienced play with MCVGs as a way to get distraction from pain symptoms while doing fun and manageable exercise. They enjoyed the slow pace and familiarity of Wii, while some considered PS3 Move to be too fast paced. Xbox Kinect was reported as the best console for exercise. There were no indication of general improvement in symptom severity or performance of ADL. CONCLUSION: This study demonstrated MCVG as an effective healthcare intervention for the women with FMS who completed the program, with regards to temporary pain relief and enjoyable low impact exercise. Implications for Rehabilitation Exercise is recommended in the management of fibromyalgia syndrome (FMS). People with FMS often find it counterintuitive to exercise because of pain exacerbation, which may influence adherence to an exercise program. Motion-controlled video games may offer temporary pain relief and fun low impact exercise for women with FMS.