Mutations or overexpression of signalling genes can result in cancer development and metastasis. In this study, we manually assembled a human cellular signalling network and developed a robust bioinformatics strategy for extracting cancer-associated single nucleotide polymorphisms (SNPs) using expressed sequence tags (ESTs). We then investigated the relationships of cancer-associated genes [cancer-associated SNP genes, known as cancer genes (CG) and cell mobility genes (CMGs)] in a signalling network context. Through a graph-theory-based analysis, we found that CGs are significantly enriched in network hub proteins and cancer-associated genes are significantly enriched or depleted in some particular network motif types. Furthermore, we identified a substantial number of hotspots, the three- and four-node network motifs in which all nodes are either CGs or CMGs. More importantly, we uncovered that CGs are enriched in the convergent target nodes of most network motifs, although CMGs are enriched in the source nodes of most motifs. These results have implications for the foundations of the regulatory mechanisms of cancer development and metastasis.

Resveratrol, a natural polyphenolic antioxidant, has been reported to possess the cancer chemopreventive potential in wide range by means of triggering tumor cells apoptosis through various pathways. It induced apoptosis through the activation of the mitochondrial pathway in some kinds of cells. In the present reports, we showed that resveratrol-induced HepG2 cell apoptosis and mitochondrial dysfunction was dependent on the induction of the mitochondrial permeability transition (MPT), because resveratrol caused the collapse of the mitochondrial membrane potential (DeltaPsi(m)) with the concomitant release of cytochrome c (Cyt.c). In addition, resveratrol induced a rapid and sustained elevation of intracellular [Ca(2+)], which compromised the mitochondrial DeltaPsi(m) and triggered the process of HepG2 cell apoptosis. In permeabilized HepG2 cells, we further demonstrated that the effect of the resveratrol was indeed synergistic with that of Ca(2+) and Ca(2+) is necessary for resveratrol-induced MPT opening. Calcium-induced calcium release from mitochondria (mCICR) played a key role in mitochondrial dysfunction and cell apoptosis: (1) mCICR inhibitor, ruthenium red (RR), prevent MPT opening and Cyt.c release; and (2) RR attenuated resveratrol-induced HepG2 cell apoptotic death. Furthermore, resveratrol promotes MPT opening by lowering Ca(2+)-threshold. These data suggest modifying mCICR and Ca(2+) threshold to modulate MPT opening may be a potential target to control cell apoptosis induced by resveratrol.

Multiple myeloma (MM) is a common and deadly cancer of blood plasma cells. A unique feature of MM is the extremely low somatic mutation rate of the p53 tumor suppressor gene, in sharp contrast with about half of all human cancers where this gene is frequently mutated. Eleven miRNAs have been reported to repress p53 through direct interaction with the 3' untranslated region. The expression of nine of them is higher in MM plasma cells than in healthy donor counterparts, suggesting that miRNA overexpression is responsible for p53 inactivation in MM. Here, we report that the environmental carcinogen benzo[a]pyrene (BaP) upregulated the expression of seven p53-targeting miRNAs (miR-25, miR-15a, miR-16, miR-92, miR-125b, miR-141, and miR-200a), while 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) upregulated two of them (miR-25 and miR-92) in MM cells. The miR-25 promoter was activated by both BaP and TCDD, and this response was mediated by the aryl hydrocarbon receptor (AhR). We screened 727 compounds that inhibit MM cell survival and down-regulate the expression of p53-targeting miRNAs. We found that (-)-epigallocatechin-3-gallate (EGCG), a constituent of green tea and a major component of the botanical drug Polyphenon® E, reduced the expression of four p53-targeting miRNAs, including miR-25, miR-92, miR-141, and miR-200a. Collectively, these data implicate polycyclic aromatic hydrocarbons and AhR in the regulation of p53-targeting miRNAs in MM and identify a potential therapeutic and preventive agent to combat this deadly disease.

Lung cancer and colorectal cancer account for over one-third of all cancer deaths in the United States. MicroRNA-301a (miR-301a) is an activator of both nuclear factor-κB (NF-κB) and Stat3, and is overexpressed in both deadly malignancies. In this work, we show that genetic ablation of miR-301a reduces Kras-driven lung tumorigenesis in mice. And miR-301a deficiency protects animals from dextran sodium sulfate-induced colon inflammation and colitis-associated colon carcinogenesis. We also demonstrate that miR-301a deletion in bone marrow-derived cells attenuates tumor growth in the colon carcinogenesis model. Our findings ascertain that one microRNA—miR-301a—activates two major inflammatory pathways (NF-κB and Stat3) in vivo, generating a pro-inflammatory microenvironment that facilitates tumorigenesis.

Matrix metalloproteinases (MMP) play a pivotal role in the pathogenesis of cardiovascular diseases. Their expressions are altered in response to a variety of stimuli, including growth factors, inflammatory markers, and cytokines. In this study, we demonstrated that platelet-derived growth factor-BB (PDGF-BB) induces a dose- and time-dependent increase in MMP-2 expression in rat vascular smooth muscle cells (VSMC). Treatment with either the Rho-associated protein kinase (ROCK) inhibitor Y-27632 or suppression of ROCK-1/2 by small interfering RNA technology significantly reduced the MMP-2 expression, thus suggesting that ROCK regulates such expression. Similar results were observed when VSMC were pretreated with either U0126 or SB203580, which are selective inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, respectively, thus suggesting that these kinases are important for the induction of MMP-2 expression by PDGF-BB. In conclusion, these results described a novel mechanism in atherosclerosis through PDGF-BB signaling in VSMC, in which MMP-2 expression is induced via extracellular signal-regulated kinases and p38 mitogen-activated protein kinase phosphorylation, as well as ROCK.

Background Asthma is a chronic disease that seriously harms the health of patients. Oxidative stress is involved in asthma. As an oxidative stress-inducible protein, sestrin2 is elevated in oxidative stress-related diseases. We aimed to explore whether sestrin2 was involved in asthma. Methods Seventy-six subjects (44 in the asthma group, 32 in the control group) were recruited in this study. Plasma sestrin2 levels, peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV 1 ) % predicted, forced vital capacity (FVC) % predicted and FEV 1 /FVC ratio were measured in controls and in asthmatics both during an exacerbation and when controlled after the exacerbation. Results The asthma group had a significant higher sestrin2 level than the control group (asthmatics during exacerbation, 1.75 ± 0.53 ng/mL vs. 1.32 ± 0.48 ng/mL, p < 0.001; asthmatics when controlled after the exacerbation, 1.56 ± 0.46 ng/mL vs. 1.32 ± 0.48 ng/mL, p = 0.021, respectively). In addition, sestrin2 was negatively correlated with FEV 1 % predicted and FEV 1 /FVC ratio in asthmatics during exacerbation (r = − 0.393, p = 0.008; r = − 0.379, p = 0.011; respectively). Moreover, negative correlations between sestrin2 and FEV 1 % predicted and FEV 1 /FVC ratio also existed in asthmatics when controlled after the exacerbation (r = − 0.543, p < 0.001; r = − 0.433, p = 0.003 respectively). More importantly, multiple linear regression analysis demonstrated that FEV 1 % predicted was independently associated with sestrin2 in asthmatics both during exacerbation and when controlled after the exacerbation. Conclusions Sestrin2 is involved in asthma. Sestrin2 levels increase in asthmatics both during exacerbation and when controlled after the exacerbation. In addition, sestrin2 is independently associated with FEV 1 % predicted.

Background Obstructive sleep apnea (OSA) is a disease seriously threatening individual health, which results in serious complications such as hypertension and stroke. These complications are associated with oxidative stress triggered by intermittent hypoxia in OSA. Sestrin2 is a crucial factor involved in oxidative stress. The goal of this study was to investigate if a relationship exists between OSA and Sestrin2. Methods We prospectively enrolled 71 subjects, and 16 patients of them with severe OSA completed 4 weeks of nasal continuous positive airway pressure (nCPAP) therapy. We measured and compared the concentration of Sestrin2 in the urine of all subjects, as well as the changes between before and after nCPAP treatment. Additionally, the correlation between Sestrin2 and sleep parameters was analyzed, and the multiple linear regression analysis with stepwise selection was performed to explore the relationship between Sestrin2 and various factors. Results A total of 71 subjects were enrolled and divided into two groups: OSA group ( n = 41), control group ( n = 30). The level of urinary Sestrin2 in OSA patients was significantly higher than that of the control group, and increased with the severity of OSA, while it reduced after nCPAP treatment. Additionally, Sestrin2 was positively correlated with apnea/hypopnea index (AHI), oxygen desaturation index, oxygen saturation < 90% percentage of recording time spent (PRTS) and high-density lipoprotein (HDL), while negatively correlated with the lowest oxygen saturation. Importantly, Sestrin2 was independently associated with AHI, oxygen saturation < 90% PRTS and HDL. Conclusions Urinary Sestrin2 is involved in OSA, and is a paramount marker of OSA severity.

In this paper, we investigate the oscillatory expression in Escherichia coli mediated by microRNA with time delays and reaction-diffusion terms. First of all, the integrated effects of delays and diffusions are first introduced into the genetic regulatory networks involving microRNAs, and a general model of genetic regulatory networks is then formulated. Second, two functional issues on gene regulatory networks, i.e. stability and oscillation of such model, are addressed in detail, and an explicit algorithm determining the properties of periodic oscillation is also presented. We demonstrate that the oscillatory expression of Escherichia coli is not only crucially dependent on the transcriptional and translational delays, but also heavily influenced by the diffusion coefficients. The conclusion is practically verified by a lot of biological experiments and observations. We also find that if the diffusion coefficients of miRNA, mRNA, and protein are suitably small, it can predict that inhomogeneous periodic oscillations can occur unless there only exhibits spatially homogeneous periodic oscillations. The obtained results indicate that the effects of transcriptional and translational delays are essential factors for designing or controlling genetic regulatory networks, in the meantime the functions of reaction-diffusion must beconsidered. Finally, numerical examples are presented to illustrate and visualize theoretical results.