Icariin modulates the sirtuin/NF­κB pathway and exerts anti­aging effects in human lung fibroblasts.

Icariin (ICA) has been used as a promising anti­aging drug; however, its underlying molecular mechanism is yet to be elucidated. The present study aimed to determine the anti­aging molecular mechanisms of ICA. D­galactose (D­gal) was used to generate a cell aging model. IMR­90 human lung fibroblasts were pretreated with different concentrations of ICA (1, 2, 4, 8 and 16 µmol/l) for 6 h and subsequently incubated with D­gal (200 mmol/l) at 37˚C for 72 h. Senescence of IMR­90 cells was assessed by senescence­associated­ß­galactosidase (SA­ß­Gal) staining assay. Cell viability, and the expression levels of p53/p21, sirtuin (SIRT) 1/6 and p50/p65 were determined via the MTT assay and western blotting respectively. The results demonstrated that D­gal notably increased the proportion of SA­ß­Gal­positive cells and decreased the viability of IMR­90 cells; however, pretreatment with ICA reversed the effects of D­gal on IMR­90 cells in a concentration­dependent manner. Furthermore, it was also demonstrated that the activation of p53/p21 and nuclear factor­κB (NF­κB) signaling, and downregulation of SIRT1/6 may be involved in IMR­90 cells, in D­gal­induced aging and ICA may effectively prevent IMR­90 cells from these changes induced by D­gal. Taken together, the results of the present study suggest that the anti­aging molecular mechanisms of ICA may be associated with the regulation of the SIRT1/NF­κB pathway.

Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Pirfenidone (PFD) is effective for pulmonary fibrosis (PF), but its action mechanism has not been fully explained. This study explored the signaling pathways involved in anti-fibrosis role of PFD, thus laying a foundation for clinical application. METHODS: Pulmonary fibrosis mice models were constructed by bleomycin (BLM), and TGF-ß1 was used to treat human fetal lung fibroblasts (HLFs). Then, PFD was added into treated mice and cells alone or in combination with ß-catenin vector. The pathological changes, inflammatory factors levels, and Collagen I levels in mice lung tissues were assessed, as well as the activity of HLFs was measured. Levels of indices related to extracellular matrix, epithelial-mesenchymal transition (EMT), Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were determined in tissues or cells. RESULTS: After treatment with BLM, the inflammatory reaction and extracellular matrix deposition in mice lung tissues were serious, which were alleviated by PFD and aggravated by the addition of ß-catenin. In HLFs, PFD reduced the activity of HLFs induced by TGF-ß1, inhibited levels of vimentin and N-cadherin and promoted levels of E-cadherin, whereas ß-catenin produced the opposite effects to PFD. In both tissues and cells, Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways were activated, which could be suppressed by PFD. CONCLUSIONS: PFD alleviated pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3ß/ß-catenin and TGF-ß1/Smad2/3 signaling pathways, which might further improve the action mechanism of anti-fibrosis effect of PFD.

SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells.

Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI. Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4-/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function. Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4-/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro. Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.

Vasogenic cerebral edema associated with the disability in activities of daily living in patients with chronic obstructive pulmonary disease.

INTRODUCTION: The aim of this study was to explore whether patients with chronic obstructive pulmonary disease (COPD) develop vasogenic cerebral edema, and whether this edema contributes to the COPD-related disability. METHODS: Eighteen stable patients with COPD and 17 matched healthy volunteers were enrolled. Apparent diffusion coefficient (ADC) values were calculated by voxel-based analysis using DTI-Studio software based on diffusion tensor imaging. COPD-related disability was calculated using activities of daily living (ADL) scale. RESULTS: In patients with COPD, ADC increased in the white matter fiber tracts including the bilateral anterior cingulum and posterior corpus callosum and in the white matter fibers connecting the bilateral insular cortices, sub-lobar cortices, and pars triangularis cortices and the left rectus and olfactory gyrus. However, after further controlling for cigarette smoking, the difference in ADC values in the posterior corpus callosum between groups disappeared. Patients with COPD had significantly higher scores in ADL than that in controls. Moreover, ADL scores were positively correlated with the increased regional ADC values. CONCLUSION: Vasogenic cerebral edema occurs in patients with COPD. Cigarette smoking may be a risk factor for COPD-related vasogenic edema. Vasogenic cerebral edema may be related to the COPD-related ADL impairment.

Hyaluronan ameliorates LPS-induced acute lung injury in mice via Toll-like receptor (TLR) 4-dependent signaling pathways.

Toll-like receptor-4 (TLR4) signaling has been implicated in innate immunity and acute inflammation following acute lung injury (ALI). As such, modulating inflammatory response through TLR4 represents an attractive therapeutic approach to treat ALI. Increasing evidence demonstrates that hyaluronan (HA) can modulate TLR4 activation and has shown early promise as a therapeutic agent in ALI. However, the mechanism associated with HA has not been fully elucidated. In the current study, we sought to determine the effects of HA on lipopolysaccharide (LPS)-induced inflammatory response and gain insights into the mechanism of action in mice with intratracheal instillation of LPS. Our results demonstrate that in contrast to mice challenged with LPS, pretreatment with HA significantly inhibited inflammatory cell recruitment, attenuated lung injury and suppressed the level of cytokine/chemokine in bronchial alveolar lavage fluid (BALF). Investigation of the mechanism responsible for inhibition of LPS activation showed HA treatment significantly inhibited the nuclear translocation of NF-κB p65 and protein expression of myeloid differentiation primary response protein (MyD88) and TIR-domain-containing adapter-inducing interferon-ß (TRIF) and p38 MAPK, JNK and ERK activation in lung tissue. Furthermore, we compared the protection effect of HA in TLR4-deficient mice with those of genetically matched wild type (WT) mice in an acute model of lung injury. However, in TLR4-deficient mice, HA pretreatment before LPS instillation fail to affect the LPS response. Therefore, our findings suggest that HA pretreatment attenuated LPS-induced ALI and the anti-inflammatory function of HA was partial dependent on TLR4, which shed new light on potential elements that regulate the lung injury response.

Robustness of a partially interdependent network formed of clustered networks.

Clustering, or transitivity, a behavior observed in real-world networks, affects network structure and function. This property has been studied extensively, but most of this research has been limited to clustering in single networks. The effect of clustering on the robustness of coupled networks, on the other hand, has received much less attention. Only the case of a pair of fully coupled networks with clustering has recently received study. Here we generalize the study of clustering of a fully coupled pair of networks and apply it to a partially interdependent network of networks with clustering within the network components. We show, both analytically and numerically, how clustering within networks affects the percolation properties of interdependent networks, including the percolation threshold, the size of the giant component, and the critical coupling point at which the first-order phase transition changes to a second-order phase transition as the coupling between the networks is reduced. We study two types of clustering, one proposed by Newman [Phys. Rev. Lett. 103, 058701 (2009)] in which the average degree is kept constant while the clustering is changed, and the other by Hackett et al. [Phys. Rev. E 83, 056107 (2011)] in which the degree distribution is kept constant. The first type of clustering is studied both analytically and numerically, and the second is studied numerically.

Cascading failures in bi-partite graphs: model for systemic risk propagation.

As economic entities become increasingly interconnected, a shock in a financial network can provoke significant cascading failures throughout the system. To study the systemic risk of financial systems, we create a bi-partite banking network model composed of banks and bank assets and propose a cascading failure model to describe the risk propagation process during crises. We empirically test the model with 2007 US commercial banks balance sheet data and compare the model prediction of the failed banks with the real failed banks after 2007. We find that our model efficiently identifies a significant portion of the actual failed banks reported by Federal Deposit Insurance Corporation. The results suggest that this model could be useful for systemic risk stress testing for financial systems. The model also identifies that commercial rather than residential real estate assets are major culprits for the failure of over 350 US commercial banks during 2008-2011.

Identifying influential directors in the United States corporate governance network.

The influence of directors has been one of the most engaging topics recently, but surprisingly little research has been done to quantitatively evaluate the influence and power of directors. We analyze the structure of the US corporate governance network for the 11-year period 1996-2006 based on director data from the Investor Responsibility Research Center director database, and we develop a centrality measure named the influence factor to estimate the influence of directors quantitatively. The US corporate governance network is a network of directors with nodes representing directors and links between two directors representing their service on common company boards. We assume that information flows in the network through information-sharing processes among linked directors. The influence factor assigned to a director is based on the level of information that a director obtains from the entire network. We find that, contrary to commonly accepted belief that directors of large companies, measured by market capitalization, are the most powerful, in some instances, the directors who are influential do not necessarily serve on boards of large companies. By applying our influence factor method to identify the influential people contained in the lists created by popular magazines such as Fortune, Networking World, and Treasury and Risk Management, we find that the influence factor method is consistently either the best or one of the two best methods in identifying powerful people compared to other general centrality measures that are used to denote the significance of a node in complex network theory.

[Pulmonary fibrosis induces erectile dysfunction in rats].

OBJECTIVE: To study the impact of pulmonary fibrosis on erectile function in rats and its mechanism. METHODS: Forty 12-week-old healthy male SD rats were randomly divided into Groups A (4-week pulmonary fibrosis), B (6-week pulmonary fibrosis), C (4-week control, and D (6-week control). The models of pulmonary fibrosis were established by injection of bleomycin at 5 mg/kg in the trachea, while the controls were injected with normal saline only. At 4 and 6 weeks, all the rats were subjected to determination of the serum testosterone (T) level, arterial blood gas analysis, measurement of intracavernous pressure/mean arterial pressure (ICP/MAP), and examination of NOS activity and cGMP content. The mRNA expressions of eNOS, iNOS and nNOS in the corpus cavernosum penis were detected by real-time PCR, and that of eNOS analyzed by Western blot. RESULTS: The 3 V and 5 V of the ICP/mapx100 in Group C were 16.37 +/- 2.19 and 27.19 +/- 3.18, significantly lower than 30.78 +/- 2.66 and 50.09 +/- 6.97 in Group A (P < 0.05); those in Group D were 10.17 +/- 1.31 and 17.40 +/- 1.74, significantly lower than 31.45 +/- 3.07 and 51.23 +/- 7.23 in Group B (P < 0.05), and so were they in Group D than in C (P < 0.05). PaO2 was significantly lower in Group C than in A ([75.50 +/- 13.87] mmHg vs [103.80 +/- 6.88] mmHg, P < 0.05) , and so was it in Group D than in B ( [83.60 +/- 5.50] mmHg vs [102.70 +/- 5.77] mmHg, P < 0.05). Group C showed a significantly increased serum T level as compared with A ([391.1 +/- 264.7] ng/dl vs [175.9 +/- 53.0] ng/dl, P < 0.05), so did Group D ([745.4 +/- 408.8] ng/dl) versus Group B ([177.8 +/- 52.3] ng/dl) and C (P < 0.05). NOS activity and cGMP content in the corpus cavernosum significantly decreased in Group C ([1.50 +/- 0.14] U/mg prot and [35.69 +/- 3.64] pmol/mg) compared with A ([2.66 +/- 0.39] U/mg prot and [51.10 +/- 7.22] pmol/mg) (P < 0.05), so did they in D ([1.40 +/- 0.20] U/mg prot and [34.55 +/- 4.30] pmol/mg) versus B ([2.75 +/- 0.36] U/mg prot and [52.15 +/- 6.86] pmol/mg) (P < 0.05), but neither showed any significant difference between Groups D and C (P > 0.05). The expression of the eNOS protein was significantly lower in Group C than in A (0.79 +/- 0.01 vs 0.87 +/- 0.01, P < 0.05), so was it in D than in B and C (0.71 +/- 0.02 vs 0.88 +/- 0.01 and 0.79 +/- 0.01, P < 0.05). The expression of eNOS mRNA was significantly higher in Group C than in A (4.46 +/- 0.92 vs 2.61 +/- 0.68, P < 0.05), but did not show any significant difference between D and B (2.79 +/- 0.60 vs 2.69 +/- 0.65, P > 0.05), nor did the expressions of nNOS mRNA and iNOS mRNA between the pulmonary fibrosis groups and the controls (P > 0.05). CONCLUSION: Pulmonary fibrosis may induce erectile dysfunction by suppressing the expression of the eNOS protein and reducing NOS activity and cGMP content in the corpus cavernosum penis of rats.

Robustness of interdependent networks under targeted attack.

When an initial failure of nodes occurs in interdependent networks, a cascade of failure between the networks occurs. Earlier studies focused on random initial failures. Here we study the robustness of interdependent networks under targeted attack on high or low degree nodes. We introduce a general technique which maps the targeted-attack problem in interdependent networks to the random-attack problem in a transformed pair of interdependent networks. We find that when the highly connected nodes are protected and have lower probability to fail, in contrast to single scale-free (SF) networks where the percolation threshold pc = 0, coupled SF networks are significantly more vulnerable with pc significantly larger than zero. The result implies that interdependent networks are difficult to defend by strategies such as protecting the high degree nodes that have been found useful to significantly improve robustness of single networks.