TLRs, NF-κB, JNK, and Liver Regeneration

While hepatocytes rarely undergo proliferation in normal livers, they quickly induce proliferation in response to loss of liver mass by toxin or inflammation-induced hepatocyte injury, trauma, or surgical resection, leading to a restoration of liver mass to its original size. Recent studies suggest that Toll-like receptor (TLR) signaling participates in this regenerative response. Myeloid differentiation factor (MyD88), a common adaptor molecule in the TLR, IL-1 and IL-18 receptor signaling, plays a key role, at least, in the early phase of liver regeneration. Currently, definite ligands which bind to TLRs and initiate this process are still unclear. TLRs stimulated by their corresponding ligands, as well as tumor necrosis factor (TNF) receptors (TNFRs), can activate downstream signal molecules, including transcription factor nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK). Previous studies have revealed the important role of TNF receptor signaling, NF-κB, and JNK in liver regeneration by using hepatocyte-specific gene-modified animals. This review will summarize the current knowledge of TLR signaling and their related molecules in liver regeneration. We will also discuss whether modulating these factors may become new therapeutic strategies to promote liver regeneration in various clinical situations

Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers

<p>Abstract</p> <p>Background</p> <p>The inhibitor of DNA-binding (ID) has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers.</p> <p>Methods</p> <p>Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patient prognosis was analyzed with a 36-month survival rate. Microvessel counts were determined by immunohistochemistry for CD34 and factor VIII-related antigen.</p> <p>Results</p> <p>ID-1 histoscores and mRNA levels both significantly (p < 0.001) increased in ovarian cancers according to clinical stage, regardless of histopathological type. Furthermore, 30 patients with high ID-1 expression had a lower survival rate (53%) compared to patients with low ID-1 expression (80%). ID-1 histoscores and mRNA levels significantly (p < 0.0001) correlated with microvessel counts in ovarian cancers.</p> <p>Conclusion</p> <p>ID-1 increased in ovarian cancer cells during tumor progression. Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers.</p

A new cyano-substituted fluorescamine superior to its original form as a fluorescent probe for amino acid detection

Available online 7 February 2018.Synthesis and spectral study of two new cyano-substituted fluorescamine as the fluorescent probes for amino acid detection have been carried out comparing with the original fluorescamine. Of the three compounds, the derivative with a cyano group at the meta-position on the 4-phenyl group was found to be superior to the original one in the reactivity toward some amino acids as well as the fluorescence intensity of the adducts. The fluorescent amino acid adducts were also applied to the peroxyoxalate chemiluminescence system as the fluorophores, in which the derivative described above was found to be more effective also in chemiluminescence than the original one. (C) 2018 Elsevier Ltd. All rights reserved.ArticleTETRAHEDRON LETTERS. 59(12):1104-1107 (2018)journal articl

The TLR4/TRIF-Mediated Activation of NLRP3 Inflammasome Underlies Endotoxin-Induced Liver Injury in Mice

Administration of heat-killed Propionibacterium acnes renders mice highly susceptible to LPS. After LPS challenge P. acnes-primed mice promptly show hypothermia, hypercoagulation (disseminated intravascular coagulation), elevation of serum proinflammatory cytokine levels, and high mortality. The surviving mice develop liver injury. As previously reported, IL-18 plays a pivotal role in the development of this liver injury. Many cell types including macrophages constitutively store IL-18 as biologically inactive precursor (pro) form. Upon appropriate stimulation exemplified by TLR4 engagement, the cells secrete biologically active IL-18 by cleaving pro-IL-18 with caspase-1. Caspase-1 is also constitutively produced as a zymogen in macrophages. Recently, NLRP3, a cytoplasmic pathogen sensor, has been demonstrated to be involved in the activation of caspase-1. Here, we review the molecular mechanisms for the liver injuries, particularly focusing on the TLR4/NLRP3-mediated caspase-1 activation process, with a brief introduction of the mechanism underlying P. acnes-induced sensitization to LPS

Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 × DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 μg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC

Pylorus preserving pancreatoduodenectomy in a 6-year-old girl with recurrent pancreatitis due to an annular pancreas

AbstractThe pancreatitis caused by an annular pancreas rarely needs a surgical management in children. Here, we report a case of a 6-year old girl in whom pylorus-preserving pancreatoduodenectomy (PPPD) was performed for the pancreatitis caused by an annular pancreas. As she had previous operations for duodenal atresia and pancreaticobiliary maljunction, PPPD was chosen as a definitive surgical treatment of annular pancreas. She has been free from symptoms for 2 years after the operation

Clinical Characteristics and Predictors of Mortality in Patients with Combined Pulmonary Fibrosis and Emphysema Syndrome and Lung Cancer

Rationale: We performed this retrospective study to clarify the clinical characteristics, survival and mortality predictors in patients with combined pulmonary fibrosis and emphysema (CPFE) and lung cancer. Methods: We retrospectively reviewed the medical records of a total of 123 patients with lung cancer, as confirmed according to histological or cytological examinations. Based on the findings of chest CT, the patients were categorized into four groups: LC+normal (n=70); LC+emphysema (n=26); LC+fibrosis (n=10); LC+CPFE (n=17). The clinical characteristics and survival of the LC+CPFE group were compared with those of the other groups. In addition, mortality predictors were evaluated in the LC+CPFE group. Results: The proportion of females was significantly higher in the LC+normal group than in the LC+CPFE and LC+emphysema groups. Significantly more patients were diagnosed with squamous cell carcinoma in the LC+CPFE group than in the LC+normal group. The proportion of patients whose primary mass was located in “nonsubpleural” areas was significantly higher in patients with CPFE who also had lung cancer in the upper lobe than in those with CPFE who also had lung cancer in the other sites. There were significant differences in survival between the LC+normal group and the other groups, whereas there were no significant differences in survival among the LC+emphysema, LC+fibrosis and LC+CPFE groups. In the LC+CPFE group, the patients with a high level of serum KL-6 at diagnosis and upper lobe lung cancer demonstrated a high risk of death. A high level of serum KL-6 at diagnosis was also independently associated with a high risk of death. Conclusions: Patients with CPFE and lung cancer may have distinct clinical characteristics. Strict follow-up is required in patients with CPFE and lung cancer whose serum KL-6 level at diagnosis is higher than the normal range and/or the primary mass of lung cancer is located in the upper lobe.ArticleJournal of Pulmonary and Respiratory Medicine.5(3):263(2015)journal articl

Parenteral Nutrition Administration Leads to Specific Alterations in the Expression of Adipocytokines and Peroxisome Proliferator‐Activated Receptors in a Rat Model

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141876/1/jpen0329-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141876/2/jpen0329.pd

Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host