PPAR-γ alleviates the inflammatory response in TNF-α-induced fibroblast-like synoviocytes by binding to p53 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg-1·d-1) or rosiglitazone (4 mg·kg-1·d-1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/- mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/-) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/- CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

Investigation of an acute gastroenteritis outbreak caused by Norovirus infection in a university / 中国学校卫生

Objective@#To investigate an acute gastroenteritis outbreak caused by Norovirus, and to provide evidence for effective school infectious outbreak prevention and control.@*Methods@#In March 2019, basic information of Huzhou Normal University and related data of cases were collected. Epidemiological characteristics were analyzed. Anal swabs of the 10 cases were collected for laboratory detection. Case definitions, specific detection criteria and procedures were based on the Diagnostic Criteria for Infectious Diarrhea (WS 271-2007) and the Technical Guidelines for the Investigation, Prevention and Control of Outbreaks of Norovirus Infection (2015 edition).@*Results@#During March 15 to March 20, a total of 13 (12 girls and 1 boy) confirmed cases were reported, all of them were from the same class, with the incidence rate being 25.00% (1/4) and 37.50% (12/32) in boys and girls, respectively. No significant sex difference was found ( χ 2=2.05， P >0.05). Anal swab specimens of 10 students were collected from laboratory were positive for Norovirus GII and have an identity of 100%.@*Conclusion@#The gastroenteritis outbreak was deduced to be attributed to GII Norovirus infection, which are likely caused by fecal contamination through person to person contact. It is suggested that schools should strengthen knowledge education on the prevention and control of infectious diseases and improve the protection awareness and ability of teachers and students to protect them.

MAP2K6-FP Enhances the Sensitiveness of Paclitaxel for Ovarian Cancer via Inducing Autophagy.

BACKGROUND: Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Recent studies have revealed an association between autophagy and drug resistance. METHODS: We previously synthesized a MAPK kinase-recombinant fusion protein, MAP2K6-FP, that contains 3 domains: a protein transduction domain TAT, a human ovarian cancer HO8910 cell-specific binding peptide, and a potential antitumor effector domain MKK6(E). In this study, we investigated the effect of MAP2K6-FP on HO8910 cells treated with paclitaxel. RESULTS: The IC50 (concentration by which 50% cell growth was inhibited) was 20 µM for paclitaxel alone, 1.5 µg/mL for MAP2K6-FP alone, and 0.3 µg/mL for MAP2K6-FP and 15 µM for paclitaxel if combined, respectively. In addition, immunohistochemistry assay demonstrated that tumor tissues from ovarian cancer patients showed higher expression of LC-3, the autophagy-related protein, compared with normal ovarian tissues. MAP2K6-FP (0, 2.5, 5, 10, 20, and 40 µg/mL) dose-dependently increased the LC-3 expression in HO8910 cells. Immunofluorescence assay showed that paclitaxel alone increased the expression of LC-3 in HO8910 cells, which was further enhanced by the combination with MAP2K6-FP. Downregulation of LC-3 expression using LC-3 small interfering RNA inhibited the cytotoxicity effect of MAP2K6-FP. Furthermore, either MAP2K6-FP alone or in combination with paclitaxel increased the ratio of expressions of Beclin-1/Bcl-2, another autophagy-related markers, compared with paclitaxel alone. CONCLUSIONS: MAP2K6-FP enhanced the sensitiveness of paclitaxel for ovarian cancer via inducing autophagy.

Arsenic and fluoride induce apoptosis, inflammation and oxidative stress in cultured human umbilical vein endothelial cells.

Excessive amount of inorganic arsenic (iAs) and fluoride (F) coexist in drinking water in many regions, which is associated with high risk of vascular diseases. However, the underlying mechanisms are not well studied. The present study was to evaluate the effects of iAs and F individual or combined exposure on endothelial activation and apoptosis in vitro. Primary human umbilical vein endothelial cells (HUVECs) were exposed to 5 µM As2O3 and/or 1 mM NaF. Changes in endothelial cell apoptosis, inflammation, oxidative stress and nitric oxide (NO) production were analyzed. The results showed that iAs and/or F induced significant increase in endothelial cell apoptosis and inflammation as indicated by the increase of mRNA and protein expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and pentraxin 3. Furthermore, iAs and/or F exposure induced intracellular reactive oxygen species and malondialdehyde generation. Results showed iAs and/or F exposure increased the activity of NADPH oxidase (NOX) and up-regulated the mRNA expression of NOX subunits p22phox. The results indicated that activation of NOX was related to oxidative stress induced by iAs and/or F. Also, iAs and/or F reduced NO production in HUVECs. The up-regulation of inflammation genes expression and oxidative stress in iAs and F co-exposed ECs were less pronounced as compared to single F-exposed cells, which showed an antagonistic effect between iAs and F. In conclusion, endothelial activation and apoptosis induced by iAs and/or F are potential mechanisms in their vascular toxicity. Oxidative stress and impaired NO production are involved in their pro-inflammatory and pro-apoptotic effects.