Articles in 2018

The bile acid rsodeoxycholic acid (UDCA) is the choice of treatment for primary biliary cholangitis patients with abnormal liver enzymes; however, its mechanism is not clear, and is the focus of this investigation. Bile acids alter mast cell (MC) histamine release. Following liver injury, such as that seen in primary sclerosing cholangitis, MCs infiltrate the liver. MC-derived histamine increases biliary damage, fibrosis, and inflammation. UDCA treatment decreases these parameters via reduced MC activation.

Collagen XVII directly binds to collagen IV at the basement membrane zone in both skin and oral mucosa. Mucous membrane pemphigoid autoantibodies targeting the C-terminus of collagen XVII hinder this binding and induce the detachment of basal cells in the oral mucosa. This mechanism leads to oral lesions that show less inflammation than the skin lesions show.

Human ischemic cardiomyopathy is defined by DNA hypermethylation, methyltransferase EZH2 induction, and transcription factor KLF15 suppression. Together these changes may mediate a gene expression pattern reflecting decreased oxidative phosphorylation and increased cellular remodeling. This study therefore identifies a novel mechanism through which coronary heart disease may be regulated.

In normal rats and a human hepatic cell line, the authors demonstrate that remifentanil upregulates IL-18BP expression in hepatocytes, and that the underlying mechanism involves activation of the transcription factors STAT1 and C/EBP β. These findings expand our understanding of the pharmacological effects of remifentanil and suggest its potential treatment benefits for IL-18 dysfunction-mediated hepatic diseases.

In this study, the authors found that interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product (SRAGE) on myocardial ischemia/reperfusion (MI/R) injuries in heart, which might be associated with the increasing expression of proteasome β5i. In addition, the increased β5i in cardiomyocytes promoted the p53 degradation which contributed to the anti-apoptosis effects of sRAGE in MI/R injuries.

Damage to the airway epithelium can be caused by numerous environmental factors. This study describes the development and characterization of a wound healing model from nasal epithelial cells grown at the air-liquid interface. It also identifies the rate of wound closure from healthy donors and the effect epidermal growth factor receptor inhibition has on wound healing.

As a central regulator of self-renewal and pluripotency maintenance in normal and neoplastic stem cells, transcription factor SOX2 expression is tightly controlled. The authors found that the histone-lysine N-methyltransferase MLL1/WDR5 complex methylates SOX2 at K42 and promotes its degradation. Conversely, the protein PHF20L1 recognizes methylated SOX2 through its MBT domain and blocks the degradation of SOX2.

Iso-alpha-acids (IAAs) are hops-derived compounds. In this study, the authors show that IAAs inhibit development of non-alcoholic fatty liver disease. They found that IAAs reduced expression of PPAR-γ and key enzymes of lipid synthesis as well as increased expression of PPAR-α, indicative of increased lipid metabolism. IAAs also reduced oxidative stress and JNK-activation, inhibited hepatic stellate cell activation and reduced proliferation and pro-fibrogenic gene expression.

The dysregulation of dermal fibroblast proliferation and apoptosis is thought to be related to hypertrophic scar formation. In this study, the authors show that the balance of autophagy in HSF is critical for fibrosis formation, and both downregulation and excessive upregulation of autophagy inhibits collagen expression via wild type p53 and the pro-survival protein Bcl-xL.

This study demonstrates that lung mesenchymal stem cells promote non-small cell lung cancer proliferation and migration in a MAPK/translation initiation/autophagy-dependent manner. The authors describe how primary and metastatic niches display opposite and critical effects, both crucial to cancer progression.

Macrophage-epithelial crosstalk regulates cell cycle progression and is essential for the maintenance of a healthy epithelial phenotype. In the present work, the authors show that macrophage-secreted lipocalin-2 is crucial in rescuing epithelial cells from cell cycle arrest and in promoting epithelial proliferation through inhibition of peroxisome proliferator-activated receptor (PPAR)-γ. Lipocalin-2 maintains the epithelial cytoskeleton structure via megalin and downstream activation of thePI3K/AKT signaling pathway.

The authors demonstrate that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) induces cardiac hypertrophy and fibrosis via TGF-β1/Smad3 signaling, suggesting that inhibition of gut microbes or generation of TMAO may become a potential target for the prevention and treatment of cardiac hypertrophy.

In this study the authors demonstrate that the secretin/secretin receptor axis plays a regulatory role in biliary proliferation and liver fibrosis through differential changes in the senescence of cholangiocytes and hepatic stellate cells in a mouse model of primary sclerosing cholangitis. Targeting senescent cholangiocytes by modulation of the secretin/secretin receptor axis may provide a key therapeutic approach in the treatment of cholestatic liver diseases.

GLI transcription factors, which mediate the Hedgehog pathway, are over-expressed in cervical cancer. RNA interference reveals an essential role of GLI2, but not GLI3, in promoting proliferation and migration and xenograft tumor growth of human cervical cancer cells. Mechanistically, the function of GLI2 is mediated by protein kinase B (AKT), and may be targeted as a novel therapeutic strategy.

This report examined secreted exosomes from two in vitro cell culture models: an epithelial to mesenchymal transition model and a cancer stem-like cell model. The authors evaluated the expression and transfer of four long non-coding RNAs (HOTAIR, MALAT, PVT1, and linc-ROR) from exosomes derived from the models. They show that there is induced proliferation and invasive properties via the transfer of lncRNAs by exosomes.

This study investigated whether quantitative computer-extracted images of tissue of lymph node (LN)-, estrogen receptor (ER)+ breast cancer could help stratify patients into discrete outcome groups. The results suggest that quantitative histomorphometric features of nuclear shape and orientation are strongly and independently predictive of patient survival in ER+, LN- breast cancer.

Blood-brain barrier dysfunction and disruption are significant events in central nervous system inflammatory processes. This study shows that TNF-α and VEGF decrease cell-surface cellular prion protein, an adhesion protein, on human brain microvascular endothelial cells, which are a major component of the blood brain barrier. They also show that loss of cellular prion protein results in decreases of the tight junction proteins claudin-5 and occludin and increases permeability of the endothelial layer.

Providing a high fat/calorie diet plus high fructose/glucose in drinking water is shown to be an optimal approach to induce nonalcoholic steatohepatitis in mice. The animal model shows remarkable necroptosis, steatosis, fibrosis and insulin resistance as well as a disordered profile of lipid metabolism and adipokines. This model should prove useful for pathophysiologic investigation and pharmacologic development.

Osteopontin is a critical mediator of post-ischemic neovascularization. Humans express three primary OPN isoforms: OPNa, OPNb, and OPNc. This study demonstrates that OPN isoforms differentially promote functional post-ischemic arteriogenesis by promoting increased macrophage migration and macrophage accumulation and survival. Future studies will determine the molecular mechanisms underlying these divergent effects.