Ring1a protects against colitis through regulating mucosal immune system and colonic microbial ecology.

Inflammatory bowel disease (IBD) represents a prominent chronic immune-mediated inflammatory disorder, yet its etiology remains poorly comprehended, encompassing intricate interactions between genetics, immunity, and the gut microbiome. This study uncovers a novel colitis-associated risk gene, namely Ring1a, which regulates the mucosal immune response and intestinal microbiota. Ring1a deficiency exacerbates colitis by impairing the immune system. Concomitantly, Ring1a deficiency led to a Prevotella genus-dominated pathogenic microenvironment, which can be horizontally transmitted to co-housed wild type (WT) mice, consequently intensifying dextran sodium sulfate (DSS)-induced colitis. Furthermore, we identified a potential mechanism linking the altered microbiota in Ring1aKO mice to decreased levels of IgA, and we demonstrated that metronidazole administration could ameliorate colitis progression in Ring1aKO mice, likely by reducing the abundance of the Prevotella genus. We also elucidated the immune landscape of DSS colitis and revealed the disruption of intestinal immune homeostasis associated with Ring1a deficiency. Collectively, these findings highlight Ring1a as a prospective candidate risk gene for colitis and suggest metronidazole as a potential therapeutic option for clinically managing Prevotella genus-dominated colitis.

We found that PcG protein Ring1a could be a new risk gene for colitis. Ring1a deficiency causes aggravated colitis by regulating the mucosal immune system and colonic microbial ecology.

[Retracted] miRNA­1207­5p is associated with cancer progression by targeting stomatin­like protein 2 in esophageal carcinoma.

Subsequently to the publication of the above article, and a Corrigendum that has already been published with the intention of showing corrected versions of Figs. 3 and 6 (DOI: 10.3892/ijo.2018.4254; published online on January 24, 2018), a concerned reader drew to the Editor's attention that there appeared to be an unexpected overlap of data in a couple of the panels showing flow cytometric data in Fig. 3A; furthermore, strikingly similar data also appeared in a paper that was submitted to the journal Cancer Gene Therapy at around the same time [Zang W, Wang T, Huang J, Li M, Wang Y, Du Y, Chen X and Zhao G: Long noncoding RNA PEG10 regulates proliferation and invasion of esophageal cancer cells. Cancer Gene Ther 22: 138­144, 2015]. Considering the latest discrepancies and concerns that have been raised with another of the figures in this paper, the Editor of International Journal of Oncology has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership of the Journal for any inconvenience caused. [International Journal of Oncology 46: 2163­2171, 2015; DOI: 10.3892/ijo.2015.2900].

New Approach to Intelligence Screening for Children With Global Development Delay Using Eye-Tracking Technology: A Pilot Study.

Objective: There has become a consensus for detecting intellectual disability in its early stages and implementing effective intervention. However, there are many difficulties and limitations in the evaluation of intelligence-related scales in low-age children. Eye-tracking technology may effectively solve some of the pain points in the evaluation. Method: We used an eye-tracking technology for cognitive assessment. The subjects looked at a series of task pictures and short videos, the fixation points of which were recorded by the eye-movement analyzer, and the data were statistically analyzed. A total of 120 children aged between 1.5 and 4 years participated in the study, including 60 typically developing children and 60 children with global development delay, all of whom were assessed via the Bayley scale, Peabody Picture Vocabulary Test (PPVT), and Gesell scale. Results: Cognitive scores from eye-tracking technology are closely related to the scores of neuropsychological tests, which shows that the technique performs well as an early diagnostic test of children's intelligence. Conclusions: The results show that children's cognitive development can be quickly screened using eye-tracking technology and that it can track quantitative intelligence scores and sensitively detect intellectual impairment.

Exosomes derived from LPS-stimulated human thymic mesenchymal stromal cells enhance inflammation via thrombospondin-1.

Inflammatory response mediated by immune cells is either directly or indirectly regulated by mesenchymal stromal cells (MSCs). Accumulating evidence suggests that thrombospondin-1 (TSP-1) is highly expressed in response to inflammation. In this work, we isolated and identified human thymic mesenchymal stromal cells (tMSCs) and detected the expression of TSP-1. We found that tMSCs expressed TSP-1 and Poly (I:C) or LPS treatment promoted the expression of TSP-1. Further, we isolated and identified exosomes originating from tMSCs (MEXs). Notably, exosomes derived from LPS-pretreated tMSCs (MEXsLPS) promoted the polarization of macrophages to M1-like phenotype and IL-6, TNF-α secretion as well as the pro-inflammatory differentiation of CD4+T cells into Th17 cells. Upon silencing the expression of TSP-1 in tMSCs, the pro-inflammatory effects of MEXsLPS were suppressed. Therefore, these findings uncovered TSP-1 as the principal factor in MEXsLPS pro-inflammatory regulation.

Identification of key gene modules and genes in colorectal cancer by co-expression analysis weighted gene co-expression network analysis.

Colorectal cancer (CRC) has been one of the most common malignancies worldwide, which tends to get worse for the growth and aging of the population and westernized lifestyle. However, there is no effective treatment due to the complexity of its etiology. Hence, the pathogenic mechanisms remain to be clearly defined. In the present study, we adopted an advanced analytical method-Weighted Gene Co-expression Network Analysis (WGCNA) to identify the key gene modules and hub genes associated with CRC. In total, five gene co-expression modules were highly associated with CRC, of which, one gene module correlated with CRC significantly positive (R = 0.88). Functional enrichment analysis of genes in primary gene module found metabolic pathways, which might be a potentially important pathway involved in CRC. Further, we identified and verified some hub genes positively correlated with CRC by using Cytoscape software and UALCAN databases, including PAICS, ATR, AASDHPPT, DDX18, NUP107 and TOMM6. The present study discovered key gene modules and hub genes associated with CRC, which provide references to understand the pathogenesis of CRC and may be novel candidate target genes of CRC.

Klf5 acetylation regulates luminal differentiation of basal progenitors in prostate development and regeneration.

Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. It remains elusive whether post-translational modifications of transcription factors can differentially determine adult stem/progenitor cell fate. Here we report that, in human and mouse prostates, Klf5 is expressed in both basal and luminal cells, with basal cells preferentially expressing acetylated Klf5. Functionally, Klf5 is indispensable for maintaining basal progenitors, their luminal differentiation, and the proliferation of their basal and luminal progenies. Acetylated Klf5 is also essential for basal progenitors' maintenance and proper luminal differentiation, as deacetylation of Klf5 causes excess basal-to-luminal differentiation; attenuates androgen-mediated organoid organization; and retards postnatal prostate development. In basal progenitor-derived luminal cells, Klf5 deacetylation increases their proliferation and attenuates their survival and regeneration following castration and subsequent androgen restoration. Mechanistically, Klf5 deacetylation activates Notch signaling. Klf5 and its acetylation thus contribute to postnatal prostate development and regeneration by controlling basal progenitor cell fate.

Retraction Note: RNAi targeting CXCR4 inhibits proliferation and invasion of esophageal carcinoma cells.

The Editor-in-Chief has retracted this article [1] because Fig. 3 shows overlap with Fig. 6 in [2], Fig. 2b in [3] and Fig. 6a in [4]. An investigation by Zhengzhou University has confirmed that these figures overlap. The data reported in this article are therefore unreliable.

[Corrigendum] miRNA-1207-5p is associated with cancer progression by targeting stomatin-like protein 2 in esophageal carcinoma.

An interested reader drew to our attention that, in the above-mentioned article, there were two figures where identity in certain of the data was shared between panels within the same figure. First, in Fig. 3B, the data shown for the EC9706 cell line/negative control (NC) experiment were derived from the same original source as those for the EC-1/Blank control experiment. Secondly, in Fig. 6B the Bcl-2 bands for the two different cell lines, EC9706 and EC-1, were inadvertently duplicated (the data shown for the EC9706 cell line were correct). We have reviewed the original files and the individual figures for the submitted composite figures, and realize that the errors occurred when we produced the composite figures. The same images were accidentally inserted twice in Figs. 3 and 6 without us being fully aware of the error. We have identified all the original images, and the corrected versions of Figs. 3 and 6 are shown opposite. We regret that these errors went unnoticed prior to publication, and thank the Editor for affording us the opportunity to publish this Corrigendum. We also regret any inconvenience caused to the readership of the journal. [the original article was published in the International Journal of Oncology 46: 2163-2171, 2015; DOI: 10.3892/ijo.2015.2900].

CCR9 AND CCR7 are overexpressed in CD4- CD8- thymocytes of myasthenia gravis patients.

INTRODUCTION: Chemokine CC motif receptors 9 and 7 (CCR9 and CCR7) play a major role in the migration of T-cell precursors to the thymus to initiate T thymopoiesis. However, their role in development of T-cells in myasthenia gravis (MG) patients has not been fully elucidated. METHODS: Expression and distribution of CCR9+ and CCR7+ cells were detected by flow cytometry and immunofluorescence. Real-time polymerase chain reaction was used to check the adhesion molecules on CD4- CD8- double-negative (DN) thymocytes. RESULTS: CCR9 and CCR7 expression by DN thymocytes increased in the MG thymus; the levels of CCR9, CCR7, interleukin-7R mRNA increased, and CXCR4 levels decreased compared with levels in the non-MG thymus. More CCR7 and CCR9 double-positive (DP) thymocytes were gathered near the subcapsular region in MG thymus. CONCLUSIONS: Enhanced expression of CCR9 and CCR7 may complicate the differentiation of DP thymocytes from the DN stage in MG thymus. Muscle Nerve, 2016 Muscle Nerve 55: 84-90, 2017.

Impacts of N-Butylphthalide on expression of growth factors in rats with focal cerebral ischemia.

This study investigates the impacts of n-butylphthalide (NBP) on the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) in rats with focal cerebral ischemia. The thread embolization method was used to prepare the rat model of cerebral ischemia-reperfusion (CIR). The animals were divided into a sham operation group, a model control group and NBP treatment group. The NBP group was orally administered 25 mg/kg NBP twice a day after the surgery. The immunohistochemistry and reverse transcription-polymerase chain reaction were performed to observe the protein and mRNA expressions of VEGF and TGF-ß 16 hours, 1 day and 2 days after inducing CIR. The mRNA and protein expressions of VEGF and TGF-ß1 in the model control group and the NBP treatment group were all increased after CIR, and those of the NBP treatment group at each post-CIR time point were higher than the model control group (p < 0.01). After CIR, the expressions of VEGF and TGF-ß1 increased, suggesting that VEGF and TGF-ß1 exhibited protective effects towards the ischemic brain injuries, and that NBP could upregulate the expressions of VEGF and TGF-ß1 in the peri-infarcted area, thus possibly protecting the ischemic brain tissues through this mechanism.

[Over-expression of CCL21 up-regulates the antigen presentation-related genes of CK8/18 positive thymic epithelial cells in patients with myasthenia gravis].

OBJECTIVE: To identify the distribution of chemokine (C-C motif) ligand 21 (CCL21) in the thymus of patients with myasthenia gravis (MG) and explore the effects of up-regulation of CCL21 on the expressions of antigen presentation-related genes in cytokeratin 8/18 (CK8/18) positive thymic epithelial cells (TECs) after transfected with CCL21 genes. METHODS: The expressions and distributions of CK8/18 and CCL21 in the thymus tissue of MG patients were detected by immunohistochemistry. The mRNA levels of CCL21, CCL19 and their receptor chemokine (C-C motif) receptor 7 (CCR7) in the thymus tissue of MG patients were determined by real-time quantitative PCR (qRT-PCR). Primary cultured CK8/18⁺ TECs were transfected with pCMV-CCL21, and the relative mRNA expressions of function-associated genes (CD80, ICAM-1, CD86, HLA-DR, HLA-A) in CK8/18⁺ TECs before and after the transfection were investigated by qRT-PCR. RESULTS: Immunohistochemical results showed that the number of CK8/18 positive cells in the hyperplastic thymus tissues of MG patients was significantly more than that in the normal controls, and the protein expression of CCL21 was also much higher in the hyperplastic thymus tissues. The qRT-PCR showed that the expressions of CCL21 and CCR7 mRNA increased significantly in hyperplastic thymus tissues of MG patients compared with those in normal controls, while there was no difference in the expression of CCL19. Furthermore, CK8/18 positive cells were found mainly located in cortico-medullary junction and medulla area. The relative mRNA expression levels of HLA-A, HLA-DR, ICAM and CD80 rose significantly in CK8/18⁺ TECs after transfected with pCMV-CCL21. CONCLUSION: The over-expression of CCL21 could increased the expressions of antigen presentation-related genes in CK8/18⁺ TECs in MG patients.

Clinico-pathological association of Henoch-Schoenlein purpura nephritis and IgA nephropathy in children.

OBJECTIVE: Henoch-Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are similar syndromes. We aimed to determine whether the crescent formation/immunocomplex in glomeruli is associated with the differences of the biochemical indexes between HSPN and IgAN. METHODS: We investigated the medical records of 137 HSPN cases and 41 IgAN cases from January 2009 to April 2014 in Nanjing Children's Hospital of Nanjing Medical University. The clinical and pathological data were analyzed and compared between HSPN and IgAN. RESULTS: HSPN patients had markedly higher levels of blood white blood cell (WBC), hemoglobulin (Hb) and platelet (PLT), lower levels of hematuria, blood nitrogen (BUN) and C4 compared with IgAN cases. Crescents formation and C3 deposition in the kidney did not affect these differences. Significantly lower levels of hematuria, blood IgG, IgM and C4 in HSPN compared with IgAN cases were observed among patients with IgG deposition. Markedly higher levels of WBC and Hb, lower levels of hematuria, creatinine (Cr), C4 in HSPN compared with IgAN cases were observed among patients with IgM deposition. No marked differences of the biochemical indexes were noted between HSPN and IgAN cases among patients with C1q deposition. Markedly higher levels of WBC and Hb, lower level of blood C4 in HSPN compared with IgAN cases were observed among patients with fibrogen deposition. CONCLUSIONS: The different levels of biochemical indexes at presentation between HSPN and IgAN may be associated with the deposition of IgG, IgM, C1q and fibrogen in the kidney.

Crescentic acute glomerulonephritis with isolated C3 deposition: a case report and review of literature.

An eight-year-old girl, presenting with palpebral edema, gross hematuria, and foam in urine, was admitted to our hospital. Investigations indicated increased serum antistreptolysin O (ASO) and anti-mycoplasma antibody titers. Renal biopsy showed crescentic poststreptococcal acute glomerulonephritis (CPAGN) with isolated C3 deposition in the glomeruli. Electro-microscope examination showed subepithelial deposition of electron dense material. She received the double pulse therapies of methylprednisolone and cyclophosphamide as well as the treatment of oral prednisolone, angiotensin converting enzyme-II (ACE-II) inhibitor, dipyridamole and traditional Chinese medicine. The complete clinical remission was achieved after 9 months. No serious adverse effects were observed during the follow-up. Our findings indicated that CPAGN with isolated C3 deposition might have a favorable prognosis after aggressive immunosuppressive treatment. However, the influence of isolated C3 deposition on CPAGN prognosis remains to be clarified.

miRNA-1207-5p is associated with cancer progression by targeting stomatin-like protein 2 in esophageal carcinoma.

Newly discovered intrinsic regulators, the miRNAs regulate gene expression by binding to the 3'-untranslated regions of the genome. Accumulating studies have indicated that miRNAs are aberrantly expressed in various human cancers. We found that miRNA-1207-5p (miR­1207-5p) was markedly downregulated in esophageal carcinoma (EC) tissues, and was correlated with EC differentiation, pathological stage and lymph node metastasis. Rates of apoptosis were increased and cell invasion ability was decreased in EC9706 and EC-1 cells transfected with a miR­1207-5p mimic. Stomatin-like protein 2 (STOML-2) was predicted to be a potential target of miR­1207-5p by bioinformatics analysis and this was confirmed by luciferase assay and western blotting. Our study showed that STOML-2 was negatively regulated by miR­1207-5p. Furthermore, overexpression of STOML-2 abolished the miR­1207-5p anti-invasion function. Based on these results, we proposed that miR­1207-5p might act as a potential therapeutic target in the treatment of EC.

Increased expression levels of S100A4 associated with hypoxia-induced invasion and metastasis in esophageal squamous cell cancer.

Here, we explored the expression of S100A4 in esophageal squamous cell cancer (ESCC) tissues and investigated its role in hypoxia-induced invasion and metastasis in ESCC cell lines EC-1 and EC-9706. Immunohistochemistry analysis demonstrated that S100A4 was overexpressed in human ESCC tissues especially in ESCC tissues with deep invasion and lymph node metastasis. Hypoxia-induced S100A4 overexpression was observed in EC-1 and EC-9706 cells, in which it was associated with invasion and metastasis. Furthermore, we used EC-1 and EC-9706 cells again to upregulate or knockdown the expression S100A4 to investigate the mechanism role of S100A4 in hypoxia-induced invasion and metastasis in ESCC cells. And the results showed that S100A4 played an important role in promoting the invasion and metastasis of EC-1 and EC-9706 cells under hypoxia. Therefore, S100A4 overexpression might be an important mechanism by which hypoxia induced invasion and metastasis, and S100A4 could also be a potential target for the treatment of ESCC.

Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2.

Myricetin, a common dietary flavonoid, is widely distributed in fruits and vegetables and is used as a health food supplement based on its anti-tumor properties. However, the effect and mechanisms of myricetin in esophageal carcinoma are not fully understood. Here, we demonstrated the effect of myricetin on the proliferation, apoptosis, and invasion of the esophageal carcinoma cell lines EC9706 and KYSE30 and explored the underlying mechanism and target protein(s) of myricetin. CCK-8 assay, transwell invasion assay, wound-healing assay, cell cycle analysis, and apoptosis assay were used to evaluate the effects of myricetin on cell proliferation, invasion, and apoptosis. Nude mouse tumor xenograft model was built to understand the interaction between myricetin and NTD RSK2. Pull-down assay was used to verify molecular mechanism. Myricetin inhibited proliferation and invasion and induced apoptosis of EC9706 and KYSE30 cells. Moreover, myricetin was shown to bind RSK2 through the NH2-terminal kinase domain. Finally, myricetin inhibited EC9706 and KYSE30 cell proliferation through Mad1 and induced cell apoptosis via Bad. Myricetin inhibits the proliferation and invasion and induces apoptosis in EC9706 and KYSE30 cells via RSK2. Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2. Our results provide novel insight into myricetin as a potential agent for the prevention and treatment of esophageal carcinoma.

Transforming growth factor-ß1-induced epithelial-mesenchymal transition in human esophageal squamous cell carcinoma via the PTEN/PI3K signaling pathway.

Epithelial-mesenchymal transition (EMT) is a crucial step for the invasive and metastatic properties of malignant tumor cells during tumor progression. Numerous signaling pathways are involved in the process of EMT in cancer, such as the EMT-inducing signal transforming growth factor (TGF)-ß and the recently demonstrated PTEN/PI3K signaling pathway. To date, no data have been reported concerning the influence of PTEN/PI3K signaling pathway on EMT in human esophageal squamous cell carcinoma (ESCC) and how TGF-ß1 and PTEN/PI3K act through multiple interconnected signaling pathways to trigger events associated with EMT and tumor progression. Our data showed that the PTEN/PI3K pathway was active in human ESCC tissues in vivo, particularly in ESCC with decreased E-cadherin and increased vimentin protein expression, poor differentiation, deep invasion and lymph node metastasis, which are responsible for EMT and tumor progression. In addition, in the human ESCC cell line (EC-1) in vitro, TGF-ß1 treatment markedly induced EMT, including morphological alterations, a decrease of E-cadherin and an increase of vimentin levels and enhanced mobility and invasiveness. Furthermore, the PTEN/PI3K pathway was also activated in the process of TGF-ß1-induced EMT in EC-1 cells in vitro, whereas inhibition of the PTEN/PI3K pathway by using pcDNA3.1 PTEN partially blocked TGF-ß1-induced EMT and reduced mobility and invasiveness. These studies suggest that TGF-ß1 and the PTEN/PI3K signaling pathway contribute to EMT and the PTEN/PI3K signaling pathway is a key regulator of TGF-ß1­induced EMT in ESCC. Disruption of the PTEN/PI3K pathway involved in TGF-ß1-induced EMT may provide possible routes for therapeutic intervention to ESCC.

Stathmin is a marker of progression and poor prognosis in esophageal carcinoma.

Stathmin, also called oncoprotein 18, is a founding member of the family of microtubule-destabilizing proteins that play a critical role in the regulation of mitosis. At the same time stathmin has been recognized as one of responsible factors in cancer cells. The aim of this study was to assess stathmin status, its correlations with clinicopathological parameters and its role as a progosnostic marker in EC patients. The protein and mRNA levels of stathmin were examined by immunohistochemistry (IHC) and in situ hybridization in 100EC tissues and adjacent noncancerous tissues. mRNA and protein expression of stathmin in three EC cell lines(EC9706, ECa109, EC1 commonly used in research) were also analyzed using immunocytochemistry, western blot and in situ hybridization. The prognostic value of Stathmin expression within the tumor tissues were assessed by Cox regression and Kaplan-Meier analysis. We showed that stathmin expression was significantly higher in EC tissues than in adjacent noncancerous tissues. High stathmin immunostaining score in the EC was positively correlated with tumor differentiation, Tumor invasion, Lymph node metastases, and TNM stage. In addition, we demonstrated that three EC cell lines examined, were constitutively expressing a high level of stathmin. Of those, EC-1 showed the strongest mRNA and protein expression for the stathmin analyzed. Kaplan-Meier analysis showed that significantly longer 5-year survival rate was seen in EC patients with high Stathmin expression, compared to those with low expression of Stathmin expression. Furthermore, multivariate Cox proportional hazard analyses revealed that Stathmin was an independent factors affecting the overall survival probability. In conclusion, our data provide a basis for the concept that stathmin might be associated with EC development and progression.. High levels of Stathmin expression in the tumor tissues may be a good prognostic marker for patients with EC.

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury.

Adriamycin (ADR)-induced nephropathy in animals is an experimental analog of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The present study was designed to test the hypothesis that the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α-mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, ADR dose dependently induced downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial ROS production, decrease in mitochondrial DNA copy number, and reduction of mitochondrial membrane potential and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1α, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1α overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1α and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1α-mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1α-mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1α may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis.