Local well-posedness of 1D degenerate drift diffusion equation

This paper proves the well-posedness of locally smooth solutions to the free boundary value problem for the 1D degenerate drift diffusion equation. At the free boundary, the drift diffusion equation becomes a degenerate hyperbolic-Poisson coupled equation. We apply the Hardy's inequality and weighted Sobolev spaces to construct the appropriate a priori estimates, overcome the degeneracy of the system and successfully establish the existence of solutions in the Lagrangian coordinates

Host microbiota dictates the proinflammatory impact of LPS in the murine liver

Gut microbiota can impact liver disease development via the gut-liver axis. Liver inflammation is a shared pathological event in various liver diseases and gut microbiota might influence this pathological process. In this study, we studied the influence of gut microbiota on the inflammatory response of the liver to lipopolysaccharide (LPS). The inflammatory response to LPS (1–10 μg/ml) of livers of specific-pathogen-free (SPF) or germ-free (GF) mice was evaluated ex vivo, using precision-cut liver slices (PCLS). LPS induced a more pronounced inflammatory response in GF PCLS than in SPF PCLS. Baseline TNF-α gene expression was significantly higher in GF slices as compared to SPF slices. LPS treatment induced TNF-α, IL-1β, IL-6 and iNOS expression in both SPF and GF PCLS, but the increase was more intense in GF slices. The anti-inflammatory markers SOCS3 and IRAK-M gene expression was significantly higher in GF PCLS than SPF PCLS at 24h with 1 µg/ml LPS treatment, and IL-10 was not differently expressed in GF PCLS than SPF PCLS. In addition, TLR-4 mRNA, but not protein, at basal level was higher in GF slices than in SPF slices. Taken together, this study shows that, in mice, the host microbiota attenuates the pro-inflammatory impact of LPS in the liver, indicating a positive role of the gut microbiota on the immune homeostasis of the liver

A nonalcoholic fatty liver disease cirrhosis model in gerbil:the dynamic relationship between hepatic lipid metabolism and cirrhosis

Nonalcoholic fatty liver disease (NAFLD) usually takes decades to develop into cirrhosis, which limits the longitudinal study of NAFLD. This work aims at developing a NAFLD-caused cirrhosis model in gerbil and examining the dynamic relationship between hepatic lipid metabolism and cirrhosis. We fed gerbil a high-fat and high-cholesterol diet (HFHCD) for 24 weeks, and recorded the gerbil's phenotype at 3, 6, 9, 12, 15, 18, 21, 24 weeks. The model's pathological process, lipid metabolism, oxidative stress, liver collagen deposition and presence of relevant cytokines were tested and evaluated during the full-time frame of disease onset. The gerbil model can induce nonalcoholic steatohepatitis (NASH) within 9 weeks, and can develop cirrhosis after 21 weeks induction. The model's lipids metabolism disorder is accompanied with the liver damage development. During the NAFLD progression, triglycerides (TG) and free fatty acids (FFA) have presented distinct rise and fall tendency, and the turning points are at the fibrosis stage. Besides that, the ratios of total cholesterol (CHO) to high-density lipoprotein cholesterol (HDL-C) exhibited constant growth tendency, and have a good linear relationship with hepatic stellate cells (HSC) (R-2 = 0.802, P <0.001). The gerbil NAFLD cirrhosis model has been developed and possesses positive correlation between lipids metabolism and cirrhosis. The compelling rise and fall tendency of TG and FFA indicated that the fibrosis progression can lead to impairment in lipoprotein synthesis and engender decreased TG level. CHO/HDL-C ratios can imply the fibrosis progress and be used as a blood indicator for disease prediction and prevention

Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs

BACKGROUND: Intestinal fibrosis is a hallmark of Crohn's disease. Here, we investigated the impact of several putative antifibrotic compounds on the expression of fibrosis markers using murine precision-cut intestinal slices. METHODS: Murine precision-cut intestinal slices were cultured for 48 hours in the presence of profibrotic and/or antifibrotic compounds. The fibrotic process was studied on gene and protein level using procollagen 1a1 (Col1α1), heat shock protein 47 (Hsp47), fibronectin (Fn2), and plasminogen activator inhibitor-1 (Pai-1). The effects of potential antifibrotic drugs mainly inhibiting the transforming growth factor β (TGF-β) pathway (eg, valproic acid, tetrandrine, pirfenidone, SB203580, and LY2109761) and compounds mainly acting on the platelet-derived growth factor (PDGF) pathway (eg, imatinib, sorafenib, and sunitinib) were assessed in the model at nontoxic concentrations. RESULTS: Murine precision-cut intestinal slices remained viable for 48 hours, and an increased expression of fibrosis markers was observed during culture, including Hsp47, Fn2, and Pai-1. Furthermore, TGF-β1 stimulated fibrogenesis, whereas PDGF did not have an effect. Regarding the tested antifibrotics, pirfenidone, LY2109761, and sunitinib had the most pronounced impact on the expression of fibrosis markers, both in the absence and presence of profibrotic factors, as illustrated by reduced levels of Col1α1, Hsp47, Fn2, and Pai-1 after treatment. Moreover, sunitinib significantly reduced Hsp47 and Fn2 protein expression and the excretion of procollagen 1. CONCLUSIONS: Precision-cut intestinal slices can successfully be used as a potential preclinical screening tool for antifibrotic drugs. We demonstrated that sunitinib reduced the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis

Peribiliary glands are key in regeneration of the human biliary epithelium after severe bile duct injury

Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We, therefore, developed a novel ex vivo model using precision-cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Post-ischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation and maturation. Proliferation of PBG cells increased after 24 h of oxygenated incubation, reaching a peak after 72 h. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (Nanog+/Sox9+) to a mature (CFTR+/secretin receptor+) and activated phenotype (increased expression of HIF-1α, Glut-1, and VEGF-A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. CONCLUSION: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behaviour of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury. This article is protected by copyright. All rights reserved

Models Analyses for Allelopathic Effects of Chicory at Equivalent Coupling of Nitrogen Supply and pH Level on F. arundinacea, T. repens and M. sativa

Alllelopathic potential of chicory was investigated by evaluating its effect on seed germination, soluble sugar, malondialdehyde (MDA) and the chlorophyll content of three target plants species (Festuca arundinacea, Trifolium repens and Medicago sativa). The secretion of allelochemicals was regulated by keeping the donor plant (chicory) separate from the three target plant species and using different pH and nitrogen levels. Leachates from donor pots with different pH levels and nitrogen concentrations continuously irrigated the target pots containing the seedlings. The allelopathic effects of the chicory at equivalent coupling of nitrogen supply and pH level on the three target plants species were explored via models analyses. The results suggested a positive effect of nitrogen supply and pH level on allelochemical secretion from chicory plants. The nitrogen supply and pH level were located at a rectangular area defined by 149 to 168 mg/l nitrogen supply combining 4.95 to 7.0 pH value and point located at nitrogen supply 177 mg/l, pH 6.33 when they were in equivalent coupling effects; whereas the inhibitory effects of equivalent coupling nitrogen supply and pH level were located at rectangular area defined by 125 to 131 mg/l nitrogen supply combining 6.71 to 6.88 pH value and two points respectively located at nitrogen supply 180 mg/l with pH 6.38 and nitrogen supply 166 mg/l with pH 7.59. Aqueous extracts of chicory fleshy roots and leaves accompanied by treatment at different sand pH values and nitrogen concentrations influenced germination, seedling growth, soluble sugar, MDA and chlorophyll of F. arundinacea, T. repens and M. sativa. Additionally, we determined the phenolics contents of root and leaf aqueous extracts, which were 0.104% and 0.044% on average, respectively

Distinct responses between healthy and cirrhotic human livers upon lipopolysaccharide challenge:possible implications for acute-on-chronic liver failure

Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure