Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice

Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2− animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2− and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH mode

HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression

Older Adults’ Experiences of a Physical Activity and Sedentary Behaviour Intervention: A Nested Qualitative Study in the SITLESS Multi-Country Randomised Clinical Trial

Background: The SITLESS programme comprises exercise referral schemes and self-management strategies and has been evaluated in a trial in Denmark, Spain, Germany and Northern Ireland. The aim of this qualitative study was to understand the implementation and contextual aspects of the intervention in relation to the mechanisms of impact and to explore the perceived effects. Methods: Qualitative methodologies were nested in the SITLESS trial including 71 individual interviews and 12 focus groups targeting intervention and control group participants from postintervention to 18-month follow-up in all intervention sites based on a semi-structured topic guide. Results: Overarching themes were identified under the framework categories of context, implementation, mechanisms of impact and perceived effects. The findings highlight the perceived barriers and facilitators to older adults’ engagement in exercise referral schemes. Social interaction and enjoyment through the group-based programmes are key components to promote adherence and encourage the maintenance of targeted behaviours through peer support and connectedness. Exit strategies and signposting to relevant classes and facilities enabled the maintenance of positive lifestyle behaviours. Conclusions: When designing and implementing interventions, key components enhancing social interaction, enjoyment and continuity should be in place in order to successfully promote sustained behaviour change

The Added Value of Large-Eddy and Storm-Resolving Models for Simulating Clouds and Precipitation

More than one hundred days were simulated over very large domains with fine (0.156 km to 2.5 km) grid spacing for realistic conditions to test the hypothesis that storm (kilometer) and large-eddy (hectometer) resolving simulations would provide an improved representation of clouds and precipitation in atmospheric simulations. At scales that resolve convective storms (storm-resolving for short), the vertical velocity variance becomes resolved and a better physical basis is achieved for representing clouds and precipitation. Similarly to past studies we found an improved representation of precipitation at kilometer scales, as compared to models with parameterized convection. The main precipitation features (location, diurnal cycle and spatial propagation) are well captured already at kilometer scales, and refining resolution to hectometer scales does not substantially change the simulations in these respects. It does, however, lead to a reduction in the precipitation on the time-scales considered – most notably over the ocean in the tropics. Changes in the distribution of precipitation, with less frequent extremes are also found in simulations incorporating hectometer scales. Hectometer scales appear to be more important for the representation of clouds, and make it possible to capture many important aspects of the cloud field, from the vertical distribution of cloud cover, to the distribution of cloud sizes, and to the diel (daily) cycle. Qualitative improvements, particularly in the ability to differentiate cumulus from stratiform clouds, are seen when one reduces the grid spacing from kilometer to hectometer scales. At the hectometer scale new challenges arise, but the similarity of observed and simulated scales, and the more direct connection between the circulation and the unconstrained degrees of freedom make these challenges less daunting. This quality, combined with already improved simulation as compared to more parameterized models, underpins our conviction that the use and further development of storm-resolving models offers exciting opportunities for advancing understanding of climate and climate change