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1.
Postprandial regulation of prouroguanylin in humans of a healthy weight and those who are overweight or with obesity.
Patterson, M, Ward, H, Halvai, D, Holm Nilsen, HA, Reeves, S
Peptides. 2020;:170179
Abstract
Uroguanylin is a peptide gut hormone proposed to have a role in signalling post meal satiety. Uroguanylin circulates as its pro-hormone, prouroguanylin. There has been limited investigation of the regulation of prouroguanylin by food; therefore we investigated prouroguanylin regulation following meals. In separate experiments we investigated the effects of high calorie (1451 kcal) and medium calorie (725 kcal), high fat meals, on plasma prouroguanylin concentrations. We then examined the effect of a 722.5 kcal high carbohydrate breakfast on prouroguanylin concentrations, comparing the response in healthy weight adults versus those who are overweight/ with obesity. The 1451 kcal meal increased prouroguanylin concentrations, versus fasting at 60 (P < 0.05), 90 (P < 0.01) and 120 (P < 0.001) minutes. After the 725 kcal meal hormone concentrations rose more slowly and were significant versus fasting concentrations at 120 min (P < 0.01). The high carbohydrate breakfast 722.5 kcal, led to an initial suppression of hormone concentrations at 30 min. post meal (P < 0.05) followed by an increase in concentrations until they were significant versus fasting at 120 min. (P < 0.01). Participants overweight/ with obesity had lower fasting prouroguanylin concentrations (P < 0.05), but post meal concentrations did not differ between the groups. Our results suggest there is a delayed increase in prouroguanylin concentrations following, large and regular sized mixed macronutrient meals rich in fat or carbohydrate. Fasting levels are suppressed in people who are overweight/ with obesity, but the post meal response remains intact. There may be potential to target post meal release of prouroguanylin in obesity.
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2.
Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity.
Barbaro, MR, Cremon, C, Morselli-Labate, AM, Di Sabatino, A, Giuffrida, P, Corazza, GR, Di Stefano, M, Caio, G, Latella, G, Ciacci, C, et al
Gut. 2020;(11):1966-1974
Abstract
OBJECTIVE Non-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm. DESIGN In a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS. RESULTS Compared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%. CONCLUSION Zonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.
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3.
Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis.
Asbjornsdottir, B, Snorradottir, H, Andresdottir, E, Fasano, A, Lauth, B, Gudmundsson, LS, Gottfredsson, M, Halldorsson, TI, Birgisdottir, BE
Nutrients. 2020;(7)
Abstract
Worldwide, up to 20% of children and adolescents experience mental disorders, which are the leading cause of disability in young people. Research shows that serum zonulin levels are associated with increased intestinal permeability (IP), affecting neural, hormonal, and immunological pathways. This systematic review and meta-analysis aimed to summarize evidence from observational studies on IP in children diagnosed with mental disorders. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the Cochrane Library, PsycINFO, PubMed, and the Web of Science identified 833 records. Only non-intervention (i.e., observational) studies in children (<18 years) diagnosed with mental disorders, including a relevant marker of intestinal permeability, were included. Five studies were selected, with the risk of bias assessed according to the Newcastle-Ottawa scale (NOS). Four articles were identified as strong and one as moderate, representing altogether 402 participants providing evidence on IP in children diagnosed with attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). In ADHD, elevated serum zonulin levels were associated with impaired social functioning compared to controls. Children with ASD may be predisposed to impair intestinal barrier function, which may contribute to their symptoms and clinical outcome compared to controls. Children with ASD, who experience gastro-intestinal (GI) symptoms, seem to have an imbalance in their immune response. However, in children with OCD, serum zonulin levels were not significantly different compared to controls, but serum claudin-5, a transmembrane tight-junction protein, was significantly higher. A meta-analysis of mean zonulin plasma levels of patients and control groups revealed a significant difference between groups (p = 0.001), including the four studies evaluating the full spectrum of the zonulin peptide family. Therefore, further studies are required to better understand the complex role of barrier function, i.e., intestinal and blood-brain barrier, and of inflammation, to the pathophysiology in mental and neurodevelopmental disorders. This review was PROSPERO preregistered, (162208).
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Dairy products influence gut hormone secretion and appetite differently: A randomized controlled crossover trial.
Hansson, P, Holven, KB, Øyri, LKL, Brekke, HK, Gjevestad, GO, Rehfeld, JF, Raza, GS, Herzig, KH, Ulven, SM
Journal of dairy science. 2020;(2):1100-1109
Abstract
Little is known about how dairy products with different nutrient contents and food matrices affect appetite sensation and gut hormone secretion. The objective of this study was to investigate how appetite sensation and gut hormone secretion in healthy adults are affected by meals with the same amount of fat but from different dairy products. Forty-seven healthy adults (70% women) were recruited to a randomized controlled crossover study with 4 dairy meals consisting of butter, cheese, whipped cream, or sour cream, corresponding to 45 g (approximately 60 energy percent) of fat. Plasma samples were collected for analysis of cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY), and ghrelin concentrations at 0, 2, 4, and 6 h after the meals and analyzed as the incremental area under the curve (iAUC0-6h) in a mixed model. Hunger, satiety, and appetite sensations were measured with a visual analog scale (VAS) immediately after finishing the meals and at 4 and 6 h postprandially. Intake of cheese induced a higher level of plasma PP-iAUC0-6h compared with butter or whipped cream, and a higher level of plasma CCK-iAUC0-6h compared with whipped cream. Intake of whipped cream increased VAS appetite at 4 h compared with cheese or sour cream, and at 6 h compared with cheese or butter. No significant meal effect was found for hunger, satiety, plasma PYY, or plasma ghrelin concentration. Intake of cheese increased postprandial plasma PP and CCK concentrations and decreased appetite compared with whipped cream but not with sour cream. These findings encourage further investigations of how different dairy products affect gut hormone secretion and appetite sensation.
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5.
Modeling the time-related fluctuations of AFP and PIVKA-II serum levels in patients with cirrhosis undergoing surveillance for hepatocellular carcinoma.
Ricco, G, Cosma, C, Bedogni, G, Biasiolo, A, Guarino, M, Pontisso, P, Morisco, F, Oliveri, F, Cavallone, D, Bonino, F, et al
Cancer biomarkers : section A of Disease markers. 2020;(2):189-196
Abstract
BACKGROUND The time-related variability of HCC biomarkers has not been investigated so far. OBJECTIVE To assess the changes of alpha-fetoprotein (AFP) and protein induced by vitamin-K absence/antagonist-II (PIVKA-II) in patients with HCC (HCC+) as compared to patients without HCC (HCC-). METHODS AFP and PIVKA-II were measured by a single laboratory using an automated chemiluminescent-enzyme-immunoassay (Fujirebio Inc., Tokyo, Japan) in 1163 sera of 418 cirrhotics (31.1% HBV, 58.6% HCV, 10.3% non-viral etiology) undergoing ultrasound HCC surveillance. The mean (range) number of effective time-points available for analysis was 2.8 (2.0 to 3.0); 124 patients with HCC were matched with 294 who remained HCC free for at least 12 months after the last specimen. AFP and PIVKA-II changes were estimated over time by means of a random-effect generalized least squares (RE-GLS) regression model under the missingness at random assumption. RESULTS Patients with and without HCC had comparable chronic liver disease etiology and staging. AFP/PIVKA-II median (25th; 75th percentile) values at the latest time-point were 4.2 (2.6; 8.6) ng/mL/32 (25; 42) mAU/mL in HCC- and 8.4 (4.4; 32.1) ng/mL/66 (32; 192) mAU/mL in HCC+ (p< 0.001). Log10AFP and log10PIVKA-II time-changes differed in HCC+ and HCC- patients. In HCC+ patients, both log10AFP and log10PIVKA-II showed an increasing trend over time. In HCC- patients, log10PIVKA-II variations were minimal as compared to log10AFP variations. The percent increase of log10AFP at 6 months vs. baseline was 11% (95%CI 5 to 17%) and 5% (95%CI 1 to 8%) for log10PIVKA-II in HCC+vs. HCC- patients. CONCLUSIONS The present retrospective study of the biological variability of AFP and PIVKA-II suggests that their time-related changes may serve as potential predictors of HCC. This topic needs to be addressed by longitudinal studies.
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6.
The N-Terminus Makes the Difference: Impact of Genotype-Specific Disparities in the N-Terminal Part of The Hepatitis B Virus Large Surface Protein on Morphogenesis of Viral and Subviral Particles.
Jiang, B, Wen, X, Wu, Q, Bender, D, Carra, G, Basic, M, Kubesch, A, Peiffer, KH, Boller, K, Hildt, E
Cells. 2020;(8)
Abstract
The N-terminus of the hepatitis B virus (HBV) large surface protein (LHB) differs with respect to genotypes. Compared to the amino terminus of genotype (Gt)D, in GtA, GtB and GtC, an additional identical 11 amino acids (aa) are found, while GtE and GtG share another similar 10 aa. Variants of GtB and GtC affecting this N-terminal part are associated with hepatoma formation. Deletion of these amino-terminal 11 aa in GtA reduces the amount of LHBs and changes subcellular accumulation (GtA-like pattern) to a dispersed distribution (GtD-like pattern). Vice versa, the fusion of the GtA-derived N-terminal 11 aa to GtD causes a GtA-like phenotype. However, insertion of the corresponding GtE-derived 10 aa to GtD has no effect. Deletion of these 11aa decreases filament size while neither the number of released viral genomes nor virion size and infectivity are affected. A negative regulatory element (aa 2-8) and a dominant positive regulatory element (aa 9-11) affecting the amount of LHBs were identified. The fusion of this motif to eGFP revealed that the effect on protein amount and subcellular distribution is not restricted to LHBs. These data identify a novel region in the N-terminus of LHBs affecting the amount and subcellular distribution of LHBs and identify release-promoting and -inhibiting aa residues within this motive.
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7.
The role of peptides cleaved from protein precursors in eliciting plant stress reactions.
Chen, YL, Fan, KT, Hung, SC, Chen, YR
The New phytologist. 2020;(6):2267-2282
Abstract
As sessile organisms, plants are exposed to diverse abiotic and biotic stresses, and thus have developed complex signaling mechanisms that orchestrate multiple stress responses. Plant peptides have recently emerged as key signaling molecules of stress responses, not only to mechanical wounding and pathogen infection but also to nutrient imbalance, drought and high salinity. The currently identified stress-related signaling peptides in plants are derived from proteolytic processing of protein precursors. Here, we review these protein-derived peptides and the evidence for their functions in stress signaling. We recommend potential research directions that could clarify their roles in stress biology, and propose possible crosstalk with regard to the physiological outcome. The stress-centric perspective allows us to highlight the crucial roles of peptides in regulating the dynamics of stress physiology. Inspired by historic and recent findings, we review how peptides initiate complex molecular interactions to coordinate biotic and abiotic stress responses in plants.
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8.
Relationship of Zonulin with Serum PCSK9 Levels after a High Fat Load in a Population of Obese Subjects.
Molina-Vega, M, Castellano-Castillo, D, Sánchez-Alcoholado, L, Plaza-Andrade, I, Perera-Martin, G, Cabrera-Mulero, A, Fernández-García, JC, Ramos-Molina, B, Cardona, F, Tinahones, FJ
Biomolecules. 2020;(5)
Abstract
Despite the fact that circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) remain unchanged after fat load in healthy lean individuals, PCSK9 has been suggested to have a role in postprandial lipemia regulation in obese individuals. On the other hand, intestinal permeability and endotoxemia have been observed to increase more in obese individuals than in non-obese individuals after a lipid load. This study aimed to analyze the relationship between PCSK9, intestinal permeability, and endotoxemia after a high fat load in obese individuals. We included 39 individuals with morbid obesity. Serum PCSK9 levels, intestinal permeability marker (zonulin), endotoxemia markers (LPS and LBP), and lipid parameters were measured before and after 3 h of fat load. A significant rise in triglycerides, apolipoprotein A1, zonulin, LPS, and LBP, and a significant decline in PCSK9, were observed after a lipid load. Linear regression analysis showed that low-density lipoprotein cholesterol (LDL-C) was independently related to PCSK9 at baseline, whereas both zonulin and LDL-C were independently related to PCSK9 levels after fat load. A relationship between zonulin and PCSK9 levels after fat load in individuals with morbid obesity may exist.
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9.
Blunted Evoked Prouroguanylin Endocrine Secretion in Chronic Constipation.
Waldman, SA, Tenenbaum, R, Foehl, HC, Winkle, P, Griffin, P
Clinical and translational gastroenterology. 2019;(7):e00016
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Abstract
OBJECTIVES Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C). METHODS Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay. RESULTS Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating. DISCUSSION These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion. TRANSLATIONAL IMPACT This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.
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Association of intestinal permeability with a NUTRIC score in critically ill patients.
Eslamian, G, Ardehali, SH, Vahdat Shariatpanahi, Z
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:1-8
Abstract
OBJECTIVES The aim of this study was to investigate the association of intestinal permeability with the Nutrition Risk in Critically Ill (NUTRIC) score and the modified NUTRIC score (mNUTRIC) in intensive care unit (ICU) hospitalized patients. METHODS One hundred and fifty ICU hospitalized adult patients admitted between October 2017 and April 2018 who stayed for >24 h in the general ICU were enrolled in the study. Nutrition status was estimated using the NUTRIC score, an ICU-specific nutrition risk assessment tool. The NUTRIC score was calculated using the exact same thresholds and point system as developed previously. Admission plasma endotoxin and zonulin concentrations were measured to assess intestinal permeability. RESULTS Median plasma endotoxin and zonulin increased with increasing mNUTRIC and NUTRIC categories in the overall study population and in the glutamine-deficient subgroup. Multivariate binary logistic regression analyses showed a significant association between the plasma endotoxin (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.8-3.52) and zonulin (OR, 1.11; 95% CI, 1.03-1.20) levels with NUTRIC category in the overall population and the glutamine-deficient subgroup. Similar results were obtained when using mNUTRIC. CONCLUSIONS Results from the present study provided evidence that higher plasma endotoxin and zonulin levels are associated with a progressively higher NUTRIC score in critically ill patients.