Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD

Influence of Ketotifen, Cromolyn Sodium, and Compound 48/80 on the survival rates after intestinal ischemia reperfusion injury in rats

<p>Abstract</p> <p>Background</p> <p>Mast cells were associated with intestinal ischemia-reperfusion injury, the study was to observe the influence of Ketotifen, Cromolyn Sdium(CS), and Compound 48/80(CP) on the survival rates on the third day after intestinal ischemia-reperfusion injury in rats.</p> <p>Methods</p> <p>120 healthy Sprague-Dawley rats were randomly divided into 5 groups, Sham-operated group (group S), model group (group M), group K, group C and group CP. Intestinal damage was triggered by clamping the superior mesenteric artery for 75 minutes, group K, C, and CP were treated with kotifen 1 mg·kg^-1, CS 50 mg·kg^-1, and CP 0.75 mg·kg^-1i.v. at 5 min before reperfusion and once daily for three days following reperfusion respectively. Survival rate in each group was recorded during the three days after reperfusion. All the surviving rats were killed for determining the concentration of serum glutamic-oxaloacetic transaminase(AST), glutamic pyruvic transaminase(ALT), the ratio of AST compare ALT(S/L), total protein(TP), albumin(ALB), globulin(GLB), the ratio of ALB compare GLB(A/G), phosphocreatine kinase(CK), lactate dehydrogenase(LDH), urea nitrogen(BUN) and creatinine(CRE) at the 3^rdday after reperfusion. And ultrastructure of IMMC, Chiu's score, lung histology, IMMC counts, the levels of TNF-α, IL-1β, IL-6 and IL-10 of the small intestine were detected at the same time.</p> <p>Results</p> <p>Intestinal ischemia-reperfusion injury reduced the survival rate. The concentrations of TP, ALB and level of IL-10 in intestine in group M decreased significantly while the concentrations of S/L, LDH and the levels of IL-6 and TNF-α in intestine increased significantly compared with group S (<it>P </it>< 0.05). Treatment with Ketotifen and CS increased the survival rate compared with group M (<it>P </it>< 0.05), attenuated the down-regulation or up-regulation of the above index (<it>P </it>< 0.05). Treatment with CP decreased the survival rate on the 3^rdday after reperfusion compared with group M(<it>P </it>< 0.05). Group K and C had better morphology in IMMC in the small intestine and in the lungs than in group M and CP, although the Chiu's score and IMMC counts remained the same in the five groups(<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>Mast cell inhibition after ischemia prior to reperfusion and following reperfusion may decrease the multi-organ injury induced by intestine ischemia reperfusion, and increase the survival rates.</p

Secondary Endoleak Management Following TEVAR and EVAR.

Endovascular abdominal and thoracic aortic aneurysm repair and are widely used to treat increasingly complex aneurysms. Secondary endoleaks, defined as those detected more than 30 days after the procedure and after previous negative imaging, remain a challenge for aortic specialists, conferring a need for long-term surveillance and reintervention. Endoleaks are classified on the basis of their anatomic site and aetiology. Type 1 and type 2 endoleaks (EL1 and EL2) are the most common endoleaks necessitating intervention. The management of these requires an understanding of their mechanics, and the risk of sac enlargement and rupture due to increased sac pressure. Endovascular techniques are the main treatment approach to manage secondary endoleaks. However, surgery should be considered where endovascular treatments fail to arrest aneurysm growth. This chapter reviews the aetiology, significance, management strategy and techniques for different endoleak types

Personality, perceived appropriateness, and acknowledgement of social influences on food intake

Social influences are powerful determinants of food intake. Whereas some people are willing to acknowledge social influences on their food intake, others seem to actively deny being influenced by social cues. Across three samples (total n=835), we examined factors that prior theory and research suggest might predict people's willingness to acknowledge social influences on their food intake. These included conformity, self-monitoring, sociotropy, self-esteem, empathy, and the Big Five personality traits. Conformity, self-monitoring, and sociotropy were the most consistent predictors of acknowledgement of social influences on food intake, and conscientiousness was also related to acknowledgement of social influences. Furthermore, those effects were mediated by the extent to which people believe that eating in response to social cues is appropriate. These findings suggest that people who are more concerned with, and attuned to, the social world are more willing to acknowledge being influenced by social factors. Importantly, individuals who are less willing to acknowledge social influences on their food intake may not actually be any less influenced by social cues. Failing to acknowledge social influences on food intake could have implications for people's ability to regulate their eating appropriately and also for their self-evaluations

Hunger, taste, and normative cues in predictions about food intake

Normative eating cues (portion size, social factors) have a powerful impact on people's food intake, but people often fail to acknowledge the influence of these cues, instead explaining their food intake in terms of internal (hunger) or sensory (taste) cues. This study examined whether the same biases apply when making predictions about how much food a person would eat. Participants (n = 364) read a series of vignettes describing an eating scenario and predicted how much food the target person would eat in each situation. Some scenarios consisted of a single eating cue (hunger, taste, or a normative cue) that would be expected to increase intake (e.g., high hunger) or decrease intake (e.g., a companion who eats very little). Other scenarios combined two cues that were in conflict with one another (e.g., high hunger + a companion who eats very little). In the cue-conflict scenarios involving an inhibitory internal/sensory cue (e.g., low hunger) with an augmenting normative cue (e.g., a companion who eats a lot), participants predicted a low level of food intake, suggesting a bias toward the internal/sensory cue. For scenarios involving an augmenting internal/sensory cue (e.g., high hunger) and an inhibitory normative cue (e.g., a companion who eats very little), participants predicted an intermediate level of food intake, suggesting that they were influenced by both the internal/sensory and normative cue. Overall, predictions about food intake tend to reflect a general bias toward internal/sensory cues, but also include normative cues when those cues are inhibitory. If people are systematically biased toward internal, sensory, and inhibitory cues, then they may underestimate how much food they or other people will eat in many situations, particularly when normative cues promoting eating are present