Qianqian Zhang

Activation of AMPK inhibits TGF-β1-induced airway smooth muscle cells proliferation and its potential mechanisms

The aims of the present study were to examine signaling mechanisms underlying transforming growth factor β1 (TGF-β1)-induced airway smooth muscle cells (ASMCs) proliferation and to determine the effect of adenosine monophosphate-activated protein kinase (AMPK) activation on TGF-β1-induced ASMCs proliferation and its potential mechanisms. TGF-β1 reduced microRNA-206 (miR-206) level by activating Smad2/3, and this in turn up-regulated histone deacetylase 4 (HDAC4) and consequently increased cyclin D1 protein leading to ASMCs proliferation. Prior incubation of ASMCs with metformin induced AMPK activation and blocked TGF-β1-induced cell proliferation. Activation of AMPK slightly attenuated TGF-β1-induced miR-206 suppression, but dramatically suppressed TGF-β1-caused HDAC4 up-expression and significantly increased HDAC4 phosphorylation finally leading to reduction of up-regulated cyclin D1 protein expression. Our study suggests that activation of AMPK modulates miR-206/HDAC4/cyclin D1 signaling pathway, particularly targeting on HDAC4, to suppress ASMCs proliferation and therefore has a potential value in the prevention and treatment of asthma by alleviating airway remodeling.

Association between psoriasis and asthma risk: A meta-analysis

BACKGROUNDnPsoriasis has been shown to be related to an increased risk of asthma, although the results remain inconclusive. Therefore, we performed a meta-analysis to determine whether psoriasis increases the risk of asthma.nnnMETHODSnA comprehensive search of medical literature data bases was conducted through May 2017. The pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated.nnnRESULTSnA total of six studies with 66,772 psoriasis cases and 577,415 controls were included. Our meta-analysis showed that psoriasis was significantly associated with the increased risk of asthma (OR 1.32 [95% CI, 1.20-1.46]). The older age patients with psoriasis (≥50 years) (OR 1.64 [95% CI, 1.44-1.88]) had a higher risk of asthma susceptibility compared with the younger patients (20-49 years old) (OR 1.25 [95% CI 1.09-1.44]). Subgroup analysis by ethnicity indicated a significant increase in asthma risk in both Asian populations (OR 1.35 [95% CI, 1.18-1.54]) and white populations (OR 1.27 [95% CI, 1.05-1.54]) with psoriasis compared with those without psoriasis.nnnCONCLUSIONnResults of this meta-analysis indicated that the patients with psoriasis had a higher risk of asthma susceptibility, especially among the older patients with psoriasis.

Increased DCLK1 correlates with the malignant status and poor outcome in malignant tumors: a meta-analysis

Doublecortin-like kinase 1 (DCLK1) has been found to be involved in malignant biological behavior of cancers and poor prognosis of cancer patients. The aim of this meta-analysis was to systematically clarify the relationships between expression level of DCLK1 and clinicopathological characteristics in tumors and assess its clinical value in cancer diagnosis and prognosis. 18 eligible studies with a total of 2660 patients were identified by searching the electronic bibliographic databases. Pooled results showed that DCLK1 was highly expressed in tissues from cancer patients compared to normal tissues (OR, 10.00), and overexpression of DCLK1 was significantly correlated with advanced clinical stage (OR, 2.48), positive lymph node metastasis (OR, 2.18), poorly differentiated cancers (OR, 1.83) and poor overall survival (HR, 2.15). The overall combined sensitivity and specificity for DCLK1 in distinguishing malignant tumors were 0.58 and 0.90, respectively. The mean diagnostic odds ratio was 12.70, and the corresponding area under the summary receiver operating characteristic curve was 0.78. In summary, our study indicated that DCLK1 could be a risk factor for development of malignant tumors and may serve as a promising diagnostic and prognostic biomarker for malignant tumors.

Prediction of target genes for miR‐140‐5p in pulmonary arterial hypertension using bioinformatics methods

The expression of microRNA (miR)‐140‐5p is known to be reduced in both pulmonary arterial hypertension (PAH) patients and monocrotaline‐induced PAH models in rat. Identification of target genes for miR‐140‐5p with bioinformatics analysis may reveal new pathways and connections in PAH. This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR‐140‐5p to provide theoretical evidences for further researches on role of miR‐140‐5p in PAH. Multiple downstream target genes and upstream transcription factors (TFs) of miR‐140‐5p were predicted in the analysis. Gene ontology (GO) enrichment analysis indicated that downstream target genes of miR‐140‐5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis found that downstream target genes were mainly located in Notch, TGF‐beta, PI3K/Akt, and Hippo signaling pathway. According to TF–miRNA–mRNA network, the important downstream target genes of miR‐140‐5p were PPI, TGF‐betaR1, smad4, JAG1, ADAM10, FGF9, PDGFRA, VEGFA, LAMC1, TLR4, and CREB. After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR‐140‐5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro.

Overexpression of DJ-1 correlates with aggressive clinicopathological characteristics and poor prognosis in malignant tumors: a meta-analysis

Purpose A number of studies have investigated the role of DJ-1 in the development and progression of malignant tumors. This meta-analysis aims to systematically estimate the rela-tionship between the expression level of DJ-1 and the malignant biological behaviors of tumors and to assess the clinical significances of DJ-1 in the prognosis and diagnosis of cancer. Materials and methods We searched PubMed, Web of Science, China National Knowledge Infrastructure and Wanfang databases from inception to December 1, 2017. Pooled odds ratio (OR) and hazard ratio (HR) with their 95% confidence interval and the diagnostic value of DJ-1 were calculated. Results Fourteen eligible studies with a total of 1,947 subjects were enrolled in our meta-analysis. The results showed that DJ-1 was overexpressed in cancer patients compared with noncancer patients (OR = 30.72), and elevated expression of DJ-1 was demonstrated to be closely associated with high tumor-node-metastasis stage (OR = 5.52), poor differentiated degree (OR = 2.46), positive lymph node metastasis (OR = 4.12) and worse overall survival (HR = 2.23). In addition, the combined sensitivity and specificity for DJ-1 to discern malignant tumors were 0.73 and 0.93, respectively. The diagnostic OR was 34.87, and the area under the summary receiver operating characteristic curve was 0.88. Conclusion This meta-analysis demonstrated that DJ-1 was an important biomarker in tumor assessment and prognosis prediction.

Resveratrol inhibits monocrotaline-induced pulmonary arterial remodeling by suppression of SphK1-mediated NF-κB activation

Aims: This study aims to explore the molecular mechanisms underlying sphingosine kinase 1 (SphK1) inducing pulmonary vascular remodeling and resveratrol suppressing pulmonary arterial hypertension (PAH). Material and methods: monocrotaline (MCT) was used to induce PAH in rats. The right ventricular systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and histological analyses including hematoxylin and eosin staining, the percentage of medial wall thickness (%MT), &agr;‐SMA staining and Ki67 staining were performed to evaluate the development of PAH. Protein levels of SphK1, nuclear factor‐kappaB (NF‐&kgr;B)‐p65 and cyclin D1 were determined using immunoblotting. Sphingosine‐1‐phosphate (S1P) concentration was measured using enzyme‐linked immunosorbent assay. Key findings: SphK1 protein level, S1P production, NF‐&kgr;B activation and cyclin D1 expression were significantly increased in MCT‐induced PAH rats. Inhibition of SphK1 by PF543 suppressed S1P synthesis and NF‐&kgr;B activation and down‐regulated cyclin D1 expression in PAH rats. Suppression of NF‐&kgr;B by pyrrolidine dithiocarbamate (PDTC) also reduced cyclin D1 expression in PAH model. Treatment of PAH rats with either PF543 or PDTC dramatically decreased RVSP, RVHI and %MT and reduced pulmonary arterial smooth muscle cells proliferation and pulmonary vessel muscularization. In addition, resveratrol effectively inhibited the development of PAH by suppression of SphK1/S1P‐mediated NF‐&kgr;B activation and subsequent cyclin D1 expression. Significance: SphK1/S1P signaling induces the development of PAH by activation of NF‐&kgr;B and subsequent up‐regulation of cyclin D1 expression. Resveratrol inhibits the MCT‐induced PAH by targeting on SphK1 and reverses the downstream changes of SphK1, indicating that resveratrol might be a therapeutic agent for the prevention of PAH.

Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-κB-mediated autophagy activation

Aims: It has been shown that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Meanwhile, activation of nuclear factor‐kappaB (NF‐&kgr;B) has been found to induce autophagy in several types of human diseases including cancer and cardiac diseases. However, it is still unknown whether NF‐&kgr;B mediates autophagy activation in PAH, and whether activation of adenosine monophosphate‐activated protein kinase (AMPK) benefits PAH by modulation of NF‐&kgr;B and autophagy. Main methods: Rat models of PAH were established by intraperitoneally injection of monocrotaline (MCT). The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and percentage of medial wall thickness (%MT) were performed to evaluate the development of PAH. The translocation of NF‐&kgr;B p65 from cytosol to nucleus, the protein levels of LC3A, LC3B, and RND3 were determined by immunoblotting. Metformin was used to activate AMPK. Key findings: NF‐&kgr;B and autophagy were significantly activated in MCT‐induced PAH rats, this was accompanied with the reduction of RND3. Pharmacological inhibition of NF‐&kgr;B suppressed MCT‐induced activation of autophagy and down‐regulation of RND3 expression and reduced RVSP, RVHI, and %MT in MCT‐induced PAH rats. In addition, activation of AMPK by metformin suppressed NF‐&kgr;B‐mediated autophagy activation and down‐regulation of RND3 and therefore reduced RVSP, RVHI, and %MT in MCT‐induced PAH. Significance: NF‐&kgr;B‐induced autophagy activation and consequent down‐regulation of RND3 contributes to the development of PAH in MCT‐treated rats. Activation of AMPK prevents the development of PAH by targeting on NF‐&kgr;B to suppress autophagy and vascular remodeling.

The value of long noncoding RNA CASC2 as a biomarker of prognosis in carcinomas: a meta-analysis

Lnc RNA Cancer Susceptibility Candidate 2(CASC2) has been shown to be aberrantly expressed in multiple types of cancer and might serve as a prognosis biomarker. The present meta-analysis was conducted to investigate whether the expression of CASC2 was associated with prognosis or clinicopathological features in correlative cancers. A total of 11 studies with 765 cancer patients were included by searching the electronic databases, the results found a significant association between high expression of CASC2 and longer OS in cancer patients (HR=0.43, 95% CI: 0.33-0.55, P =0.000).In addition, a significant correlation was observed between high level of CASC2 and earlier TNM stage(OR = 0.30, 95% CI =0.21-0.43, P < 0.001), smaller tumor size(OR = 0.28, 95% CI =0.12-0.66, P =0.004), better tumor differentiation(OR = 0.42, 95% CI =0.27-0.66, P =0.0002). In conclusion, CASC2 can serve as a novel marker predicting the prognosis and clinicopathological features in various cancers.

Clinicopathological and prognostic significance of leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) in malignant tumors: A meta-analysis

Background: Accumulating studies have demonstrated that the expression of leucine-rich repeats and immunoglobulin-like domains protein1 (LRIG1) is associated with various types of tumors. However, the conclusions of previous studies are not completely consistent. Thus, we conducted this meta-analysis to further explore the authentic value of LRIG1 in cancer outcome and clinical significance. Methods: We systematically searched electronic databases including PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure and Wanfang database. The hazard ratios (HRs), odds ratio (OR) and 95 % confidence intervals (CI) were calculated for effect measures. Results: 16 qualified studies involving 2043 patients with cancer were enrolled. High LRIG1 expression was associated with a good prognosis in malignant tumors (HR: 0.49, 95% CI=0.39-0.59). Furthermore, positive expression rate of LRIG1 was distinctly lower in cancer tissues than that in normal tissues (OR: 0.09, 95% CI=0.05-0.17). Positive LRIG1 expression was definitely related with smaller tumor size (OR: 1.64, 95% CI=1.11-2.42), early tumor stage (OR: 3.67, 95% CI=1.87-7.21), well degree of differentiation (OR: 4.35, 95% CI=2.12-8.93) and negative recurrence (OR: 0.29, 95% CI=0.16-0.53). Conclusions: LRIG1 expression was associated with a good prognosis in terms of overall survival (OS) and might act as a predictive factor for characteristics of cancer patients.

COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation

Abstract Up‐regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor &bgr;‐transduction repeat‐containing protein (&bgr;‐TrCP) have been shown to be associated with cancer cells proliferation. However, it is unclear whether CSN6 and &bgr;‐TrCP are also involved in PDGF‐induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up‐regulated CSN6 protein expression, this was accompanied with &bgr;‐TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF‐induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF‐induced &bgr;‐TrCP down‐regulation, Cdc25A up‐regulation and cell proliferation. Furthermore, pre‐treatment of cells with MG‐132 also abolished PDGF‐induced &bgr;‐TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre‐depletion of Cdc25A by siRNA transfection suppressed PDGF‐induced PASMCs proliferation. Taken together, our study indicates that up‐regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases &bgr;‐TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF‐induced PASMCs proliferation. HighlightsCSN6 is up‐regulated in PASMCs stimulated with PDGF.Activated PDGFR/PI3K/Akt signaling pathway up‐regulats CSN6 in PDGF‐induced PASMCs.CSN6 increases &bgr;‐TrCP ubiquitinated degradation and thereby up‐regulates Cdc25A.Up‐regulation of Cdc25A promotes PDGF‐induced PASMCs proliferation.