Schistosoma mansoni-Induced Oxidative Stress Triggers Hepatocellular Proliferation.

BACKGROUND & AIMS: Schistosomiasis is one of the most prominent parasite-induced infectious diseases, affecting more than 250 million people. Schistosoma mansoni causes metabolic exhaustion and a strong redox imbalance in the liver, causing parenchymal damage, and may predispose for cancer. We investigated whether oxidative stress provokes hepatocellular proliferation upon S. mansoni infection. METHODS: The cell cycle, replication stress response, and proliferation were analyzed on transcriptional and protein levels in the livers of S. mansoni-infected hamsters and by mechanistic gain- and loss-of-function experiments in human hepatoma cells. Major results were validated in human biopsy specimens of S. mansoni-infected patients. RESULTS: S. mansoni infection induced licensing factors of DNA replication and cell-cycle checkpoint cyclins in parallel with a DNA damage response in hamster hepatocytes. Moreover, even unisexual infection without egg effects, as a reflection of a chronic inflammatory process, resulted in a moderate activation of several cell-cycle markers. S. mansoni soluble egg antigens induced proliferation of human hepatoma cells that could be abolished by reduced glutathione. CONCLUSIONS: Our data suggest that hepatocellular proliferation is triggered by S. mansoni egg-induced oxidative stress.

Potential of Modification of Techno-Functional Properties and Structural Characteristics of Citrus, Apple, Oat, and Pea Dietary Fiber by High-Intensity Ultrasound.

Plant fibers are rich in dietary fiber and micronutrients but often exhibit poor functionality. Ultrasonication can affect the particle size of plant fiber, thereby influencing other techno-functional properties. Therefore, this study aimed to investigate the effects of high-intensity ultrasound on citrus, apple, oat, and pea fiber. Initially, solutions containing 1 wt% of plant fiber were homogenized using ultrasonication (amplitude 116 µm, t = 150 s, energy density = 225 kJ/L, P¯ = 325 W). Due to cavitation effects induced by ultrasound, differences in particle size and a shift in the ratio of insoluble and alcohol-insoluble fractions for dietary fiber were observed. Additionally, viscosities for citrus and apple fiber increased from 1.4 Pa·s to 84.4 Pa·s and from 1.34 Pa·s to 31.7 Pa·s, respectively, at shear rates of 100 1s. This was attributed to observed differences in the microstructure. Freeze-dried samples of purified citrus and apple fiber revealed thin and nearly transparent layers, possibly contributing to enhanced water binding capacity and, therefore, increased viscosity. Water binding capacity for citrus fiber increased from 18.2 g/g to 41.8 g/g, and a 40% increase was observed for apple fiber. Finally, ultrasound demonstrated itself be an effective technology for modifying the techno-functional properties of plant fiber, such as water binding capacity.

Influence of High-Intensity Ultrasound on Characteristics and Bioaccessibility of Pea Protein in Fiber-Enriched Suspensions.

Pea protein is of high interest for the food industry owing to its low allergenicity and high nutritional value. However, it often exhibits poor functionality, such as low solubility. The presence of dietary fiber in food products is beneficial for human health but may decrease the bioaccessibility of nutrients. Ultrasound, as a promising green technology, may influence properties of fibers and proteins and, thus, bioaccessibility. Therefore, this study investigated the effects of high-intensity ultrasound on the characteristics and protein bioaccessibility of protein-fiber suspensions. Suspensions containing different fiber compounds (1 wt.%) and pea protein (5 wt.%) were homogenized using high-intensity ultrasound (amplitude 116 µm, t = 150 s, energy density = 225 kJ/L, P¯ = 325 W). Owing to sonication-induced cavitation, the dispersibility of the protein was enhanced, and the viscosity of solutions containing citrus or apple fiber was increased. FE-SEM revealed the formation of different fiber-protein networks during sonication. Even if viscosity is known to have an impact on the bioaccessibility of nutrients, no restrictions on the digestibility of protein were detected during an in vitro digestion. Thus, protein uptake is probably not affected, and ultrasound can be used to modify the technofunctionality of fibers and proteins without any nutritional disadvantages.

Metabolic reprogramming of hepatocytes by Schistosoma mansoni eggs.

Background & Aims: Schistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma. Methods: Metabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies. Results: The infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects. Conclusions: Our findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma. Impact and implications: The authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.

Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- Mice.

BACKGROUND & AIMS: The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. METHODS: After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. RESULTS: Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. CONCLUSIONS: We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.

Schistosoma mansoni eggs induce Wnt/ß-catenin signaling and activate the protooncogene c-Jun in human and hamster colon.

Schistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/ß-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice.

The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4-/-). Lack of IL-13 protected Abcb4-/- mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4-/-/IL-13-/- double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4-/-IL-13-/- mice showed significantly reduced hepatic fibrosis. Abcb4-/- mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.