Regulation of inflammation and immunity in sepsis by E3 ligases.

Sepsis is a life-threatening organ dysfunction caused by an abnormal infection-induced immune response. Despite significant advances in supportive care, sepsis remains a considerable therapeutic challenge and is the leading cause of death in the intensive care unit (ICU). Sepsis is characterized by initial hyper-inflammation and late immunosuppression. Therefore, immune-modulatory therapies have great potential for novel sepsis therapies. Ubiquitination is an essential post-translational protein modification, which has been known to be intimately involved in innate and adaptive immune responses. Several E3 ubiquitin ligases have been implicated in innate immune signaling and T-cell activation and differentiation. In this article, we review the current literature and discuss the role of E3 ligases in the regulation of immune response and their effects on the course of sepsis to provide insights into the prevention and therapy for sepsis.

LncRNA PCAT1 promotes metastasis of endometrial carcinoma through epigenetical downregulation of E-cadherin associated with methyltransferase EZH2.

More than 140 thousands of women suffer from endometrial carcinoma in the worldwide, and over 40 thousand of the patients die before and after in surgery and chemoradiotherapy because of its metastasis. However, its molecular mechanism is much less known compared to other cancers. In this study, we demonstrated that long non-coding RNA PCAT1 is dramatically increased in the tissues and plasma from endometrial carcinoma (EC) (n = 100, all p < 0.001) controlled by its paracancerous tissue, and cell lines including RL-952, HEC-1-B, KLE, Ishikawa, and AN3CA compared to the cells from normal endometrium (all p < 0.001). When lncRNA PCAT1 was knocked-down, the KLE and AN3CA cells exhibited slow capability on proliferation and colony formation in vitro. With the silence of lncRNA PCAT1, the cells were markedly inhibited on migration and invasion in vitro (all p < 0.001), which were confirmed on the EC patient subjects. When expressions of lncRNA PCAT1 were interfered in the cells, expressions of E-cadherin but not N-cadherin and Vimentin were significantly promoted with a strong up-regulation accompanied by nearly completed recoveries on migration and invasion (all p < 0.001). In order to analyze the association of lncRNA PCAT1 and E-cadherin, we silenced the expressions of both genes and unveiled that EC migration and invasion were significantly congested (all p < 0.001). Importantly, we found that the E-cadherin down-regulation caused by lncRNA PCAT1 associates with histone methyltransferase EZH2. When over-expression of EZH2 was applied in the PCAT1 silenced cells, the expression of E-cadherin experienced significant decrease in the cell lines. Reversely, when expression of EZH2 was annulled in the PCAT1 silenced cells, the expression of E-cadherin was significantly boosted in the cells (all p < 0.001). Furthermore, the interaction of lncRNA PCAT1 and EZH2 were approved with immunoprecipitation. Our data demonstrated that the methyltransferase EZH2 related up-regulation of lncRNA PCAT1 along with down-regulation of E-cadherin could be essential in oncogenesis of endometrial carcinoma in both EC cells and patient subjects. These compact data suggest that combination of lncRNA PCAT1, EZH2 and E-cadherin could provide valued information for efficient EC diagnostics, which would propose a potential target for EC treatment with EZH2i on methyltransferation.

Hypoxia-induced microRNA-10b-3p promotes esophageal squamous cell carcinoma growth and metastasis by targeting TSGA10.

Evidence has shown that hypoxia promotes esophageal squamous cell carcinoma (ESCC) growth and metastasis, but the molecular mechanisms underlying that response remain poorly understood. MicroRNAs (miRNAs) are post-transcriptional regulators that participate in various cancer-related processes. Here, we demonstrated that hypoxia along with hypoxia-inducible factor 1α significantly increased expression of miR-10b-3p. Inhibition of miR-10b-3p weakened the effects of hypoxia on ESCC cell proliferation, migration and invasion, while miR-10b-3p overexpression had the opposite effects. Mechanistically, miR-10b-3p acted as cancer-promoting gene by targeting testis specific 10. Using a xenograft model, we observed that administration of miR-10b-3p agomir to tumors enhanced their growth and metastasis in vivo. These findings verified the potent regulatory role played by hypoxia-induced miR-10b-3p expression in ESCC progression. These results suggest that miR-10b-3p may be a useful therapeutic target for treating ESCC.

Dispersible MoS2 micro-sheets induced a proinflammatory response and apoptosis in the gills and liver of adult zebrafish.

Molybdenum disulfide (MoS2), one of the next-generation two-dimensional materials (2DMs), has attracted increasing attention due to its unique physicochemical properties. However, the aquatic toxicity of dispersible MoS2 is still unknown. Herein, we synthesized chitosan functionalized MoS2 (CS-MoS2) micro-sheets with a satisfying water-dispersible performance. The average length and width of the as-prepared CS-MoS2 micro-sheets were 5.04 µm and 3.12 µm, respectively, and they had a pristine 2H polymorph. The toxicity of CS-MoS2 micro-sheets was assessed by investigating the organs, gills and liver of adult zebrafish. We found that exposure to high concentrations of CS-MoS2 micro-sheets (10 mg L-1 and 20 mg L-1) led to lamellar fusions in the gills, and significant localized lesions, such as peripheral nuclei and vacuole formation, in the liver. In addition, treatment with 20 mg L-1 CS-MoS2 micro-sheets suppressed gene expression of antioxidant enzymes (e.g., CAT and GPx1a gene) and induced the expression levels of the proinflammatory response and apoptosis (e.g., IL-1ß, IL-6, and AIF gene) in gill and liver tissues. Further, reactive oxygen species (ROS) were generated upon treatment with 20 mg L-1 CS-MoS2 micro-sheets in both organs. To the best of our knowledge, this is the first investigation of the aquatic toxicity of dispersible MoS2 in zebrafish, and further highlights the potential environmental risk of MoS2.

Hepatic radiofrequency ablation causes an increase of circulating histones in patients with hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) has been increasingly accepted for the treatment of hepatocellular carcinoma (HCC). However, RFA has been associated with an obvious systemic inflammatory response, but little is known about the underlying mechanisms. Circulating histones are recently identified as pivotal inflammatory mediators. Hence, we investigated whether circulating histones are involved in RFA-related inflammation. METHODS: Serial blood samples were collected from 42 HCC patients undergoing RFA at 3 time points: pre-RFA, post-RFA (within 24 h), and in 4-week follow up after RFA. Plasma histones, myeloperoxidase (MPO), inflammatory cytokines (IL-1ß, IL-6, IL-10, TNF-α), liver damage parameters (ALT, AST), and creatinine were measured. RESULTS: Compared to pre-RFA (0.837 µg/ml), there was a significant increase in the levels of circulating histones within 24 h post-RFA (4.576 µg/ml, p < 0.0001); histones decreased to pre-RFA levels in 4-week follow up after RFA. Meanwhile, MPO, IL-6, and IL-10 were elevated remarkably within 24 h post-RFA, indicative of an occurrence of the inflammatory response. Notably, histone levels correlated well with MPO (r = 0.5678), IL-6 (r = 0.4851), and IL-10 (r = 0.3574), respectively. In addition, there was a significant damage of liver function in patients within 24 h post-RFA, evidenced by the increased levels of ALT and AST. No changes in creatinine levels were observed. CONCLUSIONS: These data demonstrate that circulating histones are excessively released in HCC patients treated with RFA, which may lead to systemic inflammation by stimulating neutrophil activation and promoting cytokine production. Circulating histones may act as a novel marker to indicate the extent of inflammation related to RFA.

CYP1A1 Ile462Val polymorphism and the risk of non-small cell lung cancer in a Chinese population.

AIMS AND BACKGROUND: Cytochrome P450 (CYP) 1A1 enzyme plays an important role in the metabolism of carcinogens, such as polycyclic aromatic hydrocarbons, nitroaromatics and arylamines. METHODS: The study examined the association of CYP1A1 Ile462Val polymorphism with the risk of developing non-small cell lung cancer in a Chinese population. We conducted a case-control study including 526 non-small cell lung cancer cases and 526 cancer-free controls. The odds ratios and 95％ confidence intervals were calculated by logistic regression models. RESULTS: Compared with 462Ile/Ile genotype carriers, subjects with CYP1A1 462Ile/Val or Val/Val genotype had a decreased risk of developing non-small cell lung cancer with odds ratios of 0.57 (95% CI, 0.44-0.75) and 0.54 (95% CI, 0.36-0.81), respectively. When stratified by smoking status, the decreased risk of non-small cell lung cancer associated with CYP1A1 462Ile/Val or Val/Val genotype was observed among non-smokers (OR = 0.62, 95% CI, 0.45-0.87) and among smokers (OR = 0.54, 95% CI, 0.37-0.78). When stratified by smoking-dose, the correlation between CYP1A1 genotypes and the risk of non-small cell lung cancer was detected among light smokers (OR = 0.30, 95% CI, 0.19-0.48) but not among heavy smokers (OR = 0.93, 95% CI, 0.61-1.43). CONCLUSIONS: The CYP1A1 Ile462Val variant was associated with a low risk of developing non-small cell lung cancer in a Chinese population.

Relationship between serum VEGF level and radiosensitivity of patients with nonsmall cell lung cancer among asians: a meta-analysis.

This meta-analysis aims to evaluate the relationships between serum vascular endothelial growth factor (VEGF) level and radiosensitivity in patients with nonsmall cell lung cancer (NSCLC) among Asians. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from their inception through October 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Fourteen clinical studies were included in this meta-analysis, including five case-control studies and nine cohort studies. Our meta-analysis results revealed that levels of serum VEGF in NSCLC patients were higher than that of healthy controls. There was a significant difference in serum VEGF levels between before and after radiotherapy in NSCLC patients. Further, we found significant differences in serum VEGF levels between effective and noneffective clinical response groups pre- and postradiotherapy. Serum VEGF levels showed no significant associations with tumor-node-metastasis (TNM) stage and histologic grade in NSCLC patients. NSCLC patients with positive VEGF expression had shorter overall survival than those with negative VEGF expression. Our meta-analysis suggests that serum VEGF level may be a useful biomarker in predicting radiosensitivity and prognosis of NSCLC patients among Asians.

[Cyclooxygenase 2 genetic variant interacting with tobacco smoking and the risk of lung cancer].

OBJECTIVE: To explore the association of -1195G > A genetic variant in the promoter region of cyclooxygenase 2 genetic (COX2) with the genetic susceptibility of lung cancer and its interaction with smoking. METHODS: Totally, 956 lung cancer patients recruited between January 2000 and December 2008 at Cancer Hospital, Chinese Academy of Medical Science as the case group, and 994 frequency-matched controls were randomly selected from a pool of cancer-free subjects recruited from a nutritional survey. All subjects were ethnic Han Chinese. There was no sex, age restrictions. Case group and control group were matched. Informed consent was obtained and 2 ml peripheral blood was collected from each subject. All samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism method, smoking status of the subjects was surveyed.While the OR and 95% CI were estimated by logistic regression to evaluate the relation of COX2 -1195G > A variant and the risk of lung cancer. RESULTS: The genetic allele COX2 -1195AA of control group and case group were 24.9% (247/994) and 28.3% (271/956) . Case-control analysis showed an increased risk of developing lung cancer for -1195AA genotype carriers (OR = 1.36, 95% CI: 1.03-1.79), compared with -1195GG carriers. When stratified by smoking status, the significant increased risk of lung cancer was found among smokers with COX2-1195AA genotype, with the OR (95%CI) was 1.56 (1.08-2.25); while among non-smokers, difference of lung cancer risk was not found among different genotypes (OR = 1.17; 95%CI: 0.77-1.61). Among heavy smokers (pack-year >20), -1195AA and -1195AG genotype carriers have significant increased risk of lung cancer with 1.85 (1.16-2.95) and 1.62(1.08-2.43) of OR (95%CI), respectively; among light smokers (pack-year ≤ 20), the OR (95%CI) of lung cancer risk in -1195AG and -1195AA genotype carriers were 0.78 (0.47-1.30) and 1.08 (0.60-1.94), respectively. CONCLUSION: Genetic polymorphism in the promoter of COX2 gene interacting with smoking factor plays an important role in the development of lung cancer.