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The paper by Liu et al (page 1193,this issue) presents a novel mechanism whereby epigenetic regulation of scar formation may be manipulated at the level of fibroblast DNA hydroxymethylation. The cover shows immunofluorescence staining of human fibroblasts for F actin (green) and phosphorylated focal adhesion kinase (red dots; blue = DAPI).
Micheliolide (MCL) is known for its antioxidant and anti-inflammatory effects and has multiple effects in inflammatory diseases and tumors. The authors studied the effects of an MCL derivative in two renal fibrosis models. They found that the metastasis adhesion protein metadherin (Mtdh) was activated under fibrotic conditions and that MCL suppressed its expression via the BMP/MAPK pathway.
The authors show that normal apoAI/HDL and an apoAI mimetic have protective effects on damaged podocytes in culture. In vivo, infusion of the apoAI mimetic lessens glomerular damage, proteinuria, and atherosclerosis. These findings suggest that supplemental apoAI/apoAI mimetic 4F may be novel interventions to lessen podocyte damage, and the resulting proteinuria and atherosclerosis.
The study reveals the novel role of B7H3, a co-stimulator molecule of the cell surface B7 protein superfamily, in glioblastoma multiforme (GBM). B7H3 is synchronously upregulated with glioma self-renewing cell (GSC)-related genes. B7H3 regulates GBM differentiation through activation of the TGF-β pathway and modulation of MYC. The study provides a new paradigm of B7H3 as a prognostic and therapeutic target in GBM.
Targeting splenic macrophages with immunosuppressive microRNA is a potential therapeutic strategy for sepsis. Interference of splenic macrophages by miR-146a-expressing plasmid and polyethyleneimine complex modulates the Toll-like receptor-related immunity, which results in the amelioration of excessive inflammation, multiple organ injury, and even death due to sepsis.
This study demonstrates a novel mechanism in neutrophil apoptosis. In vitro, 5-Aza-2′-deoxycytidine (Aza) promotes apoptosis by enhancing death-associated protein kinase 1 (DAPK1) expression and activity. In vivo, Aza treatment accelerates inflammatory resolution in lipopolysaccharide-induced acute respiratory distress syndrome by upregulating DAPK1 expression, resulting in apoptosis of neutrophils.
Doxorubicin inactivates the EGFR/Src/HMG-CR pathway, and decreases levels of both cholesterol and lipid rafts. Simvastatin enhances doxorubicin-induced cell death but cholesterol attenuates it. The anti-cancer effect of doxorubicin is attenuated in cholesterol-high diet-fed mice. Therefore, cholesterol control may be combined with treatment to enhance doxorubicin efficacy and reduce its side effects.
During endotoxemia, bacterial endotoxin interacts with vascular endothelial cells of blood vessels, generating endotoxin-induced endothelial fibrosis. Inhibition of endotoxemia-induced endothelial fibrosis increases the survival rate of endotoxemic rats by reversing the decreases in blood pressure associated with MODS, and inhibition of both oxidative bursts and pro-inflammatory cytokine secretion. These results suggest a novel target that may be used to generate therapeutic alternatives to lower the mortality of septic patients.
Because scar formation is regulated by genetic and epigenetic influences, the authors tested the hypothesis that abnormalities in DNA hydroxymethylation in hypertrophic scar formation. They found that 5-hydroxymethylcytosine loss in scar fibroblasts is associated with depletion of TET3 (a DNA methylation enzyme) and increased expression of focal adhesion kinase; and that these effects are partially diminished by ascorbic acid.
Relaxin-2 reduces liver steatosis in mice with high-fat diet (HFD)-induced non-alcoholic fatty liver disease with simple steatosis or methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis by activating the eNOS/NO pathway. Additionally, relaxin-2 improves insulin resistance and obesity in HFD mice. In MCD mice, relaxin-2 further attenuates hepatic inflammation and fibrosis with reduction in levels of hepatocyte apoptosis and hepatic stellate cell activation.
The prolyl hydroxylase domain (PHD) inhibitor JTZ-951 is known to stabilize hypoxia-inducible factors. Mice fed a high-fat diet that were treated with JTZ-951 showed decreased inflammation and fibrosis in white adipose tissue, and exhibited reductions in obesity, hepatic steatosis and albuminuria. These results suggest that PHD inhibition may be a new therapeutic target for obesity-related diseases.
The authors generated a CRISPR-Cas9 edited “workhorse” platform using a Ptf1-Cre; LSL-Cas9 mouse that. This model enables the relatively facile interrogation of the functional role of mutated genes in the pancreatic ductal adenocarcinoma landscape, including diverse combinations of targeted alleles using adeno-associated virus 8 as a delivery vector. The resulting pancreata demonstrate the full compendium of precursor and invasive lesions observed in human pancreatic ductal adenocarcinoma.