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

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

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 meta-analysis of the effects of long-term oxygen therapy combined with exercise rehabilitation on exercise capacity, cardiopulmonary function, and quality of life in patients with COPD

ObjectiveTo assess the effectiveness of long-term oxygen therapy (LTOT) combined with exercise rehabilitation vs. exercise rehabilitation alone in improving exercise capacity, cardiopulmonary function, and quality of life in chronic obstructive pulmonary disease (COPD) patients.MethodsA comprehensive literature search was conducted in the Chinese Biomedical Literature Database (CBM), Wanfang, China National Knowledge Infrastructure (CNKI), Cochrane Library, EMBASE, ScienceDirect, and PubMed for studies published from January 2010 to the present. Controlled clinical trials comparing oxygen therapy and/or exercise rehabilitation in COPD patients were included. Two independent reviewers extracted data and assessed risk of bias using the Cochrane Handbook (version 5.3). Meta-analysis was performed using RevMan 5.3.ResultsNine studies (N = 703) met inclusion criteria. Compared with the control group (CG), the combined LTOT and exercise group showed significant improvements in 6-min walk distance (6MWD), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio (P &lt; 0.05). PaO2 levels tended to be higher but showed substantial heterogeneity. No significant differences were observed in blood oxygen saturation, heart rate, or PaCO2. Quality of life significantly improved in the combined therapy group.ConclusionLTOT combined with exercise rehabilitation is more effective than exercise alone in improving exercise capacity, pulmonary function, and quality of life in COPD patients. However, cardiac benefits remain unclear, warranting further studies