Identification of Heavy Metals and Organic Micropollutants in Drinking Water Sources in Typical Villages and Towns in Northeast China.

This study identified and detected the existence of major pollutants in northeast China. As an alpine region and an agricultural base, this region has representative significance in pollution research. We selected 56 samples from drinking water sources of typical villages and towns, focusing on the analysis of heavy metals and organic micropollutants in northeast China. The analysis results showed that Fe and Mn were the main metal elements exceeding the standard. The exceeding rates were 17.9% and 19.6%. Experiments showed that there were 19 kinds of pesticides, 6 kinds of OPEs, 2 kinds of PAEs, 22 kinds of PPCPs. The detection rate of these 49 kinds of organic micro-pollutants were 1.79~82.14%. The characteristics of organic pollution were extensive and varied. Many underground water samples had high level of micropollutants. The water quality parameters of drinking water sources in villages and towns showed close relation to local geological conditions and agricultural activities. Actions must be taken to control these parameters from the source of pollution.

Tumor cell-derived exosomal lncRNA LOC441178 inhibits the tumorigenesis of esophageal carcinoma through suppressing macrophage M2 polarization.

Esophageal carcinoma (EC) is a highly malignant type of tumor. In a previous study, the authors found that long non-coding RNA (lncRNA) LOC441178 inhibited the tumorigenesis of EC. Moreover, exosomes derived from tumor cells containing lncRNAs were found to play a key role in the tumor environment; however, whether exosomes can affect the tumor microenvironment by carrying LOC441178 remains unclear. Thus, the present study aimed to clarify this. In order to assess the effects of exosomal LOC441178 in EC, cell invasion and migration were examined using the Transwell assay. Exosomes were identified using transmission electron microscopy, western blot analysis and nanoparticle tracking analysis. Furthermore, macrophage surface makers (CD206 and CD86) were analyzed using flow cytometry. Moreover, a subcutaneous xenograft mouse model was constructed to assess the role of TE-9 cells-derived exosomal LOC441178 in EC. The results revealed that LOC441178 overexpression notably suppressed the metastasis of EC cells. In addition, exosomes were successfully isolated from EC cells, and LOC441178 level was upregulated in exosomes derived from LOC441178-overexpressed EC cells. Exosomal LOC441178 also suppressed macrophage M2 polarization, and the polarized macrophages decreased EC cell invasion. Exosomes containing LOC441178 notably inhibited the growth of EC in mice. On the whole, the present study demonstrated that the delivery of LOC441178 by EC cell-secreted exosomes inhibited the tumorigenesis of EC by suppressing the polarization of M2 macrophages. These findings may provide a new theoretical basis for discovering new strategies against EC.

Identifying hub genes and miRNAs in Crohn's disease by bioinformatics analysis.

Introduction: Crohn's disease (CD) is a disease that manifests mainly as chronic inflammation of the gastrointestinal tract, which is still not well understood in terms of its pathogenesis. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) and miRNAs with diagnostic and therapeutic potential in CD. Materials and methods: Three CD datasets (GSE179285, GSE102133, GSE75214) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and CD tissues were identified using the GEO2R online tool. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were conducted using the clusterProfiler function in the R package. Protein-protein interaction network (PPI) analysis and visualization were performed with STRING and Cytoscape. Ten hub genes were identified using cytoHubba's MCC algorithm and validated with datasets GSE6731 and GSE52746. Finally, the miRNA gene regulatory network was constructed by Cytoscape and NetworkAnalyst to predict potential microRNAs (miRNAs) associated with DEGs. Results: A total of 97 DEGs were identified, consisting of 88 downregulated genes and 9 upregulated genes. The enriched functions and pathways of the DEGs include immune system process, response to stress, response to cytokine and extracellular region. KEGG pathway analysis indicates that the genes were significantly enriched in Cytokine-cytokine receptor interaction, IL-17 signaling pathway, Rheumatoid arthritis and TNF signaling pathway. In combination with the results of the protein-protein interaction (PPI) network and CytoHubba, 10 hub genes including IL1B, CXCL8, CXCL10, CXCL1, CXCL2, CXCL5, ICAM1, IL1RN, TIMP1 and MMP3 were selected. Based on the DEG-miRNAs network construction, 5 miRNAs including hsa-mir-21-5p, hsa-mir-93-5p, hsa-mir-98-5p, hsa-mir-1-3p and hsa-mir-335-5p were identified as potential critical miRNAs. Conclusion: In conclusion, a total of 97 DEGs, 10 hub genes and 5 miRNAs that may be involved in the progression or occurrence of CD were identified in this study, which could be regarded as biomarkers of CD.

LOC441178 Overexpression Inhibits the Proliferation and Migration of Esophageal Carcinoma Cells via Methylation of miR-182.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to play an important role in the development and progression of esophageal carcinoma (EC). Recently, lncRNA LOC441178 was shown to be dysregulated in many cancer types; however, the role of LOC441178 in EC remains unclear. MATERIALS AND METHODS: Flow cytometry, transwell and wound healing assays were used to measure the apoptosis and migration in esophageal squamous cell carcinoma (ESCC) cells. RT-qPCR was used to detect the level of miR-182 in LOC441178-overexpressed EC cells. In addition, DNA methylation status of miR-182 promoter in LOC441178-overexpressed ESCC cells was detected by methylation-specific PCR (MSP) and bisulfite sequencing PCR. RESULTS: In this study, we found that LOC441178 negatively regulated miR-182 expression in ESCC cells. In addition, overexpression of LOC441178 inhibited the proliferation and migration and induced apoptosis in ESCC cells via downregulation of miR-182. Moreover, overexpression of LOC441178 markedly inhibited the phosphorylation of Akt and phosphorylation FOXO3a and increased the expression of FOXO3a in ESCC cells via downregulation of miR-182. Mechanistically, LOC441178 overexpression epigenetically suppressed miR-182 expression via DNA methylation. In vivo experiments revealed that overexpression of LOC441178 inhibited ESCC tumor growth in mouse xenograft model. CONCLUSION: Collectively, our data suggested that LOC441178 overexpression epigenetically inhibited tumorigenesis of ESCC via DNA methylation of miR-182. These data indicated that the LOC441178/miR-182 axis might represent a novel therapeutic option for the treatment of ESCC.

Comparative proteomics analysis of primary cutaneous amyloidosis.

Primary cutaneous amyloidosis (PCA) is a localized skin disorder that is characterized by the abnormal deposition of amyloid in the extracellular matrix (ECM) of the dermis. The pathogenesis of PCA is poorly understood. The objective of the present study was to survey proteome changes in PCA lesions in order to gain insight into the molecular basis and pathogenesis of PCA. Total protein from PCA lesions and normal skin tissue samples were extracted and analyzed using the isobaric tags for relative and absolute quantitation technique. The function of differentially expressed proteins in PCA were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction analysis. The proteins that were most upregulated in PCA lesions were further analyzed by immunohistochemistry. A total of 1,032 proteins were identified in PCA lesions and control skin samples, with 51 proteins differentially expressed in PCA lesions, of which 27 were upregulated. In PCA lesions, the upregulated proteins were primarily extracellulary located. In addition, GO analysis indicated that the upregulated proteins were significantly enriched in the biological processes of epidermal development, collagen fiber organization and response to wounding (adjusted P<0.001). KEGG analysis indicated that the upregulated proteins were significantly enriched in the signaling pathways of cell communication, ECM receptor interaction and focal adhesion (adjusted P<0.001). Furthermore, the upregulated proteins were enriched in the molecular function of calcium ion binding, and the calcium binding proteins calmodulin-like protein 5, S100 calcium-binding protein A7 (S100A7)/fatty-acid binding protein and S100A8/A9 exhibited the highest levels of upregulation in PCA. This analysis of differentially expressed proteins in PCA suggests that increased focal adhesion, differentiation and wound healing is associated with the pathogenesis of PCA.

Inhibiting interleukin-18 production through the mitogen-activated protein kinase pathway, a potential role of corticotropin-releasing hormone in chronic plaque psoriasis.

Corticotropin-releasing hormone (CRH) and CRH receptors (CRH-Rs) are expressed in the skin; CRH-R1 is the predominant receptor. Whether the CRH/CRH-R1 system plays a role in psoriasis has not yet been assessed. Immunohistochemistry, real-time RT-PCR, ELISA assay, and Western blot analysis were used to investigate the expression of CRH/CRH-R1 in patients with chronic plaque psoriasis and that of IL-18 in CRH-treated HaCaT cells. CRH and CRH-R1 were downregulated in patients with chronic plaque psoriasis. In vitro, CRH attenuated the expression of IL-18 by a mitogen-activated protein kinase signaling pathway through CRH-R1 in HaCaT cells. Thus, an aberrant cutaneous CRH/CRH-R1 system exists in lesions from chronic plaque psoriasis which might play a role in psoriasis and offers further evidence for the study of CRH in the skin.

Kruppel-like factor 6 in the progression and prognosis of malignant melanoma.

OBJECTIVES: The aims of this study were to investigate the incidence of Krüppel-like factor 6 (KLF6) protein staining in patients with cutaneous malignant melanoma and examine its potential relevance to clinicopathological characteristics and tumour cell proliferation. METHODS: Clinicopathological data from patients with cutaneous malignant melanoma were analysed retrospectively. Presence of KLF6 and the antigen Ki-67 in malignant melanoma and healthy tissue samples from each patient was detected by immunohistochemistry. The proliferation index was calculated on the basis of Ki-67 expression. The relationship between KLF6 and clinicopathological characteristics was also analysed. RESULTS: KLF6 was detected more frequently in normal healthy skin tissue compared with cutaneous malignant melanoma lesions (n = 40). There was a negative correlation between the presence of KLF6 and the proliferation index. The presence of KLF6 was also significantly correlated with tumour diameter, lymph node metastasis, tumour-node-metastasis stage and 3-year survival rate. CONCLUSIONS: KLF6 protein is downregulated in human cutaneous malignant melanoma lesions compared with healthy skin tissue. KLF6 may be involved in tumour progression and may be a tumour suppressor and prognostic marker for cutaneous malignant melanoma.

Associations between tumor necrosis factor-α polymorphisms and risk of psoriasis: a meta-analysis.

BACKGROUND: Tumor necrosis factor-α (TNF-α) may play an important role in the recalcitrant inflammatory and hyperproliferative dermatosis of psoriasis, and there may be a relationship between TNF-α polymorphisms and psoriasis risk. METHODS: We performed a meta-analysis to evaluate the associations between TNF-α polymorphisms and psoriasis. Electronic searches of Pubmed, Embase, and Web of Science were performed for all publications on the associations between TNF-α polymorphisms and psoriasis through September 26, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the associations. RESULTS: Sixteen case-control studies with a total of 2,253 psoriasis cases and 1,947 controls on TNF-α 308 G/A polymorphism and fourteen studies on TNF-α 238 G/A polymorphism with 2,104 cases and 1,838 controls were finally included into the meta-analysis. Overall, TNF-α 308 G/A polymorphism was significantly associated with decreased risk of psoriasis under three genetic comparison models (for A versus G: fixed-effects OR 0.71, 95%CI 0.62-0.82, P < 0.001; for AG versus GG: fixed-effects OR 0.67, 95%CI 0.57-0.78, P < 0.001; for AA/AG versus GG: fixed-effects OR 0.67, 95%CI 0.58-0.78, P < 0.001). In addition, TNF-α 238 G/A polymorphism was associated with increased risk of psoriasis under three genetic models (for A versus G: fixed-effects OR 2.46, 95%CI 2.04-2.96, P < 0.001; for AG versus GG: fixed-effects OR 2.69, 95%CI 2.20-3.28, P < 0.001; for AA/AG versus GG: fixed-effects OR 2.68, 95%CI 2.20-3.26, P < 0.001). Subgroup analysis by ethnicity identified a significant association between TNF-α 308 G/A polymorphism and decreased risk of psoriasis in both Caucasians and Asians and a significant association between TNF-α 238 G/A polymorphism and increased risk of psoriasis in Caucasians. CONCLUSIONS: The meta-analysis suggests that TNF-α 308 G/A polymorphism is associated with decreased risk of psoriasis, while TNF-α 238 G/A is associated with increased risk of psoriasis.

A comparison of Q-switched 1064 nm Nd:YAG laser and intense pulsed light in the nonablative rejuvenation on rat model.

BACKGROUND AND OBJECTIVE: A variety of laser and IPL treatments with continued progress have been applied for nonablative skin rejuvenation; however, the complete understanding of working mechanisms and clinical appliance strategy is not clear. MATERIALS AND METHODS: The rats were divided into three groups and irradiated with Q-switched 1064 nm Nd:YAG laser and IPL. Image analysis, chemical colorimetry method, and real-time PCR (RT-PCR) were used to detect the dermal thickness, hydroxyproline, and the expression of III procollagen mRNA, respectively, at sequential time points following irradiation. In addition, the ultra-structure changes of rat skin were observed by TEM at 3 weeks after irradiation. RESULTS: Two-light treatment contributed to increase in the dermal thickness, the hydroxyproline contents and the expression of III procollagen mRNA, and the dense arrangement of collagen. The effect of collagen synthesis and remodeling could last for at least 3 months after treatment, and the YAG group is more efficient than the IPL group. The expressions of procollagen type III mRNA reached peak level at 2 weeks. CONCLUSION: The effect of different lights depends on the wavelength and the penetrated depth; the best referential treatment interval of two kinds of lights for nonablative skin rejuvenation on rat skin is 2 weeks.

Role of corticotropin-releasing hormone and receptor in the pathogenesis of psoriasis.

Psoriasis is a chronic inflammatory disease characterized by epidermal keratinocytic hyperproliferation and abnormal differentiation. It is one of the most illustrative examples of the close relation between exacerbation of disease and the psychopathologic burden of the patients. However, the mechanism remains poorly understood. In recent years, evidence has suggested that endocrine stress responses not only are under control of the central nervous system but also occur in peripheral tissue, outside of the classical HPA axis. Corticotrophin-releasing hormone (CRH) is a central component of the hypothalamic-pituitary-adrenal (HPA) axis and is an important coordinator of the systemic stress response. In peripheral sites, cutaneous CRH and CRH-receptor1 (CRH-R1) is believed to regulate various functions of the skin that are important for local homeostasis. These findings have shed new light on the role of peripheral CRH and CRH-R1 in cutaneous diseases, especially psoriasis. Many researchers focus on the pro-inflammatory role of CRH, such as CRH-induced activation of mast cells in the phenomenon of stress related exacerbation of cutaneous inflammatory diseases, and some researches demonstrated that CRH protein expression was increased in the affected skin of psoriasis. Meanwhile, it is reported that CRH could downregulate pro-inflammatory factors, such as IL-18. Tagen found CRH-R1 mRNA expression in psoriasis skin lower than that in normal controls. Previous studies revealed that the functional role of the CRH/CRH-R1 system in pathological human skin conditions remains to be identified. Interestingly, we found that both CRH and CRH-R1 were presented in psoriatic lesion, perilesional skin and normal control skin by immunohistochemistry, and lesions from patients with psoriasis showed significantly lower CRH/CRH-R1 expression compared with psoriatic perilesional skin and normal control skin. Presumably a localized circuit regulates the peripheral functions of cutaneous CRH/CRH-R1, and the aberrant expression of CRH/CRH-R1 in the skin disturbs the local homeostasis and leads to abnormal differentiation and proliferation in keratinocytes. However, dysfunction of keratinocytes may decrease CRH/CRH-R1 expression because of disharmony in differentiation and proliferation of keratinocytes. Thus, we hypothesize that a cutaneous CRH/CRH-R1 system might be aberrant in lesions of psoriasis. The detuning of CRH/CRH-R1 regulation might contribute to the formation of plaque in psoriasis. What is more important, we hypothesize that the role of CRH/CRH-R1 system might play a protective role in the pathogenesis of psoriasis. This would provide a new treatment for psoriasis. Thus, further study in vitro and in vivo has to be done to test our hypothesis.

Expression and localization of the activated mitogen-activated protein kinase in lesional psoriatic skin.

Abnormalities in several signaling pathways and in the expression and/or activation of different transcription factors in psoriatic keratinocytes have been hypothesized to play a role in the pathophysiology of psoriasis. The mitogen-activated protein kinase (MAPK) cascades are among the best characterized of intracellular signaling pathways, and they play important roles in cell proliferation, differentiation, gene expression, and inflammation. We investigated the expression, activation and distribution of extracellular signal-regulated kinases (ERKs), p38 mitogen-activated protein kinases (p38 MAPK) and c-Jun N-terminal kinases (JNKs), using immunohistochemistry and Western blot in lesional psoriatic skin and normal control skin, to clarify the possible roles of these kinases involved in the pathogenesis of psoriasis. The immunoblot analysis demonstrated that activation of ERK1/2 and p38 MAPK increased in the lesional psoriatic skin. In addition, a significant increase in p-MEK (the upstream activator of ERK), and p-CREB (a downstream transcription factor of active ERK) was also found in our experiment. The immunohistochemical study showed that the levels of phosphorylated ERK1/2 and p38 MAPK were enhanced in lesional psoriatic skin compared with controls. Phosphorylated ERK1/2 and p38 exhibited clear nuclear localization throughout the epidermal part of lesional psoriatic skin. These findings suggested that ERK1/2 and p38 pathways were involved in the pathophysiology of psoriasis.