- Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial. [Journal Article]
- EJEur J Nutr 2018 May 19
- CONCLUSIONS: Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted.
- Identifying Nonalcoholic Fatty Liver Disease Advanced Fibrosis in the Veterans Health Administration. [Journal Article]
- DDDig Dis Sci 2018 May 19
- CONCLUSIONS: While NFS and FIB-4 scores exhibit good diagnostic accuracy, FIB-4 is optimal in identifying NAFLD advanced fibrosis in the VHA. Easily implemented as a point-of-care clinical test, FIB-4 can be useful in directing patients that are most likely to have advanced fibrosis to GI/hepatology consultation and follow-up.
- Mammalian target of rapamycin complex 2 signaling in obese women changes after bariatric surgery. [Journal Article]
- NNutrition 2018 Mar 21; 54:94-99
- CONCLUSIONS: The weight loss that was induced by RYGB surgery alters the mTOR signaling pathway and specifically the mTOR complex 2 subunit. The increased expression of genes that act in this pathway such as RICTOR, PIK3 R1, and HIF1 A reflects the induced weight loss and improved metabolic indicators (e.g., insulin resistance and lipolysis) that are evidenced in this study.
- Gestational diabetes mellitus modulates cholesterol homeostasis in human fetoplacental endothelium. [Journal Article]
- BBBiochim Biophys Acta 2018 May 17
- Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endoth...
Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endothelial function. We aimed to investigate whether and how GDM affects cholesterol metabolism in human fetoplacental endothelial cells (HPEC). HPEC were isolated from fetal term placental arterial vessels of GDM or control subjects. Cellular reactive oxygen species (ROS) were detected by H2DCFDA fluorescent dye. Oxysterols were quantified by gas chromatography-mass spectrometry analysis. Genes and proteins involved in cholesterol homeostasis were detected by real-time PCR and immunoblotting, respectively. Cholesterol efflux was determined from [3H]-cholesterol labeled HPEC and [14C]-acetate was used as cholesterol precursor to measure cholesterol biosynthesis and esterification. We detected enhanced formation of ROS and of specific, ROS-derived oxysterols in HPEC isolated from GDM versus control pregnancies. ROS-generated oxysterols were simultaneously elevated in cord blood of GDM neonates. Liver-X receptor activation in control HPEC by synthetic agonist TO901319, 7-ketocholesterol, or 7β-hydroxycholesterol upregulated ATP-binding cassette transporters (ABC)A1 and ABCG1 expression, accompanied by increased cellular cholesterol efflux. Upregulation of ABCA1 and ABCG1 and increased cholesterol release to apoA-I and HDL3 (78 ± 17%, 40 ± 9%, respectively) were also observed in GDM versus control HPEC. The LXR antagonist GGPP reversed ABCA1 and ABCG1 upregulation and reduced the increased cholesterol efflux in GDM HPEC. Similar total cellular cholesterol levels were detected in control and GDM HPEC, while GDM enhanced cholesterol biosynthesis along with upregulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1) mRNA and protein levels. Our results suggest that in GDM cellular cholesterol homeostasis in the fetoplacental endothelium is modulated via LXR activation and helps to maintain its proper functionality.
- Non-alcoholic fatty liver disease: Insights from sphingolipidomics. [Journal Article]
- BBBiochem Biophys Res Commun 2018 May 17
- Non-alcoholic fatty liver disease (NAFLD) is a major clinical concern and its treatment consumes abundant resources. While accumulation of lipids in hepatocytes initiates the disease, this in itself ...
Non-alcoholic fatty liver disease (NAFLD) is a major clinical concern and its treatment consumes abundant resources. While accumulation of lipids in hepatocytes initiates the disease, this in itself is not necessarily harmful; rather, initiation of inflammation and subsequent fibrosis and cirrhosis are critical steps in NAFLD pathology. Mechanisms linking lipid overload to downstream disease progression are not fully understood; however, bioactive lipid metabolism may underlie instigation of proinflammatory signaling. With the advent of high-throughput, sensitive, and quantitative mass spectrometry-based methods for assessing lipid profiles in NAFLD, several trends have emerged, including that increases in specific sphingolipids correlate with the transition from the relatively benign condition of simple fatty liver to the much more concerning inflamed state. Continued studies that implement sphingolipid profiling will enable the extrapolations of candidate enzymes and pathways involved in NAFLD, either in biopsies or plasma from human samples, and also in animal models, from which data are much more abundant. While most data thus far are derived from targeted lipidomics approaches, unbiased, semi-quantitative approaches hold additional promise for furthering our understanding of sphingolipids as markers of and players in NAFLD.
- The Relationship Between Glycaemic Control and Non-Alcoholic Fatty Liver Disease in Nigerian Type 2 Diabetic Patients. [Journal Article]
- JNJ Natl Med Assoc 2018; 110(3):256-264
- CONCLUSIONS: The prevalence of NAFLD increases with increasing BMI and HBA1c in T2DM, while its ultrasound grade varies with BMI. Overweight, obesity and poor glycaemic control are independent predictors of NAFLD.
- Improving the oral bioavailability of tapentadol via a carbamate prodrug approach: synthesis, bioactivation, and pharmacokinetics. [Journal Article]
- DDDrug Deliv Transl Res 2018 May 17
- Tapentadol suffers from rapid clearance due to extensive metabolism in vivo, which results in low oral bioavailability. In the present study, three novel prodrugs of tapentadol (WWJ01, WWJ02, and WWJ...
Tapentadol suffers from rapid clearance due to extensive metabolism in vivo, which results in low oral bioavailability. In the present study, three novel prodrugs of tapentadol (WWJ01, WWJ02, and WWJ03) were synthesized to improve its metabolic stability and thereby improve its oral bioavailability. They all exhibited good stability in phosphate buffers, simulated gastrointestinal fluids, rat plasma, and intestinal and liver homogenates. Disappointingly, the N,N-diethylcarbamate prodrug of tapentadol (WWJ02) and the N,N-diisopropylcarbamate prodrug of tapentadol (WWJ03) were metabolized into inactive metabolites when incubated with liver microsomes. In contrast, the N,N-dimethylcarbamate prodrug of tapentadol (WWJ01) could be transformed into useful intermediates (M1, M2, and M3), followed by the further release of the active structure (tapentadol) with the addition of plasma. Additionally, the possible biotransformation pathway of WWJ01 was preliminarily studied with a qualitative approach by determining the molecular weight and fragment ions of its metabolic intermediates. Finally, pharmacokinetic studies were carried out to evaluate the oral absorption of WWJ01. WWJ01 showed distinct advantages in oral absorption efficiency, with a 2.3-fold higher bioavailability than tapentadol. These results suggest that the rational design of a carbamate prodrug of tapentadol is an efficient strategy to improve its metabolic stability and oral bioavailability.
- Difructose dianhydride improves intestinal calcium absorption, wound healing, and barrier function. [Journal Article]
- SRSci Rep 2018 May 18; 8(1):7813
- The gastrointestinal tract (GIT) is critical for nutrient absorption and is an important barrier against harmful pathogens and antigens. Difructose anhydrides (DFA)-IVs are nondigestible disaccharide...
The gastrointestinal tract (GIT) is critical for nutrient absorption and is an important barrier against harmful pathogens and antigens. Difructose anhydrides (DFA)-IVs are nondigestible disaccharides that enhance calcium and iron absorption by affecting the intestinal epithelial tissue. However, their effects on intestinal functions are not fully understood. In this study, we performed a feeding trial and found that dietary DFA-IVs improved growth performance, relative breast muscle and liver weight, and digestibility and blood calcium and iron concentrations in broilers. Additionally, dietary DFA-IVs increased expression of genes related to growth in the liver, muscle development, and absorption of calcium and iron in the intestine. In vitro experiments revealed that DFA-IV treatment improved intestinal wound-healing (migration, proliferation, and differentiation) after lipopolysaccharide (LPS) challenge in small intestinal epithelial cells. Furthermore, DFA-IV treatment enhanced the intestinal barrier function, which increased the transepithelial electrical resistance (TEER) and decreased the permeability of fluorescein isothiocyanate-dextran (FD-4) after LPS challenge in small intestinal epithelial cells. Collectively, these data indicate that DFA-IV could be used as a feed additive to enhance calcium and iron absorption by affecting the intestinal wound healing and permeability. This study may help improve our understanding of the molecular effects of DFA-IV on the intestine.
- Prospective study of coffee consumption and cancer incidence in non-white populations. [Journal Article]
- CECancer Epidemiol Biomarkers Prev 2018 May 18
- CONCLUSIONS: Based on our prospective data in diverse populations, we found a decreased risk of liver, ovarian, thyroid and endometrial cancers and melanoma associated with higher coffee intake.These results suggest that coffee drinking may protect against liver, ovarian, thyroid and endometrial cancers and melanoma.
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- Accelerated pre-senile systemic amyloidosis in PACAP knockout mice - a protective role of PACAP in age-related degenerative processes. [Journal Article]
- JPJ Pathol 2018 May 17
- Dysregulation of neuropeptides may play an important role in aging-induced impairments. Among them, pituitary adenylate cyclase activating polypeptide (PACAP) is a potent cytoprotective peptide that ...
Dysregulation of neuropeptides may play an important role in aging-induced impairments. Among them, pituitary adenylate cyclase activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life, and the well-known general cytoprotective effects of PACAP lead to age-related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre-senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age-related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal and esophageal involvement. Mass spectrometry-based proteomic analysis, re-confirmed with immunohistochemistry, revealed that apolipoprotein-AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age-related degeneration with amyloid deposit in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro-inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. This article is protected by copyright. All rights reserved.