UNC-51-like kinase 1(ULK1)is an important factor involved in regulating the initiation of autophagy.ULK1 regu-lates inflammatory cytokines through autophagy and mitochondrial oxidative stress,and is involved in the pathological processes of var-ious diseases.ULK1 and its complexes are regulated by rapamycin(mTOR)and AMP-activated protein kinase(AMPK)to initiate au-tophagy,thereby exerting differential effects on a variety of inflammatory diseases.In inflammatory diseases,mitochondrial oxidative stress can induce ULK1 into the nucleus to accelerate apoptosis.Therefore,ULK1 plays different important roles in inflammatory dis-eases.For example,ULK1 initiates airway epithelial mitochondrial autophagy in asthma,participates in mitochondrial oxidative stress in acute liver failure,affects related inflammatory factors in atherosclerosis,and modulates beneficial effects of autophagy in diabetes.This article reviews the biological function of ULK1,its impact on inflammatory diseases and the research progress of targeted drugs.

We investigated whether FTY-720 might have an effect on bleomycin-induced pulmonary fibrosis through inhibiting TGF-β1 pathway, and up-regulating autophagy. The pulmonary fibrosis was induced by bleomycin. FTY-720 (1 mg/kg) drug was intraperitoneally injected into mice. Histological changes and inflammatory factors were observed, and EMT and autophagy protein markers were studied by immunohistochemistry and immunofluorescence. The effects of bleomycin on MLE-12 cells were detected by MTT assay and flow cytometry, and the related molecular mechanisms were studied by Western Blot. FTY-720 considerably attenuated bleomycin-induced disorganization of alveolar tissue, extracellular collagen deposition, and α-SMA and E-cadherin levels in mice. The levels of IL-1β, TNF-α, and IL-6 cytokines were attenuated in bronchoalveolar lavage fluid, as well as protein content and leukocyte count. COL1A1 and MMP9 protein expressions in lung tissue were significantly reduced. Additionally, FTY-720 treatment effectively inhibited the expressions of key proteins in TGF-β1/TAK1/P38MAPK pathway and regulated autophagy proteins. Similar results were additionally found in cellular assays with mouse alveolar epithelial cells. Our study provides proof for a new mechanism for FTY-720 to suppress pulmonary fibrosis. FTY-720 is also a target for treating pulmonary fibrosis.

BACKGROUND: Gene promoter methylation is a major epigenetic change in cancers, which plays critical roles in carcinogenesis. As a crucial regulator in the early stages of B-cell differentiation and embryonic neurodevelopment, the paired box 5 (PAX5) gene is downregulated by methylation in several kinds of tumors and the role of this downregulation in esophageal squamous cell carcinoma (ESCC) pathogenesis remains unclear. METHODS: To elucidate the role of PAX5 in ESCC, eight ESCC cell lines, 51 primary ESCC tissue samples, and eight normal esophageal mucosa samples were studied and The Cancer Genome Atlas (TCGA) was queried. PAX5 expression was examined by reverse transcription-polymerase chain reaction and western blotting. Cell apoptosis, proliferation, and chemosensitivity were detected by flow cytometry, colony formation assays, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays in ESCC cell lines with PAX5 overexpression or silencing. Tumor xenograft models were established for in vivo verification. RESULTS: PAX5 methylation was found in 37.3% (19/51) of primary ESCC samples, which was significantly associated with age (P = 0.007) and tumor-node-metastasis stage (P = 0.014). TCGA data analysis indicated that PAX5 expression was inversely correlated with promoter region methylation (r = -0.189, P = 0.011 for cg00464519 and r = -0.228, P = 0.002 for cg02538199). Restoration of PAX5 expression suppressed cell proliferation, promoted apoptosis, and inhibited tumor growth of ESCC cell lines, which was verified in xenografted mice. Ectopic PAX5 expression significantly increased p53 reporter luciferase activity and increased p53 messenger RNA and protein levels. A direct interaction of PAX5 with the p53 promoter region was confirmed by chromatin immunoprecipitation assays. Re-expression of PAX5 sensitized ESCC cell lines KYSE150 and KYSE30 to fluorouracil and docetaxel. Silencing of PAX5 induced resistance of KYSE450 cells to these drugs. CONCLUSIONS As a tumor suppressor gene regulated by promoter region methylation in human ESCC, PAX5 inhibits proliferation, promotes apoptosis, and induces activation of p53 signaling. PAX5 may serve as a chemosensitive marker of ESCC.
Animals ; Carcinoma, Squamous Cell/genetics* ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Epithelial Cells/metabolism* ; Esophageal Neoplasms/genetics* ; Esophageal Squamous Cell Carcinoma/genetics* ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; PAX5 Transcription Factor/genetics* ; Tumor Suppressor Protein p53/genetics* ; Xenograft Model Antitumor Assays

Objective: To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in metastatic colon cancer undergoing first-line chemotherapy with FOLFOX.Methods: Data were collected from a retrospective survey of 158 consecutive metastatic colon cancer patients who had undergone FOLFOX chemotherapy.The clinicopathological characteristics and chemotherapy features of the patients were analyzed as potential prognostic factors.The patients were stratified by the decreased level of CIN to three groups: large decreased level (the number of neutrophil decreased more than 1.0×109 compared with that before chemotherapy),small decreased level (the number of neutrophil decreased less than 1.0×109 compared with that before chemotherapy) and the absence of neutropenia.Results: According to a multivariate COX model, decreased level of CIN was a independent prognostic factor of colon cancer patients.Hazard ratios of death were 0.687 (95% CI: 0.381-0.812, P=0.016) for patients with large decreased level of CIN and 0.817 (95% CI: 0.527-0.939,P=0.027) for those with small decreased level of CIN compared with those of absent neutropenia patients.Median overall survival was 12.9 months (95% CI: 10.4-15.4) for patients without neutropenia (A) compared with 20.8 months (95% CI: 18.3-23.1) for patients with large-decreased level of CIN (L) and with 17.3 months (95% CI: 16.2-18.8) for those with small-decreased level of CIN (S vs.L, P=0.018;L vs.A, P=0.009;S vs.A, P=0.011).Conclusion: Our results demonstrate that the decreased level of CIN is a predictor of prognosis in patients with metastatic colon cancer undergoing FOLFOX chemotherapy.Patients who have experienced large decreased level of CIN haave longer survival time than small decreased level of CIN or absent patients.To monitor CIN decreased level timely and adjust chemotherapy drug dose may help improve the prognosis.

Objective: To investigate the current bedtime routine among Chinese children less than 3 years of age and explore its dose-dependent association with sleep duration and sleep quality. Method: Healthy full-term born children aged 0-35 months were selected by stratified cluster random sampling method from 8 provinces in China following the "Hospital of Province-City-County" sampling technical route during 2012-2013.Brief Infant Sleep Questionnaire(BISQ) was used to assess sleep conditions of these children.Children′s personal and family information was obtained by Shanghai Children′s Medical Center Socio-demographic Questionnaire.Both of these questionnaires were filled in by parents. The effects of bedtime routine on children′s sleep duration and quality were analyzed by multivariate analysis of variance. Result: The children′s average age was(12±10) months(n=1 304), of whom 689 were males (52.8%, 689/1 304). There were 48.5%(632/1 304)of the parents reported that their children had not established regular sleep routines. There was a consistent dose-dependent association between bedtime routine and sleep duration, as well as other indicators for sleep quality (all P<0.05). The more regular the sleep routines, the longer the sleep duration, the earlier the children went to sleep, the shorter the sleep onset latency, the fewer the nighttime wakeup and the shorter the nighttime waking.The nighttime sleep duration was significantly longer for those with a bedtime routine 'every night’ than those who 'never’ had a bedtime routine (9.5(95%CI: 9.4-9.6)vs. 8.9(95%CI: 8.6-9.3)h, t=3.345, P=0.001). Compared with children who never had bedtime routines, children with regular bedtime routines had fewer night wakeup (1.3(95%CI: 1.2-1.4) vs. 2.4( 95%CI: 2.0-2.9), t=3.182, P=0.001) and shorter night waking duration(16.6(95%CI: 14.6-18.8) vs. 59.2 (95%CI: 47.0-72.7)min, t=6.383, P<0.01). Conclusion The percentage of children who have established regular bedtime routine is low in China. There is significant dose-dependent association between regular bedtime routine and sleep outcomes, especially sleep quality. The more regular the sleep routines, the better the sleep quality.

The demand for diagnosis and therapy of diseases should be higher in the era of precision medicine.The superparamagnetic iron oxide nanoparticles (SPION) is used in diagnosis,therapy,and monitor of diseases due to its good superparamagnetism,which has always been paid more attention in molecular imaging.The research progresses of SPION in precision medicine were reviewed in this article.

Aim To study the effects of pyrin recombi-nant protein ( PRP ) on VEGF/VEGFR2/ MMP-9 sig-naling pathway in bleomycin-induced pulmonary fibro-sis of rats. Methods Sixty male Wistar rats were ran-domly divided into groups of control ( n=10 ) , model ( n=20 ) , PRP ( n=20 ) , and SU5416 ( n=10 ) . All the rats, except for those in control group, were estab-lished as the model of interstitial pulmonary fibrosis by perfusion of bleomycin (5 mg·kg-1 ) through tracheal intubation. From the second day after modeling, all rats were intragastrically administered with drugs or sa-line, according to different groups designed. The rats were sacrificed on the 14th and 28th day, and lung samples were taken out. The pathological changes of interstitial pulmonary fibrosis were observed by HE staining and Masson staining to evaluate the degree of alveolitis and pulmonary fibrosis. Expressions of VEGF, VEGFR2, MMP-9 protein and mRNA were de-tected by immunohistochemistry and RT-PCR. Results On the 14th and 28th day, the alveolitis, pulmonary fibrosis, expression of VEGF, VEGFR2, MMP-9 and mRNA increased significantly in the model group com-pared with in the control group ( P <0. 05 ) , and de-creased significantly in PRP group than those in the model group ( P <0. 05 ) . Conclusion PRP plays a role of anti-pulmonary fibrosis via the down-regulation of VEGF/VEGFR2/MMP-9 signaling pathway.

Hypoxia plays a vital role in tumor metabolism, proliferation, apoptosis, invasion and metastasis via hypoxia-inducible factor (HIF). Epithelial to mesenchymal transition (EMT) is a crucial process to metastasis, which could be triggered by hypoxia. EMT could be regulated by HIF via multiple pathways including TGF-β, Notch, and Wnt/β-catenin. It has been shown that anti-HIF drugs combined with anti-EMT therapies could be a promising strategy for tumor therapy.
Basic Helix-Loop-Helix Transcription Factors ; Epithelial-Mesenchymal Transition ; Humans ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasms ; Transforming Growth Factor beta ; beta Catenin

PURPOSE: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Exosomes or extracellular vesicles are nanosized vesicles of endosomal origin released from inflammatory and epithelial cells that have been implicated in allergic diseases. In this study, we characterized the microRNA (miRNA) content of exosomes in AR. METHODS: Extracellular vesicles were isolated from nasal mucus from healthy control subjects (n=10) and patients with severe AR (n=10). Vesicle RNA was analyzed by using a TaqMan microRNA assays Human Panel-Early Access kit (Applied Biosystems, Foster City, CA, USA) containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis for the differentially expressed miRNAs were performed using DIANA-mirPath. RESULTS: Twenty-one vesicle miRNAs were up-regulated and 14 miRNAs were under-regulated significantly (P<0.05) in nasal mucus from AR patients when compared to healthy controls. Bioinformatic analysis by DIANA-mirPath demonstrated that 32 KEGG biological processes were significantly enriched (P<0.05, FDR corrected) among differentially expressed vesicle miRNA signatures. Among them, the B-cell receptor signaling pathway (P=3.709E-09), the natural killer cell-mediated cytotoxicity (P=8.466E-05), the T-cell receptor signaling pathway (P=0.00075), the RIG-I-like receptor signaling pathway (P=0.00127), the Wnt signaling pathway (P=0.00130), endocytosis (P=0.00440), and salivary secretion (P=0.04660) were the most prominent pathways enriched in quantiles with differential vesicle miRNA patterns. Furthermore, miR-30-5p, miR-199b-3p, miR-874, miR-28-3p, miR-203, and miR-875-5p, involved in B-cell receptor and salivary secretion signaling pathways, were selected for validation using independent samples from 44 AR patients and 20 healthy controls. MiR-30-5p and miR-199b-3p were significantly increased in extracellular vesicles from nasal mucus when compared to healthy controls, while miR-874 and miR-28-3p were significantly down-regulated. In addition, miRNA-203 was significantly increased in AR patients, while miRNA-875-5p was found to be significantly decreased in AR patients. CONCLUSIONS: This study demonstrated that vesicle miRNA may be a regulator for the development of AR.
B-Lymphocytes ; Biological Processes ; Endocytosis ; Epithelial Cells ; Exosomes ; Humans ; MicroRNAs* ; Mucus* ; Receptors, Antigen, T-Cell ; Rhinitis* ; RNA ; Wnt Signaling Pathway

Aim To investigate the effects of sesamin on inflammation response of asthma and to explore its possible mechanism of action. Methods Forty male BALB/c mice were randomly divided into five groups with 8 mice in each group: normal group, ovalbumin ( OVA) group, sesamin low dose group, sesamin high dose group and dexamethasone( DXM) group. Asthma model mice were induced by OVA in vivo. The left lung was isolated for pathological examination. Experi-ment of ELISA and Western blot were used to deter-mine the effect of sesamin on IL-4 , IL-5 , IL-13 and IFN-γ expression. Hematoxylin and eosin stain was used to investigate pathological examination in lung tis-sue. Western blot was performed to detect the IκBαphosphorylation and NF-κB nuclear translocation. Re-sults The mice developed the following pathophysio-logical features of asthma: increased numbers of in-flammatory cells, increased levels of IL-4, IL-5 and IL-13 , decreased level of IFN-γ in bronchoalveolar lavage fluids ( BALF ) and lung tissues ( P <0. 05 ) , and increased IκBα phosphorylation and NF-κB nucle-ar translocation in lung tissues ( P <0. 05 ) . Adminis-tration of sesamin markedly reduced airway inflammato-ry cell recruitment, reduced the production of IL-4, IL-5 , IL-13 and increased IFN-γ in BALF and lung tissues( P <0. 05 ) . The increased IκBα phosphoryla-tion and NF-κB nuclear translocation after OVA inhala-tion were inhibited by the administration of sesamin. Conclusion Sesamin attenuates inflammation re-sponse of asthma through suppression of NF-κB activa-tion.