Dendritic cells (DCs) and macrophages play important roles in maintaining intestinal homeostasis. However, the molecular mechanisms that regulate the differentiation and responses of intestinal DCs and macrophages remain poorly understood. Here, we have identified microRNA miR-223 as a key molecule for regulating these processes. Deficiency of miR-223 led to a significantly decreased number of intestinal CX3CR1(hi) macrophages at steady state. Both intestinal CX3CR1(hi) macrophages and CD103(+) conventional DCs (cDCs) in miR-223-deficient mice exhibited a strong pro-inflammatory phenotype. Moreover, miR-223-deficient monocytes gave rise to more monocyte-derived DCs (moDCs) and produced more pro-inflammatory cytokines upon stimulation. Using a mouse model of colitis, we demonstrated that the miR-223 deficiency resulted in more severe colitis. Target gene analysis further identified that the effects of miR-223 on DCs and macrophages were mediated by directly targeting C/EBPβ. Taken together, our study identifies a role for miR-223 as a critical regulator of intestinal homeostasis.

BackgroundBone cancer pain (BCP) is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies show several chemokines (for example, CCL2, CXCL10) in the spinal cord are involved in the pathogenesis of BCP. Here we investigated whether and how spinal CXCL1 contributes to BCP.MethodsMouse prostate tumor cell line, RM-1 cells were intramedullary injected into the femur to induce BCP. The mRNA expression of CXCL1 and CXCR2 was detected by quantitative real-time PCR. The protein expression and distribution of CXCL1, NFκB, and CXCR2 was examined by immunofluorescence staining and western blot. The effect of CXCL1 neutralizing antibody, NFκB antagonist, and CXCR2 antagonist on pain hypersensitivity was checked by behavioral testing.ResultsIntramedullary injection of RM-1 cells into the femur induced cortical bone damage and persistent (>21 days) mechanical allodynia and heat hyperalgesia. Tumor cell inoculation also produced CXCL1 upregulation in activated astrocytes in the spinal cord for more than 21 days. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody at 7 days after inoculation attenuated mechanical allodynia and heat hyperalgesia. In cultured astrocytes, TNF-α induced robust CXCL1 expression, which was dose-dependently decreased by NFκB inhibitor. Furthermore, inoculation induced persistent NFκB phosphorylation in spinal astrocytes. Intrathecal injection of NFκB inhibitor attenuated BCP and reduced CXCL1 increase in the spinal cord. Finally, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after inoculation. Inhibition of CXCR2 by its selective antagonist SB225002 attenuated BCP.ConclusionNFκB mediates CXCL1 upregulation in spinal astrocytes in the BCP model. In addition, CXCL1 may be released from astrocytes and act on CXCR2 on neurons in the spinal cord and be involved in the maintenance of BCP. Inhibition of the CXCL1 signaling may provide a new therapy for BCP management.

BackgroundThe objective of this study was to investigate the role and mechanism of long non-coding RNA MIAT in gastric cancer (GC).MethodsReal-time PCR was used to determine MIAT level in 120 GC tissues, and in two gastric cancer cell lines. The clinicopathological characteristics of MIAT in GC patients were analyzed. Small interfering RNA specific for MIAT (si-MIAT) and lentivector for si-MIAT was performed to down-regulate MIAT expression in GC cells and in animal tumor model, respectively. The interaction of MIAT and miR-141 was measured by RNA pull-down assay and RNA immunoprecipitation. The biological function of si-MIAT on GC cell growth and metastasis were explored through flow cytometry assay, invasion and migration assay in vitro.ResultsMIAT was highly expressed in GC tissues and cell lines and correlated with differentiation degree, TNM stage, distant metastasis, and lymph node metastasis. MIAT knockdown inhibited GC growth and metastasis both in vitro and in vivo. Furthermore, MIAT acted as miR-141 sponge and regulated its target gene DDX5 expression. In BGC-823 and MGC-803 cells with si-MIAT, DDX5 overexpression resulted in an increase of cell proliferation, migration and invasion.ConclusionsOur data indicated that MIAT played an oncogenic role in GC growth and metastasis, and could serve as a novel molecular target for treating GC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0725-3) contains supplementary material, which is available to authorized users.

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Significant down-regulation of miR-34a in hypoxic lung tissue, pulmonary artery and PASMCs was identified and then effects of miR-34a in modulating cell proliferation in human pulmonary artery smooth muscle cells (hPASMCs) was investigated in vitro. Reduction of miR-34a levels in hPASMCs caused increased proliferation and these effects were reversed by overexpression of miR-34a. miR-34a overexpression down-regulated platelet-derived growth factor receptor alpha (PDGFRA) expression, which is a key factor in PAH development. These results suggest that miR-34a is a potential regulator of proliferation in PASMCs, and that it could be used as a novel treatment strategy in PAH.

BackgroundThe Brain Trauma Foundation (BTF) guidelines published in 2007 suggest some indications for intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI). However, some studies had not shown clinical benefit in patients with severe TBI; several studies had even reported that ICP monitoring was associated with an increased mortality rate. The effect of ICP monitoring has remained controversial, regardless of the ICP monitoring guidelines. Here we performed a meta-analysis of published studies to assess the effects of ICP monitoring in patients with severe TBI.MethodsWe searched three comprehensive databases, the Cochrane Library, PUBMED, and EMBASE, for studies without limitations published up to September 2015. Mortality, ICU LOS, and hospital LOS were analyzed with Review Manager software according to data from the included studies.ResultsEighteen eligible studies involving 25229 patients with severe TBI were included in our meta-analysis. The results indicated no significant reduction in the ICP monitored group in mortality (hospitalized before 2007), hospital mortality (hospitalized before 2007), mortality in randomized controlled trials. However, overall mortality, mortality (hospitalized after 2007), hospital mortality (hospitalized after 2007), mortality in observational studies (hospitalized after 2007), 2-week mortality, 6-month mortality, were reduced in ICP monitored group. Patients with an increased ICP were more likely to require ICP monitoring.ConclusionSuperior survival was observed in severe TBI patients with ICP monitoring since the third edition of “Guidelines for the Management of Severe Traumatic Brain Injury,” which included “Indications for intracranial pressure monitoring,” was published in 2007.

Background Cardiovascular disease (CVD), one of the most common comorbidities of coronavirus disease 2019 (COVID-19), has been suspected to be associated with adverse outcomes in COVID-19 patients, but their correlation remains controversial. Method This is a quantitative meta-analysis on the basis of adjusted effect estimates. PubMed, Web of Science, MedRxiv, Scopus, Elsevier ScienceDirect, Cochrane Library and EMBASE were searched comprehensively to obtain a complete data source up to January 7, 2021. Pooled effects (hazard ratio (HR), odds ratio (OR)) and the 95% confidence intervals (CIs) were estimated to evaluate the risk of the adverse outcomes in COVID-19 patients with CVD. Heterogeneity was assessed by Cochran’s Q-statistic, I2test, and meta-regression. In addition, we also provided the prediction interval, which was helpful for assessing whether the variation across studies was clinically significant. The robustness of the results was evaluated by sensitivity analysis. Publication bias was assessed by Begg’s test, Egger’s test, and trim-and-fill method. Result Our results revealed that COVID-19 patients with pre-existing CVD tended more to adverse outcomes on the basis of 203 eligible studies with 24,032,712 cases (pooled ORs = 1.41, 95% CIs: 1.32-1.51, prediction interval: 0.84-2.39; pooled HRs = 1.34, 95% CIs: 1.23-1.46, prediction interval: 0.82-2.21). Further subgroup analyses stratified by age, the proportion of males, study design, disease types, sample size, region and disease outcomes also showed that pre-existing CVD was significantly associated with adverse outcomes among COVID-19 patients. Conclusion Our findings demonstrated that pre-existing CVD was an independent risk factor associated with adverse outcomes among COVID-19 patients.

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