Role of Toll-Like Receptors and Their Downstream Molecules in the Development of Nonalcoholic Fatty Liver Disease

Activation of innate immunity is associated with the development of liver disease, including non-alcoholic fatty liver disease (NAFLD). In the innate immune system, Toll-like receptors (TLRs) are sensors that recognize bacterial and viral components such as lipopolysaccharide, bacterial DNA, and peptidoglycan. Recent data have demonstrated that the liver is exposed to a high load of TLR ligands due to bacterial overgrowth and increased intestinal permeability in NAFLD. Upon stimulation by these TLR ligands, hepatic immune cells produce various mediators that are involved in host defense. On the other hand, these mediators alter lipid metabolism, insulin signaling, and cell survival. Indeed, some TLR-deficient mice demonstrate lesser degrees of NAFLD even though TLR ligands are increased. This paper will highlight the recent progress on the study of TLR signaling and their downstream molecules in the development of NAFLD

Requirement of Gαq/Gα11 Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis

Background & AimsProliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein–coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis.MethodsIntestinal tissues from control (Gnaqflox/floxGna11+/+), Int-Gq knock-out (KO) (VilCre+/-Gnaqflox/floxGna11+/+), G11 KO (Gnaqflox/floxGna11-/-), and Int-Gq/G11 double knock-out (DKO) (VilCre+/-Gnaqflox/floxGna11-/-) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gαq/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gαq/11 in colon.ResultsPaneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear β-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid–Schiff–positive cells, and Muc2-positive cells were unusually observed in the ulcerative region.ConclusionsThe Gαq/11-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/β-catenin signaling was reduced significantly in the crypt base in Gαq/G11-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis

Comparison of Moral Distress and Burnout Experienced by Mental Health Nurses in Japan and England : A Cross-sectional Questionnaire Survey

Aims: To compare moral distress and burnout experienced by mental health nurses in hospitals both in Japan and England. Methods: This is a cross-national study, and a cross-sectional design was adopted. An anonymous questionnaire containing 43 moral distress items, a 16 item burnout scale, and demographic data was administered to convenient samples; 391 nurses in Japan, and 460 nurses in England. Among the participants, 289 nurses (73.9%) in Japan, and 36 nurses (7.8%) in England responded. Results: The moral distress items which were commonly felt by nurses in both countries dealt with a lack of staff. Several differences, however, existed between the two, which reflected poor conditions such as long term social hospitalization in Japan. The nurses in England felt moral distress in a wider variety of situations, though they confront them less frequently than the nurses in Japan. Only in England was it found that the older nurses became, and the more experience they had accumulated, the less intensely they felt moral distress. The nurses in both countries felt the same levels of exhaustion, and cynicism, but as far as professional efficacy, the scores of the nurses in England were much higher than those of the nurses in Japan. Conclusions: If nurses feel no moral distress, there will be no improvements of care. Nurses should have moral sense, and do their best to improve the situations without being burned out

MCP-1 INHIBITS DNA SYNTHESIS IN RAT PANCREATIC STELLATE CELLS

Activated pancreatic stellate cells (PSCs) synthesize various kinds of cytokines and chemokines including monocyte chemoattractant protein-1 (MCP-1) and play major roles in promoting inflammation and fibrogenesis in the pancreas. MCP-1 is a potent chemotactic factor for leukocytes and it has recently been shown that the target is not restricted. The aim of this study was to investigate whether MCP-1 exerts a biological effect on PSCs. Cultured rat PSCs secreted MCP1 independent of the concentration of transforming growth factor-β1 (TGF-β 1) in the culture media. Although PSCs lack the typical receptor system (C-C chemokine receptor 2 (CCR2)), MCP-1 inhibited DNA synthesis in PSCs without activation, suggesting the presence of CCR2-independent MCP-1 signaling pathway. Further, MCP-1 inhibited the proliferation of PSCs in which TGF-β 1/Smad pathway was blocked by the dominant-negative Smad2/3 over-expression. MCP-1 did not affect the phosphorylation state of mitogen-activated protein kinase (MAPK), Akt, nor epidermal growth factor receptor (EGFR). Taken together, MCP-1 inhibited DNA synthesis of cultured rat PSCs in an autocrine or paracrine manner without activation and this effect was exerted through CCR2-independent and TGF-β1/Smad-independent pathway. These data provide new insights to better understand MCP-1 participation in pancreatic inflammation and also to develop a new strategy for its treatment

Role of toll-like receptors and their downstream molecules in the development of nonalcoholic Fatty liver disease.

Activation of innate immunity is associated with the development of liver disease, including non-alcoholic fatty liver disease (NAFLD). In the innate immune system, Toll-like receptors (TLRs) are sensors that recognize bacterial and viral components such as lipopolysaccharide, bacterial DNA, and peptidoglycan. Recent data have demonstrated that the liver is exposed to a high load of TLR ligands due to bacterial overgrowth and increased intestinal permeability in NAFLD. Upon stimulation by these TLR ligands, hepatic immune cells produce various mediators that are involved in host defense. On the other hand, these mediators alter lipid metabolism, insulin signaling, and cell survival. Indeed, some TLR-deficient mice demonstrate lesser degrees of NAFLD even though TLR ligands are increased. This paper will highlight the recent progress on the study of TLR signaling and their downstream molecules in the development of NAFLD