Curcumin reduces lung inflammation via Wnt/ß-catenin signaling in mouse model of asthma.

OBJECTIVES: Asthma is a chronic inflammatory, heterogeneous airway disease affecting millions of people around the world. Curcumin has been found to have anti-inflammatory and antifibrosis effects. Researchers reported that curcumin regulated Wnt/ß-catenin signaling in lots of cells. However, whether curcumin regulates the levels of Wnt/ß-Catenin signaling in lung tissues and DCs (dendritic cells) remains unclear. In this study, we assessed the effects of curcumin on DCs and asthma. METHODS: C57BL/6 mice immunized with OVA (ovalbumin) were challenged thrice with an aerosol of OVA every second day for 8 days. Dexamethasone or curcumin was administered intraperitoneally to OVA-immunized C57BL/6 mice on day 24 once a day for 9 days. Mice were analyzed for effects of curcumin on asthma, inflammatory cell infiltration and cytokine levels in lung tissue. DCs were isolated from mouse bone morrow. The surface markers CD40, CD86 and CD11c of DCs was detected by FACS (fluorescence activated cell sorting) and the function of DCs was detected by mixed lymphocyte reaction. The expression of GSK-3ß and ß-catenin was detected by Western Blot. RESULTS: Results showed that OVA increased the number of inflammatory factors in BALF (bronchoalveolar lavage fluid), elevated lung inflammation scores in mice. Curcumin dose-dependently reversed the alterations induced by OVA in the asthmatic mice. Curcumin activated Wnt/ß-catenin signaling pathway in DCs and asthmatic mouse lungs. CONCLUSIONS: Curcumin could influence the morphology and function of DCs, ease asthma symptom and inflammatory reaction through the activation of Wnt/ß-catenin signaling. These results provide new evidence new evidence for application of curcumin on asthma.

[Effect of Needle Embedded in Neiguan (PC6) on Changes of ECG in Chronic Myocardial Ischemia Model Mini-pigs].

Objective To observe the effect of needle embedded in Neiguan (PC6) on electro- cardiogram (ECG) changes in model mini-pigs with chronic myocardial ischemia. Methods The protein shrink narrow ring (Ameroid Ring) was placed in the proximal part of the left coronary anterior descend- ing branch of 12 Chinese mini-pigs to prepare animal model. One died during the modeling. Chronic myo- cardial ischemia mini-pig models were established after 4 weeks. Successfully modeled 11 mini-pigs were divided into the test group (n =6) and the control group (n =5). Needle were embedded in Neiguan (PC6) of the test group and Zusanli (ST36) of the control group at week 4 after modeling. Electroacupuncture (EA) at corresponding acupoint twice (once before embedding and at week 2 after embedding) , 20 min each time. Changes of Q wave of ECG, heart rate, and ST-T interval were observed in the two groups be- fore and after modeling, before and after EA. Results Compared with before modeling in the same group, the absolute value of Q wave both increased in the two groups after modeling (P <0. 05, P <0. 01J. No statistical difference existed in heart rate in the two groups between before and after modeling (P> 0. 05). Compared with before needling in the same group, ST-T interval was prolonged in the test group (P <0. 05). Compared with the control group at the same time point, the absolute value of Q wave was re- duced before EA, ST-T interval was prolonged after EA in the test group (P <0. 05). No statistical differ- ence existed in heart rate between the control group and the test group before EA (P >0. 05). Conclusion Needle embedded in Neiguan (PC6) could arrive at therapeutic effect of myocardial ischemia possibly through improving myocardial blood supply.

IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells.

Drug resistance is a big problem in cancer treatment and one of the most prominent mechanisms underlain is overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2. Inhibition of ABC transporters is an important approach to overcome drug resistance. The inositol-requiring enzyme 1α (IRE1α), an arm of unfolded protein response (UPR), splices XBP1 mRNA to generate an active transcription factor XBP1s. UPR is implicated in drug resistance. However, the underlying mechanism is unclear. We found that the anticancer drugs such as 5-fluorouracil (5-FU) activated the IRE1α-XBP1 pathway to induce the expression of ABCB1, ABCC1 and ABCG2 in colon cancer cells. Inhibition of IRE1α RNase activity with small molecule 4µ8c suppressed the drug-induced expression of these ABC transporters and sensitized 5-FU-resistant colon cancer cells to drug treatment. In vivo xenograft assay indicates that administration of 4µ8C substantially enhanced the efficacy of 5-FU chemotherapy on 5-FU-resistant colon cancer cells. These results suggest that IRE1α-targeting might be a strategy to cope with drug resistance of colon cancer.

Prolyl hydroxylase 3 controls the intestine goblet cell generation through stabilizing ATOH1.

Intestinal epithelia self-renew constantly and generate differentiated cells such as secretary goblet cells. The intestine goblet cells secrete gel-forming mucins that form mucus to create a barrier of defense. We reported previously that loss of prolyl hydroxylase (PHD) 3 led to disruption of the intestinal epithelial barrier function. However, the underlying mechanism remains elusive. Here, we demonstrate that PHD3 controls the generation of intestine goblet cell. We found that genetic ablation of Phd3 in mice intestine epithelial cells reduced the amount of goblet cells. Mechanistically, PHD3 bounds the E3 ubiquitin ligase HUWE1 and prevented HUWE1 from mediating ubiquitination and degradation of ATOH1, an essential driver for goblet cell differentiation. The prolyl hydroxylase activity-deficient variant PHD3(H196A) also prevented ATOH1 destruction. A genetic intestine epithelial PHD3(H196A)-knockin had no effect on ATOH1 expression or goblet cell amount in mice, suggesting that the PHD3 prolyl hydroxylase activity is dispensable for its ability to control ATOH1 expression and goblet cell generation. In dextran sulfate sodium (DSS)-induced experimental colitis, PHD3-knockout rather than PHD3(H196A)-knockin sensitized the mice to DSS treatment. Our results reveal an additional critical mechanism underlying the regulation of ATOH1 expression and goblet cell generation and highlight that PHD3 plays a role in controlling intestine goblet cell generation in a hydroxylase-independent manner.

[Spatial Heterogeneity of Soil Respiration in the Soil Erosion Area of West Mountains in Fujian Province, China].

The spatial heterogeneity of soil respiration (Rs) is of great significance in accurately estimating the carbon budget in erosion areas. This study investigated the soil respiration (Rs), total nitrogen (TN), carbon-nitrogen ratio (C/N), soil organic carbon content (SOC), leaf area index (LAI), soil temperature (T10), and soil moisture (W) in 59 soil samples collected from Hetian Town in Fujian Province. Both classical statistics and geostatistics were used to analyze the spatial heterogeneity of soil respirations and other measured factors. The variability of Rs and other measured factors in the samples ranked from the largest to the smallest: LAI > SOC > TN > Rs > C/N > T10 > W. Rs was positively correlated with T10 (P<0.01) and with TN (P<0.05), but not significantly correlated with other factors (P>0.05); TN, SOC and T10 could be used to explain the spatial variation of soil respiration among the samples. The results from geo-statistical analysis showed that Rs was in a medium spatial autocorrelation, with 52.89% of spatial heterogeneity caused by structural factors and 47.11% of spatial heterogeneity resulted from random factor; the fractal dimensions of soil respiration and its interacted factors were ranked as: Rs > LAI > C/N > T10 > SOC > W > TN; the spatial distribution patterns of Rs were similar with those of TN and T10, but different from those of C/N, SOC or LAI. At the 95% confidence level and 90% estimation accuracy, the reasonable sampling number of Rs was 62.

House dust mite allergens mediate the activation of c­kit in dendritic cells via Toll­like receptor 2.

Several studies have demonstrated that the c­kit proto­oncogene and its ligand, stem cell factor, are important in the development of asthma. House dust mite (HDM; Dermatophagoides pteronyssinus) allergens are a major trigger in the development and exacerbation of asthma. HDM allergens can induce the activation of c­kit in dendritic cells (DCs), leading to the development of allergic asthma. Previous studies have demonstrated that activation of Toll­like receptor 2 (TLR2) evokes a T helper (Th)2 immune response and promotes experimental asthma. The aim of the present study was to assess whether HDM mediates the activation of c­kit in DCs via TLR2. Monocyte­derived DCs were generated from C57BL/6 mice, and cultured with interleukin (IL)­4 and granulocyte­macrophage colony­stimulating factor. The DCs were then sensitized with HDM (10 µg/ml) for 72 h. TLR2­specific small interfering (si)RNA was used to silence and inhibit the expression of TLR2 in the DCs. The expression levels of c­kit and B7 (CD80/CD86) were measured, by analyzing the DC culture supernatant for the presence of IL­6 and IL­12. Inhibition of TLR2 using specific siRNA downregulated the expression of c­kit in the HDM­activated DCs. In addition, silencing of TLR2 inhibited the expression of CD80/CD86, decreased the production of IL­6, and increased the production of IL­12. These results indicated that TRL2 are important in the activation of c­kit by HDM in DCs.