The Prevalence of Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-analysis.

It is increasingly recognized that cognitive symptoms are a common sequelae of relapsing-remitting multiple sclerosis and are associated with adverse functional consequences. However, estimates of cognitive impairment (CIm) prevalence vary widely. This study aimed to determine the pooled prevalence of CIm among adults with RRMS and investigate moderators of prevalence rates. Following prospective registration (PROSPERO; CRD42021281815), electronic databases (Embase, Scopus, Medline, and PsycINFO) were searched from inception until March 2023. Eligible studies reported the prevalence of CIm among adults with RRMS, as determined through standardized neuropsychological testing and defined as evidence of reduced performance across at least two cognitive domains (e.g., processing speed, attention) relative to normative samples, healthy controls, or premorbid estimates. The electronic database search yielded 8695 unique records, of which 50 met selection criteria. The pooled prevalence of cognitive impairment was 32.5% (95% confidence interval 29.3-36.0%) across 5859 participants. Mean disease duration and age were significant predictors of cognitive impairment prevalence, with samples with longer disease durations and older age reporting higher prevalence rates. Studies which administered more extensive test batteries also reported significantly higher cognitive impairment prevalence. Approximately one third of adults with RRMS experience clinical levels of CIm. This finding supports the use of routine cognitive testing to enable early detection of CIm, and to identify individuals who may benefit from additional cognitive and functional support during treatment planning.

Psychosocial Factors Associated with Cognitive Function in Prostate Cancer Survivors on Hormonal Treatments: A Systematic Review.

Hormonal treatments (HT) for prostate cancer (e.g., androgen deprivation therapy) yield clinical and survival benefits, yet adverse cognitive changes may be a side effect. Since psychosocial factors are largely modifiable, interventions targeting these factors may help mitigate these adverse cognitive effects. This systematic review aimed to identify a range of psychosocial factors associated with cognitive function in individuals with prostate cancer undergoing HT and to determine whether these factors mitigate or exacerbate this effect. Applying PRISMA guidelines, a comprehensive search of relevant databases conducted in September 2023 using terms related to prostate cancer, hormone therapy, and cognitive outcomes was undertaken. The search yielded 694 unique abstracts, with 11 studies included for analysis examining the relationship between cognitive function and the following psychosocial factors: psychological distress, fatigue, insomnia, and coping processes. Findings were mixed with only two studies reporting significant associations between cognitive performance with fatigue and depression. Three studies that included measures of perceived cognitive function identified associations with depression, anxiety, fatigue, insomnia, illness threat appraisals, and coping styles. However, no studies found evidence for an association between self-reported and objective measures of cognitive functioning. Evidence regarding the association of interpersonal factors is lacking. Moreover, whether these factors mitigate or exacerbate the effect of HT on cognitive function still needs to be determined. Overall, the research exploring the association between psychosocial factors and cognitive function in prostate cancer survivors undergoing HT is still in its infancy. Further research is required to optimize the implementation of neuropsychological interventions for prostate cancer survivors.

Parent-offspring similarity in hunger and thirst sensations.

The internal (i.e., interoceptive) sensations that characterise hunger vary between people, and this may also be the case for thirst, although it has not been so well explored. There are probably both heritable and learning-based causes for this interoceptive variability. Consequently, it would seem plausible that parents and their offspring would have more similar patterns of hunger and thirst than pairs of strangers. We tested this idea, in addition to exploring its potential moderating variables, by studying the similarity of self-reported hunger and thirst sensations in 170 students and their primary caregivers from childhood. Both students and caregivers completed the same online-survey, covering hunger and thirst sensations, beliefs about the causes of hunger and thirst, the Three Factor Eating Questionnaire (revised) and demographic data. We find evidence of robust student-caregiver similarity in interoceptive hunger and thirst sensations (medium effect sizes), with these being moderated by caregiver beliefs about the homeostatic nature of each state (medium effect sizes). This suggests a potential role for caregivers in the development of their offspring's interoceptive cues for hunger and for thirst. In addition, thirst, like hunger, appears to be multidimensional, and varies between people. The implications of these findings are discussed.

Human hunger as a memory process.

Hunger refers to (1) the meaning of certain bodily sensations; (2) a mental state of anticipation that food will be good to eat; and (3) an organizing principal, which prioritizes feeding. Definitions (1) and (2) are the focus here, as (3) can be considered their consequent. Definition (1) has been linked to energy-depletion models of hunger, but these are no longer thought viable. Definition (2) has been linked to learning and memory (L&M) models of hunger, but these apply just to palatable foods. Nonetheless, L&M probably forms the basis for hunger generally, as damage to declarative memory can eradicate the experience of hunger. Currently, there is no general L&M model of hunger, little understanding of how physiology intersects with a L&M approach, and no understanding of how Definitions (1) and (2) are related. We present a new L&M model of human hunger. People learn associations between internal (e.g., tummy rumbles) and external cues (e.g., brand names) and food. These associations can be to specific foods (episodic memories) or food-related categories (semantic memories). When a cue is encountered, it may lead to food-related memory retrieval. If retrieval occurs, the memory's affective content allows one to know if food will be good to eat now-hunger-a cognitive operation learned in childhood. These memory processes are acutely inhibited during satiety, and chronically by multiple biological parameters, allowing physiology to modulate hunger. Implications are considered for the process of making hunger judgments, thirst, the cephalic phase response, and motivational and lay theories of hunger. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights.

Ductular reaction and fibrosis are hallmarks of many liver diseases including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Liver fibrosis is the accumulation of extracellular matrix often caused by excess collagen deposition by myofibroblasts. Ductular reaction is the proliferation of bile ducts (which are composed of cholangiocytes) during liver injury. Many other cells including hepatic stellate cells, hepatocytes, hepatic progenitor cells, mesenchymal stem cells, and immune cells contribute to ductular reaction and fibrosis by either directly or indirectly interacting with myofibroblasts and cholangiocytes. This review summarizes the recent findings in cellular links between ductular reaction and fibrosis in numerous liver diseases.

Bile Acids in Autoimmune Liver Disease: Unveiling the Nexus of Inflammation, Inflammatory Cells, and Treatment Strategies.

As bile acids not solely play an essential role in nutrition absorption, but also in regulating metabolic functions as well as immune response, bile acids and their signaling pathways are increasingly acknowledged as potential therapeutic targets in the context of chronic liver diseases. Bile acid receptors such as G protein bile acid-activated receptor 1 and farnesoid X receptor are expressed in different immune cells engaged in innate immunity. Recently, a series of studies have revealed distinct functions of bile acids and bile acid receptors within the adaptive immune system. In addition, a variety of molecules targeting bile acid receptors and transporters are currently in advanced stages of clinical development. Autoimmune liver diseases including conditions like primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis can lead to chronic inflammation, fibrosis, and even cirrhosis and liver failure. In this review, we focus on the role of bile acids in the inflammatory aspects of autoimmune liver diseases.

The Association of APOE ε4 Allele with Retinal Layer Thickness and Microvasculature in Older Adults: Optic Nerve Decline and Cognitive Change Study.

PURPOSE: To investigate the relationship between the apolipoprotein E (APOE) ε4 allele and retinal structural and vascular characteristics in older adult participants from several research studies. We also studied the relationship between these structural and vascular characteristics with multifocal visual evoked potential (mfVEP) indices, neuropsychological parameters and MRI brain volumes in these participants. METHODS: In this study, 109 participants with a mean (SD) age of 67.1 (9.0) years were recruited. Participants were classified as APOE ε4 carriers or non-carriers based on the presence or absence of the ε4 allele. Baseline measurements included peripapillary retinal nerve fibre layer optical coherence tomography (RNFL OCT), and OCT-angiography (OCT-A) for evaluation of the retinal layer thickness and vessel density (VD) parameters. A multifocal visual evoked potential (mfVEP) test, including amplitude and latency, was used to assess the visual pathway function. Finally, cognitive function was evaluated using a battery of neuropsychological tests. OCT-A images were analysed in ImageJ to quantify VD in the superficial and deep vascular plexus and the size of the foveal avascular zone (FAZ). The relationship between carriers of APOE ε4 allele and these ocular parameters was analysed using generalised estimating equation (GEE) models and data adjusted for age, sex and inter-eye differences as within-subject variables (p < 0.05). RESULTS: Twenty-four participants were APOE ε4 carriers. Temporal RNFL thickness was decreased in APOE ε4 carriers (p < 0.01). Vessel density between carriers and non-carriers was not significantly different at either the superficial or deep level. The FAZ area was significantly smaller in ε4 carriers in both superficial (p < 0.01) and deep layers (p < 0.003). CONCLUSIONS: Retinal abnormalities were present in participants with increased genetic risk of dementia due to presence of the ε4 allele. These findings provide preliminary evidence for their potential role in the diagnosis of dementia.

Habitual intake of fat and sugar is associated with poorer memory and greater impulsivity in humans.

The vicious cycle model of obesity suggests that repeated habitual intake of a diet high in fat and sugar (HFS) results in impairment in hippocampal function which in turn increases impulsive behaviours, making it harder to resist unhealthy diet choices. Evidence from studies with rodents consistently show switching to a HFS diet impairs performance on hippocampally-sensitive memory tasks. The limited literature in humans also suggest impaired memory and increased impulsivity related to higher habitual HFS intake. However, these changes in memory and impulsivity have been looked at independently. To investigate how these effects are inter-related, three experiments were conducted where relative HFS intake was related to measures of memory and impulsivity. In Experiment 1 (90 female participants), HFS was associated with higher scores on the Everyday Memory Questionnaire-revised (EMQ), and higher scores on the total, Attention (BISatt) and Motor (BISmot) sub-scales of the Barratt Impulsiveness Scale (BIS11). Experiment 2 (84 women and 35 men), replicated the association between HFS and EMQ, and also found HFS related to poorer performance on the hippocampally-sensitive 4 mountain (4MT) memory task. The association between HFS intake and the BISatt replicated, but there were no significant associations with other BIS11 measures or delay-discounting for monetary rewards. Experiment 3 (199 women and 87 men) replicated the associations between DFS and 4MT and EMQ, and also found an association with overall recall, but not response inhibition, from a Remembering Causes Forgetting task: HFS was also significantly associated with BIS total, BISatt and BISmot. In all three studies these associations remained when potential confounds (BMI, age, gender, hunger state, restrained and disinhibited eating) were controlled for. Mediation analysis found that the effect of HFS on memory at least part mediated the relationship between HFS and impulsivity in Experiments 1 and 3, but not 2. Overall these data provide some support for the vicious cycle model, but also suggest that trait impulsivity may be a risk factor for poor dietary choice.

Sex-Dependent Differences in Cholestasis: Why Estrogen Signaling May Be a Key Pathophysiological Driver.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases that have significant clinical impact with debilitating symptoms and mortality. While PBC is predominantly seen in perimenopausal and postmenopausal women, men who are diagnosed with PBC have worse clinical outcomes and all-cause mortality. In contrast, 60% to 70% of patients with PSC are men; the data indicate that female sex may be an independent factor against PSC-related complications. These findings suggest a sex-dependent biological basis for these differences. Estrogen has been implicated in the pathogenesis of intrahepatic cholestasis of pregnancy and may induce cholestasis through a variety of interactions. However, it is unclear why some sexual dimorphic features may provide a protective effect despite known estrogen models that induce cholestasis. This article provides a brief introductory background and discusses the sexual dimorphism in clinical presentation in PSC and PBC. It also explores the role of estrogen signaling in pathogenesis and how it relates to intrahepatic cholestasis of pregnancy. Studies have already targeted certain molecules involved in estrogen signaling, and this review discusses these studies that identify estrogen-related receptor, estrogen receptor-α, estrogen receptor-ß, farnesoid X receptor, and mast cells as possible targets, in addition to long noncoding RNA H19-induced cholestasis and sexual dimorphism. It also explores these interactions and their role in the pathogenesis of PBC and PSC.

Mast Cell and Innate Immune Cell Communication in Cholestatic Liver Disease.

Mast cells (MCs) contribute to the pathogenesis of cholestatic liver diseases (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). PSC and PBC are immune-mediated, chronic inflammatory diseases, characterized by bile duct inflammation and stricturing, advancing to hepatobiliary cirrhosis. MCs are tissue resident immune cells that may promote hepatic injury, inflammation, and fibrosis formation by either direct or indirect interactions with other innate immune cells (neutrophils, macrophages/Kupffer cells, dendritic cells, natural killer, and innate lymphoid cells). The activation of these innate immune cells, usually through the degranulation of MCs, promotes antigen uptake and presentation to adaptive immune cells, exacerbating liver injury. In conclusion, dysregulation of MC-innate immune cell communications during liver injury and inflammation can lead to chronic liver injury and cancer.

Development of Scaffold-Free Three-Dimensional Cholangiocyte Organoids to Study the Progression of Primary Sclerosing Cholangitis.

Organoids are novel in vitro models to study intercellular cross talk between the different types of cells in disease pathophysiology. To better understand the underlying mechanisms driving the progression of primary sclerosing cholangitis (PSC), scaffold-free multicellular three-dimensional cholangiocyte organoids (3D-CHOs) were developed using primary liver cells derived from normal subjects and patients with PSC. Human liver samples from healthy donors and patients with PSC were used to isolate primary cholangiocytes [epithelial cell adhesion molecule (EpCam)+/ cytokeratin-19+], liver endothelial cells (CD31+), and hepatic stellate cells (HSCs; CD31-/CD68-/desmin+/vitamin A+). 3D-CHOs were formed using cholangiocytes, HSCs, and liver endothelial cells, and kept viable for up to 1 month. Isolated primary cell lines and 3D-CHOs were further characterized by immunofluorescence, quantitative RT-PCR, and transmission electron microscopy. Transcription profiles for cholangiocytes (SOX9, CFTR, EpCAM, AE, SCT, and SCTR), fibrosis (ACTA2, COL1A1, DESMIN, and TGFß1), angiogenesis (PECAM, VEGF, CDH5, and vWF), and inflammation (IL-6 and TNF-α) confirmed PSC phenotypes of 3D-CHOs. Because cholangiocytes develop a neuroendocrine phenotype and express neuromodulators, confocal immunofluorescence was used to demonstrate localization of the neurokinin-1 receptor within cytokeratin-19+ cholangiocytes and desmin+ HSCs. Moreover, 3D-CHOs from patients with PSC confirmed PSC phenotypes with up-regulated neurokinin-1 receptor, tachykinin precursor 1, and down-regulated membrane metalloendopeptidase. Scaffold-free multicellular 3D-CHOs showed superiority as an in vitro model in mimicking PSC in vivo phenotypes compared with two-dimensional cell culture, which can be used in PSC disease-related research.

Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. METHODS: Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. RESULTS: Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. CONCLUSIONS: ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.

Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies.

Cholestatic liver diseases are named primarily due to the blockage of bile flow and buildup of bile acids in the liver. Cholestasis can occur in cholangiopathies, fatty liver diseases, and during COVID-19 infection. Most literature evaluates damage occurring to the intrahepatic biliary tree during cholestasis; however, there may be associations between liver damage and gallbladder damage. Gallbladder damage can manifest as acute or chronic inflammation, perforation, polyps, cancer, and most commonly gallstones. Considering the gallbladder is an extension of the intrahepatic biliary network, and both tissues are lined by biliary epithelial cells that share common mechanisms and properties, it is worth further evaluation to understand the association between bile duct and gallbladder damage. In this comprehensive article, we discuss background information of the biliary tree and gallbladder, from function, damage, and therapeutic approaches. We then discuss published findings that identify gallbladder disorders in various liver diseases. Lastly, we provide the clinical aspect of gallbladder disorders in liver diseases and ways to enhance diagnostic and therapeutic approaches for congruent diagnosis. © 2023 American Physiological Society. Compr Physiol 13:4909-4943, 2023.

Predictors of state-based changes in wanting and liking.

People report wanting food when they are hungry, and on eating it they typically report liking the experience. After eating, both wanting and liking decline, but wanting declines to a greater extent, which we term the 'affective discrepancy effect'. In this study we examine the predictors - state, sensory and memory-based - of these affective changes. Hungry participants undertook three tasks: (1) written recollections of what certain foods are like to eat; (2) ratings of wanting and expected flavour liking and fillingness when looking at snacks, and ratings of food and flavour liking when eating them; (3) ratings of bodily state. These tasks were then repeated after lunch. State-based changes in food liking were best predicted by changes in flavour liking. For state-based change in wanting, memory-based information about flavour liking and fillingness from tasks (1) and (2) were all significant predictors. For recollections about eating (task 1), mentions of food fillingness significantly increased pre-to post-lunch and this was the best predictor of the affective discrepancy effect. Recollections of food fillingness are state-dependent, and can arise unbidden (i.e., such recollective content was unprompted). This may reflect one way that memory may selectively influence wanting, and hence whether food intake is initiated or not.

Interoceptive hunger, eating attitudes and beliefs.

Interoceptive individual differences have garnered interest because of their relationship with mental health. One type of individual difference that has received little attention is variability in the sensation/s that are understood to mean a particular interoceptive state, something that may be especially relevant for hunger. We examined if interoceptive hunger is multidimensional and idiosyncratic, if it is reliable, and if it is linked to dysfunctional eating and beliefs about the causes of hunger. Participants completed a survey just before a main meal, with most retested around 1 month later. We found that interoceptive hunger has 11 dimensions, and while people differ considerably in their combinations of interoceptive hungers, these represent only 4% of all possible permutations. Hunger reports were reliable. We found relationships between variability in hunger interoception and dysfunctional eating, especially for uncontrolled eating. We also found that hunger beliefs were in some cases strongly related to aspects of hunger interoception. The implications of these findings are discussed.

The psychological basis of reductions in food desire during satiety.

Satiety-the reduced desire to eat, drink or have sex in their respective aftermath-is particularly important for feeding, where it assists energy balance. During satiety, the anticipated pleasure of eating is far less than the actual pleasure of eating. Here we examine two accounts of this effect: (i) satiety signals inhibit retrieval of pleasant food memories that form desirable images, allowing unpleasant memories into mind; (ii) feelings of fullness reflect what eating would be like now, negating the need for imagery. To test these accounts, participants undertook two tasks pre- and post-lunch: (i) judging desire for palatable foods either with or without imagery impairing manipulations; (ii) explicitly recollecting food memories. Impairing imagery reduced desire equally, when hungry and sated. Food-memory recollections became more negative/less positive when sated, with this correlating with changes in desire. These findings support the first account and suggest imagery is used when hungry and when sated to simulate eating, and that the content of these memory-based simulations changes with state. The nature of this process and its implications for satiety more generally are discussed.

Prolonged administration of a secretin receptor antagonist inhibits biliary senescence and liver fibrosis in Mdr2 -/- mice.

BACKGROUND AND AIMS: Secretin (SCT) and secretin receptor (SR, only expressed on cholangiocytes within the liver) play key roles in modulating liver phenotypes. Forkhead box A2 (FoxA2) is required for normal bile duct homeostasis by preventing the excess of cholangiocyte proliferation. Short-term administration of the SR antagonist (SCT 5-27) decreased ductular reaction and liver fibrosis in bile duct ligated and Mdr2 -/- [primary sclerosing cholangitis (PSC), model] mice. We aimed to evaluate the effectiveness and risks of long-term SCT 5-27 treatment in Mdr2 -/- mice. APPROACH AND RESULTS: In vivo studies were performed in male wild-type and Mdr2 -/- mice treated with saline or SCT 5-27 for 3 months and human samples from late-stage PSC patients and healthy controls. Compared with controls, biliary SCT/SR expression and SCT serum levels increased in Mdr2 -/- mice and late-stage PSC patients. There was a significant increase in ductular reaction, biliary senescence, liver inflammation, angiogenesis, fibrosis, biliary expression of TGF-ß1/VEGF-A axis, and biliary phosphorylation of protein kinase A and ERK1/2 in Mdr2 -/- mice. The biliary expression of miR-125b and FoxA2 decreased in Mdr2 -/- compared with wild-type mice, which was reversed by long-term SCT 5-27 treatment. In vitro , SCT 5-27 treatment of a human biliary PSC cell line decreased proliferation and senescence and SR/TGF-ß1/VEGF-A axis but increased the expression of miR-125b and FoxA2. Downregulation of FoxA2 prevented SCT 5-27-induced reduction in biliary damage, whereas overexpression of FoxA2 reduced proliferation and senescence in the human PSC cell line. CONCLUSIONS: Modulating the SCT/SR axis may be critical for managing PSC.

p16 INK4A drives nonalcoholic fatty liver disease phenotypes in high fat diet fed mice through biliary E2F1/FOXO1/IGF-1 signaling.

BACKGROUND AND AIMS: NAFLD is characterized by steatosis, hepatic inflammation, and fibrosis, which can develop into NASH. Patients with NAFLD/NASH have increased ductular reaction (DR) and biliary senescence. High fat/high cholesterol diet feeding increases biliary senescence, DR, and biliary insulin-like growth factor-1 (IGF-1) expression in mice. p16/IGF-1 converges with fork-head box transcription factor O1 (FOXO1) through E2F1. We evaluated p16 inhibition on NAFLD phenotypes and biliary E2F1/FOXO1/IGF-1 signaling. APPROACH AND RESULTS: 4-week wild-type (C57BL/6J) male mice were fed a control diet (CD) or high fat/high cholesterol diet and received either p16 or control Vivo Morpholino (VM) by tail vein injection 2× during the 16th week of feeding. We confirmed p16 knockdown and examined: (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling. Human normal, NAFLD, and NASH liver samples and isolated cholangiocytes treated with control or p16 VM were evaluated for p16/E2F1/FOXO1/IGF-1 signaling. p16 VM treatment reduced cholangiocyte and hepatocyte p16. In wild-type high fat/high cholesterol diet mice with control VM, there were increased (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling; however, p16 VM treatment reduced these parameters. Biliary E2F1/FOX-O1/IGF-1 signaling increased in human NAFLD/NASH but was blocked by p16 VM. In vitro , p16 VM reduced biliary E2f1 and Foxo1 transcription by inhibiting RNA pol II binding and E2F1 binding at the Foxo1 locus, respectively. Inhibition of E2F1 reduced biliary FOXO1 in vitro. CONCLUSION: Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.

The development of interoceptive hunger signals.

Hunger is often reported when people experience certain internal sensations (e.g., fatigue) or when they anticipate that a food will be good to eat. The latter results from associative learning, while the former was thought to signal an energy deficit. However, energy-deficit models of hunger are not well supported, so if interoceptive hungers are not "fuel gauges," what are they? We examined an alternate perspective, where internal states signaling hunger, which are quite diverse, are learned during childhood. A basic prediction from this idea is offspring-caregiver similarity, which should be evident if caregivers teach their child the meaning of internal hunger cues. We tested 111 university student offspring-primary caregiver pairs, by having them complete a survey about their internal hunger states, alongside other information that may moderate this relationship (i.e., gender, body mass index, eating attitudes, and beliefs about hunger). We observed substantial similarity between offspring-caregiver pairs (Cohen's ds from 0.33 to 1.55), with the main moderator being beliefs about an energy-needs model of hunger, which tended to increase similarity. We discuss whether these findings may also reflect heritable influences, the form that any learning might take, and the implications for child feeding practices.

Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies.

Growth hormone (GH) and downstream insulin-like growth factor 1 (IGF1) signaling mediate growth and metabolism. GH deficiency causes short stature or dwarfism, and excess GH causes acromegaly. Although the association of GH/IGF1 signaling with liver diseases has been suggested previously, current studies are controversial and the functional roles of GH/IGF1 signaling are still undefined. GH supplementation therapy showed promising therapeutic effects in some patients, such as non-alcoholic fatty liver disease, but inhibition of GH signaling may be beneficial for other liver diseases, such as hepatocellular carcinoma. The functional roles of GH/IGF1 signaling and the effects of agonists/antagonists targeting this signaling may differ depending on the liver injury or animal models. This review summarizes current controversial studies of GH/IGF1 signaling in liver diseases and discusses therapeutic potentials of GH therapy.