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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 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.
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 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.
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.
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.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset myopathy caused by the expansion of polyalanine in the PABPN1 gene. Abnormal accumulation of PABPN1 on the inner membrane of mitochondria was detected in mouse and cell models of OPMD. The localization of expanded PABPN1 in mitochondria may be associated with mitochondrial dysfunction.
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.
This study reveals the role of Parkin-dependent apoptosis in lipopolysaccharideinduced acute respiratory distress syndrome (ARDS). Polydatin, an herbal resveratrol-related glucoside, significantly activates Parkin-dependent mitophagy to protect against mitochondria-dependent apoptosis and lung injury. Thus, polydatin may be useful for the treatment of ARDS.
There are adjacent TCF/LEF and SMAD consensus binding sites in cyclin D2 and Bmp4 promoters. TCF7, LEF1 and activated SMADs enhance while TCF7L2 inhibits cyclin D2 and Bmp4 expression. Wnt activation increases TCF7 and LEF1 to replace TCF7L2 in these promoters for transcriptional activation and thus promotes cardiomyocyte proliferation.
In this study, the authors show that machine learning is a useful tool for complex pathological assessment of Alzheimer disease and other tauopathies. Using deep learning classifiers, we now have the potential to integrate cell- and region-specific annotations with clinical, genetic, and molecular data, providing unbiased data for clinicopathological correlations that will enhance our knowledge of the neurodegeneration.
Intractable pulmonary fibrosis is a major cause of death in patients with acute respiratory distress syndrome (ARDS), while lipopolysaccharide (LPS) is an important etiological factor in ARDS and pulmonary fibrosis. This study provides convincing evidence that LPS promote lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway. Intervention by targeting inhibition of lung fibroblast autophagy may be a constructive means for treatment of pulmonary fibrosis.
Clear cell renal cell carcinoma (ccRCC) is characterized by activation of hypoxia-inducible factors and enhanced aerobic glycolysis. In this study, the authors found that ccRCC maintains high levels of fructose-1,6-bisphosphate (FBP) through the downregulation of aldolase B. In turn, FBP regulates the redox status of the tumor by suppressing NADPH oxidase isoform NOX4 activity. Thus, aldolase B and FBP are critical regulators of reactive oxygen species and contribute to tumor progression.
In this paper the authors outline the known neuropathology of mild traumatic brain injury (mTBI). They employed immunohistochemistry and gene expression profiling techniques in two post-mortem cases in order to propose markers of DNA damage as the driver of pathology and symptoms after mTBI.
Continuously cultivated iPSCs with chromosome 21 trisomy spontaneously reverted to normal diploids. This trisomy rescue occurred without genetic manipulation, chemical treatment, or exposure to irradiation. The revertant cells can serve as a reference for drug screening and as raw materials for regenerative medicine and cell-based therapy.
The authors report that pathogenic TDP-43 is increased and closely associated with mitochondria in degenerating skeletal muscles of patients with inclusion body myositis, while key subunits of mitochondrial oxidative phosphorylation complexes I and III are reduced, implying a potential role of mitochondria and associated TDP-43 for disease pathogenesis.
Osteoblast-specific cell-surface molecules are believed to be involved in the molecular modulation of bone remodeling. The authors describe a unique cell-surface molecule, A7 antigen, that is specifically expressed in cells of osteoblast lineage. Cross-linking of cell-surface A7 antigen stimulates osteoclastogenesis and markedly suppresses calcification. A7 antigen appears to be a novel recruitment molecule for osteoclasts and trigger of calcification
We revealed that the pathogenesis of mTORi-induced lung injury may be involved in alveolar epithelial injury via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.
The authors identified and compared the primary and contributing diagnoses for people with primary age-related tauopathy (PART) to those with Alzheimer’s disease neuropathologic change (ADNP). Clinicians diagnose AD less frequently in those with PART, recognizing a distinction in the clinical presentation between PART and ADNP.