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The FGF/FGFR signaling axis deregulation of the fibroblast growth factor receptor (FGFR) family is closely related to tumorigenesis, tumor progression and drug resistance to anticancer therapy. And fibroblast growth factor receptor 3 (FGFR3) is one member of this family. In this study, we aimed to investigate the effect of siRNA-induced knockdown of FGFR3 on the biological behaviors of intrahepatic cholangiocarcinoma (ICC). The expression levels of FGFR3 were determined in three intrahepatic cholangiocarcinoma cell lines RBE, HUCCT1 and HCCC9810 cell lines by Western blot. FGFR3 expression in RBE cell line was knocked down by siRNA. Our study found that knockdown of FGFR3 inhibited the migration, invasion and proliferation of ICC cells using Wound healing assay, Transwell migration and invasion assays and Cell proliferation assay. And significantly down-regulated the protein expression levels of MMP2, cyclinD1, and N Cadherin, but had no significant effect on MMP9, cyclinD3, vimentin, E-cadherin protein. In addition, we found that ERK/c-Myc presumably is its signaling pathway by bioinformatics analysis and Western blot verification. To sum up, knockdown of FGFR3 inhibited the migration, invasion and proliferation of ICC cells. It demonstrated that FGFR3 probably becomes a therapeutic target for ICC and increases the proportion of potentially curable intrahepatic cholangiocarcinoma patients treated with FGFR inhibitors. [ABSTRACT FROM AUTHOR]

Background: Anti-malarial drug artesunate (ART), a semi-synthetic derivative of artemisnin, has immunosuppressive effects on several autoimmune diseases, including Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Colitis. However, molecular mechanisms of ART, especially on follicular helper T cells (Tfh), central players in SLE pathology, are far from clear.Purpose: The object for this work is to investigate the therapeutic effect of ART on lupus-prone MRL/lpr mice and its regulatory function on Tfh cells.Study Design and Methods: MRL/lpr mice were used to explore therapeutic effects of ART on lupus-prone MRL/lpr mice and its regulatory functions on Tfh cells. Then, experiments of renal function were accomplished using the biochemical kits. Effects of ART on histopathology of kidneys, inflammatory factors and autoantibodies were examined using H&E staining, ELISA and real-time PCR. Flow cytometry and western blot analysis were used to examine effects of ART on Tfh differentiation and Jak2-Stat3 signaling pathway.Results: Upon oral administration, ART significantly prolonged the survival of MRL/lpr mice, ameliorated the lupus nephritis symptoms, decreased the levels of anti-dsDNA antibodies deposited in the kidney, and the levels of pathogenic cytokines (IL-6, IFN-γ and IL-21). After ART treatment, T-cell compartment in the spleen of MRL/lpr mice was restored in terms of reduction in the number of Tfh cells and in the maintenance of the ratio of Tfr to follicular regulatory T cells (Tfh). In addition, ART has significantly inhibited the phosphorylation levels of Jak2 and Stat3 in the MRL/lpr mice.Conclusion: ART showed therapeutic effects on lupus-prone MRL/lpr mice by inhibiting the differentiation of Tfh cells as well as altering the activation status of Jak2-Stat3 signaling cascade. [ABSTRACT FROM AUTHOR]

Aims Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, which plays an important role in the innate immunity and inflammation. However, its role in myocardial ischemia/reperfusion (I/R) injury remains unknown. In this study, we sought to determine the role of NOD2 on cardiac I/R injury. Main methods Mice were induced 30 min ischemia followed by 24 h of reperfusion. Histological examinations were performed on heart sections with Evans blue and triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, immunohistochemistry and immunofluorescence staining. The messenger RNA (mRNA) expression and protein levels were detected by real-time polymerase chain reaction (RT-PCR) and western blot analysis respectively. Key findings I/R injury markedly upregulated NOD2 expression in heart tissue. Treatment of WT mice with NOD2 ligand (MDP) significantly increased infarct size, the number of apoptotic cells and inflammatory cells, as compared with wild-type mice after I/R injury. Furthermore, MDP enhanced I/R-induced cardiomyocyte apoptosis and inflammation in vitro, and these effects were attenuated by NOD2-siRNA. The mechanism of NOD2 on cardiac I/R injury is partly associated with JNK, p38MAPK and NF-κB signaling pathways. Significance NOD2 aggravates myocardial I/R injury by inducing cardiomyocyte apoptosis and inflammation through JNK, p38MAPK and NF-κB signaling pathways. This study provides insight into better understanding the molecular mechanism of NOD2, which may be served as a potential target for the treatment of myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Jiang-Xian HuGan (JXHG) formulated by five natural products including Freshwater clam (Corbicula fluminea) , Curcuma longa L., Ligustrum lucidum , Eclipta prostrata (L.) L. and Paeonia lactiflora Pall. , has exhibited a great hepatoprotective effect. Aim of this study We investigated the effect of JXHG on concanavalin A (ConA)-induced acute live injury in mice, and to elucidate its underlying molecular mechanisms. Materials and methods Jiangkanling Capsule (900 mg/kg), low-dose JXHG (LJXHG, 700 mg/kg), high-dose JXHG (HJXHG, 1400 mg/kg) were administered to mice by oral gavage daily for 20 days prior to a single intravenous injection of ConA (20 mg/kg). Liver injury was evaluated by measuring the serum levels of enzymes and cytokines as well as liver histological analysis. We also measured the hepatic expression of cytokines at mRNA levels and the proteins related to NF-κB and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways. Result Our results showed that JXHG pretreatment significantly alleviated ConA-induced live injury as evidenced by decreased serum levels of glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST), and reduced hepatocyte apoptosis and mortality. Furthermore, JXHG was able to significantly reduce the serum levels of proinflammatory cytokines, down-regulate the mRNA expression of interleukin-6 (IL-6) and interferon-γ (IFN-γ), and up-regulate IL-10 as well as superoxide-dimutase-1 (SOD1), glutathione reductase (GSR) and Glutathione peroxidase 2 (GPX2) mRNA in the liver tissues after Con A injection. In addition, JXHG pretreatment dramatically suppressed the phosphorylation of NF-κB p65 (p65), increased Nrf2 expression, and decreased the expression ratio of cleaved caspase-3/caspase-3 in liver tissues. Conclusion These results suggest that JXHG protects against ConA-induced acute live injury through inhibiting NF-κB mediated inflammatory pathway and promoting Nrf2 mediated anti-oxidative stress signaling pathway. [ABSTRACT FROM AUTHOR]

Objective Although several statistical methods for adjusting for missing data have been developed and are widely applied in research, few studies have investigated these methods in adjusting for missingness in datasets that aim to estimate the prevalence of dementia. We attempted to develop a more feasible approach for handling missingness in a cross-sectional study among elderly. Methods Five methods of estimating prevalence, including stratified weighting (SW), inverse-probability weighting (IPW), hot deck imputation (HDI), ordinal logistic regression (OLR) and multiple imputation (MI), were applied to handle the missing data yielded by a dataset that include 2231 non-responders. Results Compared with the results of the complete case analysis, the differences in the prevalence rates of dementia and mild cognitive impairment (MCI) calculated by the prevalence-estimating methods after adjusting for non-responders were less than 7% and 6%, respectively. In contrast to the results of other methods, the estimated prevalence of dementia and MCI calculated by MI increased when more predictive factors were included, and the lowest rate of missing data was achieved using MI. Using the participants’ ages, the cognitive screening sores and activity of daily life sores as predictive variables when correcting for missingness induced relatively larger effects on the estimated dementia prevalence. Conclusions When adjusting for missingness while estimating the prevalence of dementia in cross-sectional studies, a simple method, such as SW, is recommended when limited information is available, whereas MI is the preferred method when additional information is available. Further simulation studies are needed to determine the optimal approach. [ABSTRACT FROM AUTHOR]

Abstract: Chinese grasslands have undergone great changes in land use in recent decades. Approximately 18.2% of the present arable land in China originated from the cultivation of grassland, but its impact on the carbon cycle has not been fully understood. This study was conducted in situ for 3 years to assess the comprehensive effects of cultivation of temperate steppe on soil organic carbon (SOC) and soil respiration rates as well as ecosystem respiration. As compared with those in the Stipa baicalensis steppe, the SOC concentrations at depths of 0–10 and 10–20cm in the spring wheat field were found to have decreased by 38.3 and 17.4% respectively from 29.5 and 21.9gkg−1 to 18.2 and 18.1gkg−1 after a cultivation period of 30 years. Accordingly, the total amounts of soil respiration through the growing season (from April to September) in 2002, 2003 and 2004 were 265.2, 282.2 and 237.4gCm−2 respectively in the spring wheat field, which were slightly lower than the values of 342.2, 412.0 and 312.1gCm−2 in the S. baicalensis steppe, while ecosystem respiration of 690.9, 991.2 and 569.6gCm−2 respectively in the spring wheat field were markedly higher than those of 447.0, 470.9 and 429.7gCm−2 in the steppe plot. Similar seasonal variations of ecosystem respiration and soil respiration existed in both sample sites. Respiration rates were higher and greater differences existed in both ecosystem respiration and soil respiration during the exuberant growth stage of plants (from mid-June to mid-August). However, in the slower-growth period of the growing season (before late May and after late August), the CO2 effluxes of the two sample sites were similar and remained at a relatively low level. The results also showed that ecosystem respiration and soil respiration were under similar environmental controls in both sample sites. Soil water content at a depth of 0–10cm and soil temperatures at 5 and 10cm were the main factors affecting the variations in ecosystem respiration and soil respiration rates in droughty years of 2002 and 2004 and in the rainy 2003, respectively. This study suggests that the conversion of the grassland to the spring wheat field has increased the carbon loss of the whole ecosystem due to the change of vegetation cover type and significantly reduced the carbon storage of surface soil. In addition, the tillage of grassland had different effects on ecosystem respiration and soil respiration. The effects were also dissimilar in different growth stages, which should be fully considered when assessing and predicting the effects of cultivation on the net CO2 balance of grassland ecosystems. [Copyright &y& Elsevier]

• Mechanism between IGFBPrP1 and autophagy in liver fibrogenesis is poorly understood. • IGFBPrP1 promoted autophagy and contributed to hepatic stellate cell activation. • H19 is an autophagy promoter to accelerate IGFBPrP1-induced autophagy. • Mutual regulation occurred between H19 and PI3K/AKT/mTOR pathway in IGFBPrP1-induced hepatic stellate cells activation. • New insights for further studies on the prevention and treatment of liver fibrosis. Our previous study found that insulin-like growth factor binding protein-associated protein (IGFBPrP1) drives hepatic stellate cells (HSCs) activation, and IGFBPrP1 and transforming growth factor β1 (TGFβ1) likely interact with each other to promote HSCs activation. TGFβ1 reportedly promotes autophagy and contributes to HSCs activation; however, the mechanism between IGFBPrP1 and autophagy in liver fibrogenesis is yet unknown. Moreover, long noncoding RNA (lncRNA) H19 participates in autophagy regulation and plays a crucial function in liver fibrosis. To define the relationship between IGFBPrP1 and autophagy and the role of H19 in IGFBPrP1-induced hepatic fibrosis. IGFBPrP1 and autophagy were detected in bile duct ligation (BDL)-induced hepatic fibrosis. Adenovirus-mediated IGFBPrP1 was transfected into mouse liver and JS-1 cells with or without LY294002 or rapamycin to examine the effects of IGFBPrP1 on HSCs activation and autophagy as well as the PI3K/AKT/mTOR pathway. lncRNA H19 in liver fibrosis tissues and JS-1 cells induced by IGFBPrP1 were detected, then autophagy and HSCs activation level were detected in JS-1 cells by IGFBPrP1 with H19 overexpression or knowdown. IGFBPrP1 expression and autophagy level were concomitantly increased in liver tissue with BDL-induced hepatic fibrosis. Furthermore, we found that IGFBPrP1 stimulated autophagy and HSCs activation in vivo and in vitro , and PI3K/AKT/mTOR signaling pathway was involved in the regulation of autophagy by IGFBPrP1. In addition, H19 promoted autophagy by interacting with the PI3K/AKT/mTOR pathway in IGFBPrP1-induced HSCs activation. IGFBPrP1 promoted autophagy and contributed to HSCs activation via mutual regulation between H19 and the PI3K/AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]

Wang-bi tablet (WB) consists of 17 traditional Chinese medicines and has been used for treating rheumatoid arthritis (RA) in China for many years, however, its pharmacologic mechanism is not clear. The aim of this study was to investigate the therapeutic effect of WB on collagen-induced mouse arthritis and explored the underlying mechanism. DBA/1 mice were used to establish a type II collagen-induced arthritis (CIA) model. From the day of arthritis onset, mice were treated daily by gavage with either total glucosides of paeony (TGP, 0.37 g/kg/d) or WB at a lower (1.11 g/kg/d, WBL) or higher dose of (3.33 g/kg/d, WBH) for 8 weeks. The severity of arthritis, levels of cytokines and the activation of signaling pathways were determined. Our results revealed that WB treatment effectively alleviated inflammatory symptoms and prevented bone erosions and joint destructions. It obviously decreased the serum concentration of pro-inflammatory cytokines TNF-α, IL-6 and IL-17α, while increased the concentration of anti-inflammatory cytokine IL-10. Interestingly, the proportion of splenic Treg cells were increased significantly. In vitro experiments showed that WB inhibited the differentiation of osteoclasts. Consistently, the mRNA levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CtsK), and the activation of NF-κB and JAK-STAT3 signaling pathways in the paws of CIA mice were inhibited by WB treatment. On the other hand, up-regulation of osteogenic genes Runx2, Osterix mRNA, and activation of Wnt/β-catenin signaling pathway along with a decreased receptor activator of nuclear factor κB ligand (RANKL) expression were found in WB treated mice. Our results suggest that the therapeutic effect of Wang-bi tablet could be attributed to its inhibitory activity on NF-κB and STAT3 signaling pathway-mediated osteoclast differentiation, and its enhancement on Wnt/β-catenin signaling pathway-mediated osteoblast functions. Image 1 [ABSTRACT FROM AUTHOR]