EZH2/hSULF1 axis mediates receptor tyrosine kinase signaling to shape cartilage tumor progression.

Chondrosarcomas are primary cancers of cartilaginous tissue and capable of alteration to highly aggressive, metastatic, and treatment-refractory states, leading to a poor prognosis with a five-year survival rate at 11 months for dedifferentiated subtype. At present, the surgical resection of chondrosarcoma is the only effective treatment, and no other treatment options including targeted therapies, conventional chemotherapies, or immunotherapies are available for these patients. Here, we identify a signal pathway way involving EZH2/SULF1/cMET axis that contributes to malignancy of chondrosarcoma and provides a potential therapeutic option for the disease. A non-biased chromatin immunoprecipitation sequence, cDNA microarray analysis, and validation of chondrosarcoma cell lines identified sulfatase 1 (SULF1) as the top EZH2-targeted gene to regulate chondrosarcoma progression. Overexpressed EZH2 resulted in downregulation of SULF1 in chondrosarcoma cell lines, which in turn activated cMET pathway. Pharmaceutical inhibition of cMET or genetically silenced cMET pathway significantly retards the chondrosarcoma growth and extends mice survival. The regulation of EZH2/SULF1/cMET axis were further validated in patient samples with chondrosarcoma. The results not only established a signal pathway promoting malignancy of chondrosarcoma but also provided a therapeutic potential for further development of effective target therapy to treat chondrosarcoma.

Handgrip strength, tumor necrosis factor-α, interlukin-6, and visfatin levels in oldest elderly patients with cognitive impairment.

INTRODUCTION: Handgrip strength is associated with mild cognitive impairment. Tumor necrosis factor [TNF]-α and interleukin [IL]-6 were pro-inflammatory cytokines influencing the severity of initial neurological deficit. Visfatin is a novel adipokine and has a strong correlation with inflammation. The relationships of TNF-α, IL-6 and visfatin are not consistent, and no study has investigated them in the elderly patients with cognitive impairment. METHODS: This study included patients aged ≥75 years at the emergency department from August 2018 to February 2019. All patients underwent comprehensive geriatric assessment and blood tests for fasting plasma TNF-α, IL-6 and visfatin levels. RESULTS: We enrolled 106 elderly patients with a mean age of 87.3 years, including 62 (58.4%) patients in cognitive impairment group (Mini-Mental State Examination [MMSE] < 24) and 44 (41.5%) patients in the non-cognitive impairment group. Compared to the non-cognitive impairment group, the cognitive impairment group had significantly lower handgrip strength, and significantly higher TNF-α, IL-6 and visfatin levels. TNF-α positively correlated with IL-6. Both TNF-α and IL-6 negatively correlated with Barthel index and MMSE. Handgrip strength negatively correlated with TNF-α but positively correlated with Barthel index and MMSE scores. Backward and stepwise multiple logistic regression analyses showed that the independent predictor for cognitive impairment was handgrip strength and age. CONCLUSION: The cognitive impairment group had significantly higher serum TNF-α, IL-6, and visfatin levels. The independent predictors of cognitive impairment were handgrip strength and age. Handgrip strength negatively correlated with TNF-α and IL-6 but positively with Barthel index and MMSE scores.

Ginkgolide C reduced oleic acid-induced lipid accumulation in HepG2 cells.

Ginkgolide C, isolated from Ginkgo biloba, is a diterpene lactone that has multiple biological functions and can improve Alzheimer disease and platelet aggregation. Ginkgolide C also inhibits adipogenesis in 3T3-L1 adipocytes. The present study evaluated whether ginkgolide C reduced lipid accumulation and regulated the molecular mechanism of lipogenesis in oleic acid-induced HepG2 hepatocytes. HepG2 cells were treated with 0.5 mM oleic acid for 48 h to induce a fatty liver cell model. Then, the cells were exposed to various concentrations of ginkgolide C for 24 h. Staining with Oil Red O and the fluorescent dye BODIPY 493/503 revealed that ginkgolide C significantly reduced excessive lipid accumulation in HepG2 cells. Ginkgolide C decreased peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein 1c to block the expression of fatty acid synthase. Ginkgolide C treatment also promoted the expression of adipose triglyceride lipase and the phosphorylation level of hormone-sensitive lipase to enhance the decomposition of triglycerides. In addition, ginkgolide C stimulated CPT-1 to activate fatty acid ß-oxidation, significantly increased sirt1 and phosphorylation of AMP-activated protein kinase (AMPK), and decreased expression of acetyl-CoA carboxylase for suppressed fatty acid synthesis in hepatocytes. Taken together, our results suggest that ginkgolide C reduced lipid accumulation and increased lipolysis through the sirt1/AMPK pathway in oleic acid-induced fatty liver cells.

Phloretin attenuates LPS-induced acute lung injury in mice via modulation of the NF-κB and MAPK pathways.

Phloretin, which can be isolated from apple trees, has demonstrable anti-inflammatory and anti-oxidant effects in macrophages. We previously reported that phloretin could inhibit the inflammatory response and reduce intercellular adhesion molecule 1 (ICAM-1) expression in interleukin (IL)-1ß-activated human lung epithelial cells. In the present study we now evaluate whether phloretin exposure could ameliorate lipopolysaccharide (LPS)-induced acute lung injury in mice. Intra-peritoneal injections of phloretin were administered to mice for 7 consecutive days, prior to the induction of lung injury by intra-tracheal administration of LPS. Our subsequent analyses demonstrated that phloretin could significantly suppress LPS-induced neutrophil infiltration of lung tissue, and reduce the levels of IL-6 and tumor necrosis factor (TNF)-α in serum and bronchoalveolar lavage fluid. We also found that phloretin modulated myeloperoxidase activity and superoxide dismutase activity, with decreased gene expression levels for chemokines, proinflammatory cytokines, and ICAM-1 in inflamed lung tissue. Phloretin also significantly reduced the phosphorylation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), thus limiting the inflammatory response, while promoting expression of heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2, both of which are cytoprotective. Our findings suggest that, mechanistically, phloretin attenuates the inflammatory and oxidative stress pathways that accompany lung injury in mice via blockade of the NF-κB and MAPK pathways.