Background and Aims
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well ...understood.
Approach and Results
We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor FXR activity), patatin‐like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy‐proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium‐dependent BA transporter inhibitor (SC‐435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model.
Conclusions
Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.
A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The ...quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFβ) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more ...severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
To evaluate the effectiveness of transvaginal ultrasound (TVUS) versus the transabdominal ultrasound (TAUS) guided embryo transfer (ET) in obese patients undergoing Intracytoplasmic sperm injection ...(ICSI).
A prospective randomized controlled trial.
University hospital.
Eight hundred participants with BMI ≥30 received the long agonist protocol. They were randomized into 2 equal groups of 400 patients. Each group had either TAUS guided ET or TVUS guided ET.
Our primary outcomes were clinical pregnancy rate, degree of patient pain assessed by visual analogue scale (VAS). The secondary outcomes were live birth rate, implantation rate, miscarriage and chemical pregnancy rates, duration of ET.
Our results showed a significant higher chemical and clinical pregnancy rates in the TVUS group in comparison to TAUS group (45.3% vs. 38.3%, p=0.045) and (37.8% vs. 30.8%, p=0.044) respectively. There was tendency for increased live birth rates in the TVUS group however it did not reach statistical significance (50.2% vs. 44.8%). The VAS of the pain was significantly less in TVUS group in comparison to the TAUS group (2.1 ±0.7 vs. 4.5 ±1.3), also abdominal discomfort was significantly less in TVUS group in comparison to the TAUS group (13% vs. 58%) p= value 0.0001.
This study showed superior role of TVUS guided ET over TAUS regarding less pain and better pregnancy and live birth rates in obese participants.
Clinical trial. Gov identifier NCT03473028.
Feature selection is an NP-hard combinatorial problem, in which the number of possible feature subsets increases exponentially with the number of features. In the case of large dimensionality, the ...goal of feature selection is to determine the smallest possible features considering the most informative subset. In this paper, we proposed a hybrid feature selection optimization model for Cancer Classification called, ENSVM. Our model is based on using the Elastic Net (EN) method that regulates and selects variables for gene selection of genomic microarray data. We applied three different optimization techniques namely Social Ski-Driver (SSD), Randomized SearchCV (RS) and Elastic NetCV (ENCV) for determining Elastic Net with traditional Support Vector Machines for classification. To evaluate the model, we compared the results of applying ENSVM to seven genomic microarray data with the SSD-SVM model and SVM with (RBF) kernel without any feature selection method. The results of the comparison revealed the effect of ENSVM in selecting the optimal feature subset that maximized the classification performance. Accordingly, minimizing the number of features is significant when analyzing high dimensional data for performance nevertheless accuracy. Moreover, the ENSVM model is superior compared with the SSD-SVM model.
Transport stress (TS) not only affects animal welfare but also eventually leads to higher morbidity and mortality. Moreover, TS could induce heart injury in animals, but the possible mechanism has ...yet to be fully explored. Astragalus polysaccharide (APS) is a main active component of Radix Astragali, which has an extensive anti-stress effect. However, the effect of APS on TS-induced heart injury has not yet been elucidated. In this study, a chick model of simulated TS was used. 240 newly hatched chicks were arranged into 4 groups: Control (Con), Transport group (T), Transport + water group (TW), and Transport + APS group (TA). Before transport, the chicks of the TW and TA groups were treated with deionized water and APS (0.25 mg/mL, 100 µL) by oral drops respectively. The histopathological analysis of myocardial tissue was assessed by hematoxylin and eosin staining. qRT-PCR and Western Blotting assays were employed to measure the expression of genes and proteins. Semiquantitative PCR was performed for the X box-binding protein-1 (XBP-1) mRNA splicing assay. The results indicated that APS significantly reduced TS-induced myocardial histopathological changes. Meanwhile, TS induced endoplasmic reticulum stress (ERS), evidenced by an activation of the unfolded protein response (UPR) signaling pathway and up-regulation of ERS-markers (P < 0.05). Moreover, TS markedly triggered autophagy induction by activating AMP-activated protein kinase (AMPK), reflected by augmented LC3-II/LC3-I, AMPK phosphorylation and autophagy-related genes (ATGs) expression (P < 0.05). Importantly, our study manifested that treatment of APS could reduce TS-induced ERS and AMPK-activated autophagy, accordingly alleviating heart injury of transported chicks. In summary, these findings indicate that TS induces heart injury in chicks via an ERS-UPR-autophagy-dependent pathway, and APS as an effective therapeutic method to alleviate it.
Disease risk variants are likely to affect gene expression in a context- and cell-type specific manner. The membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs8736 ...metabolic-dysfunction-associated fatty liver disease (MAFLD)-risk variant was recently reported to be a negative regulator of toll-like receptors (TLRs) signalling in macrophages. Whether this effect is generic or cell-type specific in immune cells is unknown.
We investigated the impact of modulating TLR signaling on MBOAT7 expression in peripheral blood mononuclear cells (PBMCs). We also examined whether the rs8736 polymorphism in MBOAT7 regulates this effect. Furthermore, we measured the allele-specific expression of MBOAT7 in various immune cell populations under both unstimulated and stimulated conditions.
We show that MBOAT7 is down-regulated by TLRs in PBMCs. This effect is modulated by the
rs8736 polymorphism. Additionally, we provide evidence that MBOAT7 acts primarily as a modulator of TLR signalling in mononuclear phagocytes.
Our results highlight the importance of studying Genome-Wide Association Studies (GWAS) signals in the specific cell types in which alterations of gene expression are found.
Abstract
In the modern poultry industry, newly hatched chicks are unavoidably transported from the hatching to the rearing foster. Stress caused by multiple physical and psychological stressors ...during transportation is particularly harmful to the liver. Astragalus polysaccharide (APS) possesses multiple benefits against hepatic metabolic disorders. Given that transport stress could disturb hepatic glucolipid metabolism and the role of APS in metabolic regulation, we speculated that APS could antagonize transport stress-induced disorder of hepatic glucolipid metabolism. Firstly, newly hatched chicks were transported for 0, 2, 4, and 8 h, respectively. Subsequently, to further investigate the effects of APS on transport stress-induced hepatic glucolipid metabolism disturbance, chicks were pretreated with water or APS and then subjected to transport treatment. Our study suggested that APS could relieve transport stress-induced lipid deposition in liver. Meanwhile, transport stress also induced disturbances in glucose metabolism, reflected by augmented mRNA expression of key molecules in gluconeogenesis and glycogenolysis. Surprisingly, APS could simultaneously alleviate these alterations via peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)/Sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) pathway. Moreover, APS treatment regulated the level of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma (PPARγ), thereby alleviating transport stress-induced alterations of VLDL synthesis, cholesterol metabolism, lipid oxidation, synthesis, and transport-related molecules. These findings indicated that APS could prevent the potential against transport stress-induced hepatic glucolipid metabolism disorders via PGC-1α/SIRT1/AMPK/PPARα/PPARγ signaling system.
Transport stress is harmful to the liver and could disrupt hepatic glucolipid metabolism homeostasis. Astragalus polysaccharide (APS) may be a potential feed addition to antagonize the transport stress-induced hepatic glucolipid disorders in chicks through modulation of serum stress levels, lipid metabolism, gluconeogenesis, and glycogenolysis.
Lay Summary
In the modern poultry industry, newly hatched chicks are unavoidably transported from the hatching to the rearing foster. During transportation, chicks are frequently subjected to various physical and psychological stressors, which can lead to alterations in blood composition, hormones, metabolites, enzymes, and behavior. These alterations adversely affect animal health and welfare. Stress caused by transportation is especially harmful to liver, which can cause significant effects on liver function, and disturb hepatic lipid metabolism and glucose metabolic. The current study demonstrated that Astragalus polysaccharide (APS) possesses multiple benefits against hepatic metabolic disorders. Administration of APS to chicks before transport could prevent transport-induced stress and hepatic glucolipid metabolism disorders.
Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that ...TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The goal of the research was to investigate and analyze how Nubian building Environmental systems could be an inspiring way to develop and to rebuild the new city of Aswan and similar contemporary ...cities in hot arid regions. The paper also identifies the main economic, social and cultural consequences of using Nubian Vernacular systems for defining contemporary sustainable and restorative buildings and how these systems were ignored after Nubian displacement by the Government due to the high-dam project establishment. Moreover, it illuminates the most important techniques and methodologies of Nubian village planning and construction and how these ways could achieve maximum passive cooling, thermal comfort, least energy consumption and finally the sustainable development required in the 21st century. Keywords: Nubian houses, Vernacular architecture, Sustainable development
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