Is Non-Alcoholic Fatty Liver Disease Connected with Cognition? The Complex Interplay between Liver and Brain

The prevalence of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), is increasing in parallel with the rising rates of obesity and type 2 diabetes. Approximately one in four adults are diagnosed with liver steatosis globally. NAFLD is associated with insulin resistance, hypertension, obesity, visceral adiposity, and dyslipidaemia. These risk factors are often accompanied by inflammation and oxidative stress, which also play a role in extrahepatic diseases, including conditions related to the central nervous system, such as mild cognitive impairment and Alzheimer’s disease. The number of people living with dementia is approximately 55 million and is estimated to increase to approximately 2 billion people by 2050. Recent studies have found that NAFLD is associated with poorer cognition. The aim of this review was to summarise the findings of hitherto studies that have linked NAFLD with cognition and dementia, as well as to discuss the potential liver–brain pathways

Liver Atrophy Associated With Monolobar Caroli's Disease

The association of the atrophy-hypertrophy complex in monolobar Caroli’s disease (Type I) is reported in a 30 year old male who presented with recurrent cholangitis. Ultrasound and CT scan showed localised, right sided, saccular biliary dilatation in a normal sized liver. Severe right lobar atrophy was detected at operation and the resected right lobe weighed only 140 gms. Distortion of the hilar vascular anatomy and posterior displacement of the right hepatic duct orifice were problems encountered at surgery

The Effect of L-Theanine Incorporated in a Functional Food Product (Mango Sorbet) on Physiological Responses in Healthy Males: A Pilot Randomised Controlled Trial

Consumption of L-Theanine (L-THE) has been associated with a sensation of relaxation, as well as a reduction of stress. However, these physiological responses have yet to be elucidated in humans where L-THE is compared alongside food or as a functional ingredient within the food matrix. The aim of this study was to determine the physiological responses of a single intake of a potential functional food product (mango sorbet) containing L-THE (ms-L-THE; 200 mgw/w) in comparison to a flavour and colour-matched placebo (ms). Eighteen healthy male participants were recruited in this randomised, double-blind, placebo-controlled trial. The participants were required to consume ms-L-THE or placebo and their blood pressure (BP) (systolic and diastolic), heart rate (HR), and heart rate variability (HRV) were monitored continuously over 90 minutes. Eleven males (age 27.7 ± 10.8 years) completed the study. Changes in area under the curve for systolic and diastolic blood pressure and HRV over the 90 minute observation period indicated no differences between the three conditions (all p > 0.05) or within individual groups (all p > 0.05). The values for heart rate were also not different in the placebo group (p = 0.996) and treatment group (p = 0.066), while there was a difference seen at the baseline (p = 0.003). Based on the findings of this study, L-THE incorporated in a food matrix (mango sorbet) demonstrated no reduction in BP or HR and showed no significant parasympathetic interaction as determined by HRV high-frequency band and low-frequency/high-frequency ratio. Further studies should be focussed towards the comparison of pure L-THE and incorporation within the food matrix to warrant recommendations of L-THE alongside food consumption

Physicochemical, antioxidant and sensory properties of Mango Sorbet containing L-theanine as a potential functional food product

The non-proteinous amino acid L-theanine (L-THE) is associated with a range of health benefits including improvements in immune function, cardiovascular outcomes and cognition. The aims of this study were to develop a food product (mango sorbet; ms-L-THE) containing physiologically relevant doses of L-THE (0.2/100 g w/w) and determine its antioxidant, physicochemical and sensory properties in comparison to a mango sorbet without L-THE (ms). Total phenolic and flavanol content, and antioxidant analysis (DPPH, FRAP and ABTS) were determined spectrophotometrically. Both products were also evaluated for acceptability and likeability in healthy participants using the 9-point hedonic scale. Any differences that could be caused by the addition of L-THE were examined using the triangle test. Results indicated no significant differences between ms-L-THE and ms in taste of the products (p > 0.05), and the ms-L-THE was well received and accepted as a potential commercial product. Findings of the DPPH assay indicated significant difference between the two products (p < 0.05). In conclusion, we have successfully created a mango sorbet that contains a potentially physiologically relevant concentration of L-THE with antioxidant properties that could be used as a novel method of L-THE delivery to clinical and healthy populations

Assessing the diet quality of individuals with rheumatic conditions:a cross-sectional study

Arthritis is a significant cause of chronic pain and disability, affecting around 3.5 million Australians. However, little is known regarding the overall diet quality of those living with arthritis. This study aimed to assess the dietary quality of Australians living in the Australian Capital Territory region with arthritis. This cross-sectional study analysed dietary intake data of individuals living with arthritis using a validated food frequency questionnaire. Dietary quality was assessed using the Healthy Eating Index-2015 (HEI-2015) to examine associations between diet composition, age, income and arthritis impact using the short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF). Participants, predominantly female (82.6%), were grouped by age: 18-50 years (n = 32), 50-64 years (n = 31), and 65 + years (n = 23). Significant correlations were observed between age and HEI-2015 (rs = 0.337, p = 0.002) and income and AIMS2-SF (rs = - 0.353, p < 0.001). The mean HEI-2015 score for the 18-49 years group was fair (72.1 ± 12.3), lower than both the 50-64 years group score of good (81.5 ± 9.72) (p = 0.004), and the 65 + years group score of good (81.8 ± 12.1) (p = 0.007). Dietary fibre, seafood and plant protein, fatty acids, and refined grains were identified as dietary components of concern for the 18-49 years group, and total fruit and added sugar were components of concern for people in the worst tertile for the AIMS2-SF. People aged between 18 and 49 years are consuming a lower quality diet compared to people aged 50 years and over. Further research is needed to understand why this association is occurring in this high socioeconomic region of Australia (a high-income country)

The association between sleeping time and metabolic syndrome features among older adults living in Mediterranean region. The MEDIS study.

Background: Metabolic Syndrome (MetS) as a combination of features has been known to significantly increase Cardiovascular Disease (CVD) risk, whilst MetS presence is linked to lifestyle parameters including physical activity and dietary habits; recently, the potential impact of sleeping habits has also become an issue under consideration. The aim of this study was to investigate the role of sleep quantity in several MetS components. Methods: Design:Cross-sectional observational study. Setting: 26 Mediterranean islands and the rural Mani region (Peloponnesus) of Greece. Participants: during 2005-2017, 3130 older (aged 65-100 years) Mediterranean residents were voluntarily enrolled. Measurements: Dietary habits (including MedDietScore assessment), physical activity status, socio-demographic characteristics, lifestyle parameters (sleeping and smoking habits) and clinical profile aspects including Metabolic Syndrome (MetS) components (i.e., waist circumference, systolic and diastolic blood pressure, fasting glucose, triglycerides, LDL and HDL-cholesterol) were derived through standard procedures. Results: The number of daily hours of sleep was independently associated with greater waist circumference (b coefficient per 1 hour=0.91, 95% Confidence Interval (CI); 0.34, 1.49), higher LDL-cholesterol levels (b per 1 hour=3.84, 95%CI; 0.63, 7.05) and lower diastolic blood pressure levels (b per 1 hour=-0.98, 95%CI; - 1.57, -0.39) after adjusting for participants’ age, gender, body mass index, daily walking time, level of adherence to Mediterranean diet and smoking status. No association was revealed between hours of sleep per day and fasting glucose, triglycerides, HDL-cholesterol and systolic blood pressure. Conclusions: Increased hours of sleep is an indicator of metabolic disorders among elderly inviduals, and further research is needed to identify the paths through which sleep quantity is linked to MetS features in different age-groups

Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers

Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -β. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells

ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation

Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1L−/− mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15−/− mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15−/− mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection

Telomere-Mediated Chromosomal Instability Triggers TLR4 Induced Inflammation and Death in Mice

BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+), mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/-) mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups

Longitudinal retinal changes in MOGAD

OBJECTIVE: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD. METHODS: Eighty MOGAD patients and 139 healthy controls (HC) were included. OCT data was acquired with 1) Spectralis spectral domain OCT (MOGAD (N=66) and HC (N=103)) and 2) Cirrus HD-OCT (MOGAD (N=14) and HC (N=36)). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fibre layer (pRNFL) were quantified. RESULTS: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HC (p12 months ago (p<0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with HC. INTERPRETATION: Our study suggests the absence of attack-independent retinal damage in MOGAD. Yet, ongoing neuroaxonal damage or oedema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in MOGAD. This article is protected by copyright. All rights reserved