Mast cells expressing interleukin 17 in the muscularis propria predict a favorable prognosis in esophageal squamous cell carcinoma

The proinflammatory cytokine interleukin 17 (IL-17) is considered to play a crucial role in diverse human tumors; however, its role in disease progression remains controversial. This study investigated the cellular source and distribution of IL-17 in esophageal squamous cell carcinoma (ESCC) in situ and determined its prognostic value. Immunohistochemistry, immunofluorescence and immunoelectron microscopy were used to identify IL-17-expressing cells in ESCC tissues, paying particular attention to their anatomic localization. Kaplan–Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival in 215 ESCC patients with long-term follow-up (>10 years). The results showed that mast cells, but not T cells or macrophages, were the predominant cell type expressing IL-17 in ESCC tissues. Unexpectedly, these IL-17⁺ cells were highly enriched in the muscularis propria rather than the corresponding tumor nest (p < 0.0001). The density of IL-17⁺ cells in muscularis propria was inversely associated with tumor invasion (p = 0.016) and served as an independent predictor of favorable survival (p = 0.007). Moreover, the levels of IL-17⁺ cells in muscularis propria were positively associated with the density of effector CD8⁺ T cells and activated macrophages in the same area (both p < 0.0001). This finding suggested that mast cells may play a significant role in tumor immunity by releasing IL-17 at a previously unappreciated location, the muscularis propria, in ESCC tissues, which could serve as a potential prognostic marker and a novel therapeutic target for ESCC.     

Up-regulation of neutrophil activating protein in Helicobacter pylori under high-salt stress: Structural and phylogenetic comparison with bacterial iron-binding ferritins

It is generally accepted that most gastrointestinal diseases are probably caused by the bacterial pathogen Helicobacter pylori (H. pylori). In this study we have focused on the comparison of protein expression profiles of H. pylori grown under normal and high-salt conditions by a proteomics approach. We have identified about 190 proteins whose expression levels changed after growth at high salt concentration. Among these proteins, neutrophil-activating protein (NapA) was found to be consistently up-regulated under osmotic stress brought by high salts. We have investigated the effect of high salt on secondary and tertiary structures of NapA by circular dichroism spectroscopy followed by analytical ultracentrifugation to monitor the change of quaternary structure of recombinant NapA with increasing salt concentration. The loss of iron-binding activity of NapA coupled with noticeable energetic variation in protein association of NapA as revealed by isothermal titration calorimetry was found under high salt condition. The phylogenetic tree analysis based on sequence comparison of 16 protein sequences encompassing NapA proteins and ferritin of H. pylori and other prokaryotic organisms pointed to the fact that all H. pylori NapA proteins of human origin are more homologous to NapA of Helicobacter genus than to other bacterial NapA. Based on computer modeling, NapA proteins from H. pylori of human isolates are found more similar to ferritin from H. pylori than to NapA from other species of bacteria. Taken together, these results suggested that divergent evolution of NapA and ferritin possessing dissimilar and diverse sequences follows a path distinct from that of convergent evolution of NapA and ferritin with similar dual functionality of iron-binding and ferroxidase activities.     

Growth characteristics of Adiantum reniforme var. sinensis and A. capillus‐veneris in response to light and soil moisture

Adiantum reniforme var. sinensis (Adiantaceae) is an endangered fern endemic to the Three Gorges region in southwest China. To elucidate possible ecophysiological mechanisms restricting its distribution, effects of the availability of light (28%, 14% and 7% of open field) and soil moisture (60% and 40% of field capacity) on dry matter production and allocation, leaf morphology and water use efficiency (WUE) were examined in A. reniforme var. sinensis and its widespread congener A. capillus‐veneris. Both species had lower root/shoot ratio (R/S) and higher specific leaf area (SLA) when grown at low light. However, A. reniforme var. sinensis showed less plasticity for total leaf area (LA) and leaf area ratio (LAR) than A. capillus‐veneris, and its root mass, total mass and WUE decreased as light availability decreased. Under water stress, all traits of both species except WUE were significantly affected. However, drought stress decreased total mass of A. capillus‐veneris but did not have a significant effect on A. reniforme var. sinensis. Compared with A. capillus‐veneris, A. reniforme var. sinensis had significantly higher R/S but lower values for other analyzed traits. These results suggest that A. reniforme var. sinensis is relatively superior in drought tolerance but inferior at low light, allowing it to persist in habitats with low soil moisture and high light availability but with few coexisting species present.     

Intraspecific molecular phylogeny and phylogeography of the Meriones meridianus (Rodentia: Cricetidae) complex in northern China reflect the processes of desertification and the Tianshan Mountains uplift

The phylogeographical patterns and demographic history of mitochondrial DNA (cytochrome b, N = 327; D‐loop, N = 252) and nuclear DNA (IRBP gene, N = 235) haplotypes were studied for the Meriones meridianus complex in northern China, a desert‐dwelling gerbil species complex. The phylogenetic analyses, which were performed on the separate and combined (mitochondrial + nuclear) datasets, revealed two divergent clades (Clade A and Clade B) corresponding to distinct geographical regions. Clade A contained the haplotypes found mostly in individuals from the Tianshan Mountains area. Clade B contained haplotypes from populations located in other deserts in northern China. The divergence times indicated that the history of the M. meridianus complex was influenced by the uplift of the Tianshan Mountains and climate‐induced habitat fluctuations. In the Pleistocene, the expansion of forests and grasslands during interglacial period led to the isolation of the M. meridianus complex, which preferred to inhabit deserts. Hence, long geological isolation and the M. meridianus complex adaptation to local ecological conditions led to its genetic divergence. Clade A had long‐lasting demographic stability, most likely because the populations of this clade remained in a stable desert environment for a long time. However, the extension of other deserts and disappearance of palaeolakes during the last glacial period resulted in demographic expansion of Clade B. Furthermore, our genetic data indicated that two subspecies may exist within the M. meridianus complex. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2013, 110 , 362–383.     

Inhibiting neuropeptide Y Y1 receptor modulates melanocortin receptor- and NF-κB-mediated feeding behavior in phenylpropanolamine-treated rats

Neuropeptide Y (NPY) and nuclear factor-kappa B (NF-κB) are involved in regulating anorexia elicited by phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether NPY Y1 receptor (Y1R) is involved in this process, and a potential role for the proopiomelanocortin system was identified. Rats were given PPA once a day for 4 days. Changes in the hypothalamic expression of the NPY, Y1R, NF-κB, and melanocortin receptor 4 (MC4R) levels were assessed and compared. The results indicated that food intake and NPY expression decreased, with the largest reductions observed on Day 2 (approximately 50% and 45%, respectively), whereas NF-κB, MC4R, and Y1R increased, achieving maximums on Day 2 (160%, 200%, and 280%, respectively). To determine the role of Y1R, rats were pretreated with Y1R antisense or a Y1R antagonist via intracerebroventricular injection 1 h before the daily PPA dose. Y1R knockdown and inhibition reduced PPA anorexia and partially restored the normal expression of NPY, MC4R, and NF-κB. The data suggest that hypothalamic Y1R participates in the appetite-suppression from PPA by regulating MC4R and NF-κB. The results of this study increase our understanding of the molecular mechanisms in PPA-induced anorexia.     

Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt/β-catenin signaling in developing cleft palate

Retinoic acid (RA) contributes to cleft palate; however, the cellular and molecular mechanisms responsible for the deleterious effects on the developing palate are unclear. Wnt signaling is a candidate pathway in the cleft palate and is associated with RA in organ development; thus, we aim to investigate whether RA-induced cleft palate also results from altered Wnt signaling. Administration of RA to mice altered cell proliferation and apoptosis in craniofacial tissues by regulating molecules controlling cell cycle and p38 MAPK signaling, respectively. This altered cell fate by RA is a crucial mechanism contributing to 100% incidence of cleft palate. Moreover, Wnt/β-catenin signaling was completely inhibited by RA in the early developing palate via its binding and activation with RA receptor (RAR) and is responsible for RA-induced cleft palate. Furthermore, PI3K/Akt signaling was also involved in actions of RA. Our findings help in elucidating the mechanisms of RA-induced cleft palate.     

<Emphasis Type="Italic">Sorting nexin 24</Emphasis> genetic variation associates with coronary artery aneurysm severity in Kawasaki disease patients

Background

The sorting nexin (SNX) family is involved in endocytosis and protein trafficking and plays multiple roles in various diseases. The role of SNX proteins in Kawasaki disease (KD) is not known. We attempted to test whether genetic SNX variation associates with the risk of coronary artery aneurysm (CAA) formation in KD.

Methods and results

Chi-square tests were used to identify SNX24 genetic variants associated with KD susceptibility and CAA formation in KD; models were adjusted for fever duration and time of first administration of intravenous immunoglobulin. We obtained clinical characteristics and genotypes from KD patients (76 with CAA and 186 without CAA) in a population-based retrospective KD cohort study (n?=?262). Clinical and genetic factors were associated with CAA formation in KD. In addition, endothelial cell inflammation was evaluated. Significant correlation was observed between KD with CAA complications and the rs28891 single-nucleotide polymorphism in SNX24. Patients with CC?+?CT genotypes had lesser CAA complications. In lipopolysaccharide-treated human umbilical vein endothelial cells, siRNA knockdown of SNX24 significantly decreased gene expression of the proinflammatory cytokines IL-1 beta, IL-6, and IL-8.

Conclusions

Polymorphisms in SNX24 may be used as genetic markers for the diagnosis and prognosis of CAA formation in KD.