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Kudingcha is a particularly bitter tasting tea that has been widely used in China to eliminate fever and itching eyes, and to clear blood toxins. Kudingcha is considered of value for its potential anticancer effects that are attributed to the presence of characteristic bioactive ingredients. The chlorogenic acid (CGA) derivatives 3-0-caffeoylquinic acid, 5-0-caffeoylquinic acid, 3,5-0-dicaffeoylquinic acid, and 4,5-0-dicaffeoylquinic acid were separated from Ilex kudingcha C.J. Tseng extract by high-performance liquid chromatography (HPLC)-photodiode array detector (PDA) and HPLC-nuclear magnetic resonance (NMR). In Tg(flk1:EGFP) zebrafish embryos at 52 hours postfertilization (hpf), angiogenesis was significantly inhibited by kudingcha extract (KDCE) at concentrations of 400 and 500 μg/mL and CGA also showed significant inhibition in embryos treated with 80, 100, and 130 μg/mL. Endothelial cell apoptosis showed a dose-dependent increase in response to KDCE and CGA. CGA derivatives from KDCE could have potential as anticancer agents against tumor angiogenesis.

In the present study, we propose a theoretical framework to predict the recovery rates of platelets and white blood cells in the process of centrifugal separation of whole blood contained in a tube for the preparation of platelet-rich plasma. Compared to previous efforts to optimize or standardize the protocols of centrifugation, we try to further the physical background (i.e., based on the multiphase flow phenomena) of analysis to develop a universal approach that can be applied to widely different conditions. That is, one-dimensional quasi-linear partial differential equation to describe the centrifugal sedimentation of dispersed phase (red and white blood cells) in continuous phase (plasma) is derived based on the kinematic-wave theory. With the information of whole blood volume and tube geometry considered, it is possible to determine the positions of interfaces between supernatant/suspension and suspension/sediment, i.e., the particle concentration gradient in a tube, for a wide range of centrifugation parameters (time and acceleration). While establishing a theory to predict the recovery rates of the platelet and white blood cell from the pre-determined interface positions, we also propose a new correlation model between the recovery rates of plasma and platelets, which is found to be a function of the whole blood volume, centrifugal time and acceleration, and tube geometry. The present predictions for optimal condition show good agreements with available human clinical data, obtained from different conditions, indicating the universal applicability of our method. Furthermore, the dependence of recovery rates on centrifugal conditions reveals that there exist a different critical acceleration and time for the maximum recovery rate of platelets and white blood cells, respectively. The other parameters such as hematocrit, whole blood volume and tube geometry are also found to strongly affect the maximum recovery rates of blood cells, and finally, as a strategy for increasing the efficiency, we suggest to dilute the whole blood, increase the whole blood volume with a tube geometry fixed.

Argonaute 2 (Ago2) protein is the major vehicle of microRNAs (miRNAs)-guided gene repression and silencing processes. Although the crystal structure of human Ago2 (hAgo2) has recently been disclosed, the information of dynamically structural character of protein-RNA recognition is still lacking. Molecular dynamics simulations were used to systematically explore hAgo2 in the presence and absence of RNA duplex. Stable direct and water-mediated hydrogen bonds were observed between guide RNA backbone atoms and hAgo2, especially for nucleotides 2-7. In addition, water-mediated hydrogen bonds are indicated to be critical in the specific recognition between hAgo2 and the conserved adenine in position 1 of target RNA. The core domains (N, PAZ, MID, and PIWI) possess rigid body movements during the simulations. The motions of N-PAZ and PIWI-MID are negatively correlated with or without RNA binding and PAZ domain is identified as the most mobile domain in both systems. The reorientation of PAZ domain not only influences the binding of helix-7 and RNA duplex, the initial pairing process, but also the shape of N-PAZ cleft, where the supplemental base pairing occurs. It is speculated that PAZ domain could be a key regulator in hAgo2-mediated miRNA-induced gene regulation., (© 2017 John Wiley & Sons A/S.)

NSD3 is a histone lysine methyltransferase that methylates histone H3 at lysine 36. NSD3 is located at chromosome 8p11.23, the locus that exhibits strong cancer relevance. Thus, NSD3 is likely involved in multiple human cancers. Nevertheless, its roles in human carcinogenesis remain unknown. In the present study, we demonstrated that silencing of NSD3 in osteosarcoma, the most common primary bone cancer in children and adolescents, results in a marked decrease in the number of viable cancer cells, accompanied by increases in the cell population at the G2/M phase and the number of apoptotic cells. In addition, 549 NSD3‑regulated genes were identified and a set of selected candidate genes were validated. Bioinformatic analysis revealed that NSD3 negatively regulates a number of genes that are involved in the process of negative regulation of signal transduction as well as negative regulation of signaling and cell communication. Our results indicate the oncogenic roles of NSD3 in the development and progression of human osteosarcoma, and implicate NSD3 as a potential molecular target for selective therapy for human osteosarcoma.

Farrerol is a 2,3-dihydro-flavonoid isolated from rhododendron. In this study, a sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the determination of farrerol in rat plasma. Liquid-liquid extraction by ethyl ether was used for sample preparation. Chromatographic separation was achieved on an Agilent UHPLC XDB-C 18 column (2.1 × 100 mm, 1.8 μm) with water and methanol (30:70, v/v) as the mobile phase. An electrospray source was applied and operated in negative ion mode; selection reaction monitoring was used for quantification using target fragment ions m/z 299 → 179 for farrerol and m/z 267 → 252 for internal standard. Calibration plots were linear in the range of 2.88-1440 ng/mL for farrerol in rat plasma. Intra- and inter-day precisions were <11.6%, and the accuracy ranged from -13.9 to 11.9%. The UHPLC-MS/MS method was successfully applied in pharmacokinetics and bioavailability studies of farrerol in rats., (Copyright © 2017 John Wiley & Sons, Ltd.)

Unopposed phosphoinositide 3-kinase (PI3K) activity and 3-phosphoinositide production in Jurkat cells, due to a mutation in the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor-suppressor protein, results in deregulation of PH domain-containing proteins including the serine/threonine kinase PKB. In Jurkat cells, PKB is constitutively active and phosphorylated at the activation-loop residue (Thr308). 3-Phosphoinositide-dependent protein kinase-1 (PDK1), an enzyme that also contains a PH domain, catalyses Thr308 phosphorylation of PKB in addition to other kinase families such as PKC isoforms. It is unknown, however, whether the loss of PTEN in Jurkat cells also results in unregulated PDK1 activity and whether such loss has an impact on activation-loop phosphorylation of other PDK1 substrates e.g. PKC. In this study, we addressed whether loss of PTEN in Jurkat cells affects PDK1 catalytic activity and intracellular localization. We demonstrated that reducing the level of 3-phosphoinositides in Jurkat cells with pharmacological inhibitors of PI3K or expression of PTEN does not affect PDK1 activity or its intracellular localization. We conclude, therefore, that although Jurkat cells lack PTEN expression, only a subset of pathways downstream of PDK1 are perturbed as a consequence of PTEN loss., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

8-Hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, has been recently shown to exert anti-inflammatory effects through inhibition of Rac1. Inflammation in adipose tissue is a hallmark of obesity-induced insulin resistance, but the therapeutic potential of 8-OHdG in treatment of metabolic diseases has not been fully elucidated. The aim of this study was to examine the effect of exogenously administered 8-OHdG on adipose tissue and whole body metabolism. In cultured adipocytes, 8-OHdG inhibited adipogenesis and reversed TNFα-induced insulin resistance. In high-fat diet (HFD)-induced obese mice, 8-OHdG administration blunted the rise in body weight and fat mass. The decrease in adipose tissue mass by 8-OHdG was due to reduced adipocyte hypertrophy through induction of adipose triglyceride lipase and inhibition of fatty acid synthase expression. 8-OHdG also inhibited the infiltration of macrophages, resulting in amelioration of adipose tissue inflammation and adipokine dysregulation. Moreover, 8-OHdG administration ameliorated adipocyte as well as systemic insulin sensitivity. Both in vivo and in vitro results showed that 8-OHdG induces AMPK activation and reduces JNK activation in adipocytes. In conclusion, our results show that orally administered 8-OHdG protects against HFD-induced metabolic disorders by regulating adipocyte metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation., Methods and Results: Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase α (p-AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor-γ, PGC-1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31 + /c-Kit + progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion., Conclusions: These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Rationale: Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown. We hypothesized that therapeutic hypothermia (TH) following CA is associated with the inhibition of PDK activity and increased PDH activity. We further hypothesized that an inhibitor of PDK activity, dichloroacetate (DCA), would improve PDH activity and post-CA outcomes., Methods and Results: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 12-minute KCl-induced CA followed by cardiopulmonary resuscitation. Compared to normothermic (37°C) CA controls, administering TH (30°C) improved overall survival (72-hour survival rate: 62.5% vs. 28.6%, P<0.001), post-resuscitation myocardial function (ejection fraction: 50.9±3.1% vs. 27.2±2.0%, P<0.001; aorta systolic pressure: 132.7±7.3 vs. 72.3±3.0 mmHg, P<0.001), and neurological scores at 72-hour post CA (9.5±1.3 vs. 5.4±1.3, P<0.05). In both heart and brain, CA increased lactate concentrations (1.9-fold and 3.1-fold increase, respectively, P<0.01), decreased PDH enzyme activity (24% and 50% reduction, respectively, P<0.01), and increased PDK protein expressions (1.2-fold and 1.9-fold, respectively, P<0.01). In contrast, post-CA treatment with TH normalized lactate concentrations (P<0.01 and P<0.05) and PDK expressions (P<0.001 and P<0.05), while increasing PDH activity (P<0.01 and P<0.01) in both the heart and brain. Additionally, treatment with DCA (0.2 mg/g body weight) 30 min prior to CA improved both myocardial hemodynamics 2 hours post-CA (aortic systolic pressure: 123±3 vs. 96±4 mmHg, P<0.001) and 72-hour survival rates (50% vs. 19%, P<0.05) in normothermic animals., Conclusions: Enhanced PDH activity in the setting of TH or DCA administration is associated with improved post-CA resuscitation outcomes. PDH is a promising therapeutic target for improving post-CA outcomes.

Objectives: Exposure to psychosocial stress is a risk factor for cardiovascular disease. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4 in stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE -/- ) mice., Methods and Results: ApoE -/- mice fed a high-fat (HF) diet were randomly assigned to one of non-stress and immobilized stress groups for 12weeks. Chronic stress accelerated vascular senescence and atherosclerotic plaque growth at the aortic roots. Stressed mice had increased levels of plasma DPP4 and decreased levels of plasma GLP-1 and adiponectin (APN) and adipose APN expression. Stress increased plaque macrophage infiltration, neovessel density, and elastin fragmentation, lessened the plaque collagen content, and increased the levels of toll-like receptor-2 (TLR2), TLR4, C-X-C chemokine receptor-4, cathepsins S and K, osteopontin, peroxisome proliferator-activated receptor-α, p16 INK4A , p21, and gp91phox mRNAs and/or proteins. Stressed aortas had also increased matrix metalloproteinase-2 (MMP-2) and MMP-9 activities. DPP4 inhibition with anagliptin reversed stress-related atherosclerotic lesion formation, and this benefit was abrogated by APN blocking. In vitro, the GLP-1 receptor agonist exenatide stimulated APN expression in 3T3-L1 cells., Conclusions: These results indicate that the DPP4 inhibition-mediated benefits are likely attributable, at least in part, to attenuation of plaque inflammation, oxidative stress and proteolysis associated with GLP-1-mediated APN production in ApoE -/- mice under stress. Thus, DPP4 will be a novel therapeutic target for the treatment of stress-related cardiovascular disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE -/- ) mice fed a high-fat (HF) diet., Methods: ApoE -/- mice fed the HF diet were assigned to non-stressed and immobilized-stress groups for 12 weeks. Mice fed the HF diet were divided into 2 groups and administered vehicle or exenatide for 12 weeks under stress conditions., Results: Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor-α, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice., Conclusions: These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE -/- mice under chronic stress., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: DPP4 (Dipeptidyl peptidase-4)-GLP-1 (glucagon-like peptide-1) and its receptor (GLP-1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3-adrenergic receptor)/CXCL12 (C-X-C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4-GLP-1/GLP-1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress., Methods and Results: Male 8-week-old mice were subjected to 4-week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP-1 levels and the brain GLP-1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca-1 high c-Kit high CD48 low CD150 high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress-activated HSC proliferation was reversed by DPP4 depletion and by GLP-1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress., Conclusions: These findings suggest that DPP4 can regulate chronic stress-induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12-dependent mechanism that is mediated by the GLP-1/GLP-1R axis, suggesting that the DPP4 inhibition or the GLP-1R stimulation may have applications for treating inflammatory diseases., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Defects are one of the crucial factors influencing the photocatalytic activities of TiO 2 nanoparticles (NPs), as they directly affect the charge separation efficiencies. However, we found that the effect of bulk or surface defects on the photocatalytic performance of TiO 2 is totally different. Here, we controllably synthesized four kinds of uniform TiO 2 NPs, which were used to investigate how the bulk and surface defects influenced the photoactivities of samples with different particle sizes. Through XPS and EPR analysis, bulk and surface defects were observed in all the TiO 2 samples and their amounts had been reduced after the calcination process. The reduction of bulk and surface defects enhanced the photoactivities of TiO 2 NPs with diameters >10 nm, but the situation was inverse for those samples with diameters <10 nm. Therefore, we demonstrated that bulk defects play a dominate role in the change in photoactivity in particles larger than 10 nm, while surface defects are more important than bulk defects for particles less than 10 nm.

Background: Exercise train (ET) stimulates muscle response in pathological conditions, including aging. The molecular mechanisms by which exercise improves impaired adiponectin/adiponectin receptor 1 (AdipoR1)-related muscle actions associated with aging are poorly understood. Here we observed that in a senescence-accelerated mouse prone 10 (SAMP10) model, long-term ET modulated muscle-regenerative actions., Methods: 25-week-old male SAMP10 mice were randomly assigned to the control and the ET (45 min/time, 3/week) groups for 4 months. Mice that were maintained in a sedentary condition served controls., Results: ET ameliorated aging-related muscle changes in microstructure, mitochondria, and performance. The amounts of proteins or mRNAs for p-AMPKα, p-Akt, p-ERK1/2, p-mTOR, Bcl-XL, p-FoxO3, peroxisome proliferators-activated receptor-γ coactivator, adiponectin receptor1 (adpoR1), and cytochrome c oxidase-IV, and the numbers of CD34 + /integrin-α 7 + muscle stem cells (MuSCs) and proliferating cells in the muscles and bone-marrow were enhanced by ET, whereas the levels of p-GSK-3α and gp91phox proteins and apoptotic cells were reduced by ET. The ET also resulted in increased levels of plasma adiponectin and the numbers of bone-marrow (BM)-derived circulating CD34 + /integrin-α 7 + MuSCs and their functions. Integrin-α 7 + MuSCs of exercised mice had improved changes of those beneficial molecules. These ET-mediated aged muscle benefits were diminished by adiponectin and AdipoR1 blocking as well as AMPK inhibition. Finally, recombinant mouse adiponectin enhanced AMPK and mTOR phosphorylations in BM-derived integrin-α 7 + cells., Conclusions: These findings suggest that ET can improve aging-related impairments of BM-derived MuSC regenerative capacity and muscle metabolic alterations via an AMPK-dependent mechanism that is mediated by an adiponectin/AdipoR1 axis in SAMP10 mice., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Dipeptidyl peptidase IV (DPP-IV) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase and transmits intracellular signals through a small intracellular tail. DPP-IV exists in human blood in a soluble form, and truncates a large number of peptide hormones, chemokines, cytokines, and growth factors in vitro and in vivo. DPP-IV has gained considerable interest as a therapeutic target, and a variety of DPP-IV inhibitors that prolong the insulinotropic effects of glucagon-like peptide-1 (GLP-1) are widely used in clinical settings as antidiabetic drugs. Indeed, DPP-IV is upregulated in proinflammatory states, including obesity and cardiovascular disease with and without diabetes mellitus. Consistent with this maladaptive role, DPP-IV inhibitors seem to exert a protective role in cardiovascular disease. In addition to their GLP-1-dependent vascular protective actions, DPP-IV inhibitors exhibit GLP-1-independent beneficial effects on angiogenesis/neovascularization via several signaling pathways (e.g., stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, vascular endothelial growth factor-A/endothelial nitric oxide synthase, etc.). This review focuses on recent findings in this field, highlighting the role of DPP-IV in therapeutic angiogenesis/neovascularization in ischemic heart disease and peripheral artery disease.

The mechanism by which angiogenesis declines with aging is not fully understood. Soluble vascular endothelial growth factor receptor 1 (VEGFR1) form (sFlt1) contributes to endothelial dysfunction in pathological conditions. However, the roles of sFlt1 in ischemia-induced neovascularizationof aged animals have not been investigated. To study aging-related sFlt1 change and its impact on ischemia-induced neovascularization, a hindlimb ischemia model was applied to young and aged mice. Blood flow imaging assay revealed that the blood flow recovery remained impaired throughout the follow-up period. At day 14, immunostaining showed lesser capillary formation in the aged mice. An ELISA showed that the aged mice had increased plasma sFlt-1 levels at indicated time points after surgery. On operative day 4, the aged ischemic muscles had decreased levels of p-VEGFR2 and p-Akt and increased levels of sFlt-1, Wnt5a, and SC35 genes or/and protein as well as increased numbers of inflammatory cells (macrophages and leucocytes) and matrix metalloproteinase-9 activity. Immnunofluorescence showed that Flt-1 was co-localized with CD11b + macrophages of aged ischemic muscles. Hypoxia stimulated sFlt1 expression in CD11b + cells of aged bone-marrow (BM), and this effect was diminished by siWnt5a. The cultured medium of aged mice BM-derived CD11b + cells suppressed human endothelial cell (EC) and endothelial progenitor cell (EPC) angiogenic actions induced by VEGF, and these decreases were improved by treatment with siWnt5a-conditioned medium. Thus, aging appears to decline neovascularization in response to ischemic stress via the VEGFR2/Akt signaling inactivation in ECs and ECPs that is mediated by Wnt5a/SC35 axis activated macrophages-derived sFlt1 production in advanced age.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in parallel with worldwide epidemic of obesity. Reactive oxygen species (ROS) contributes to the development and progression of NAFLD. Peroxisomes play an important role in fatty acid oxidation and ROS homeostasis, and catalase is an antioxidant exclusively expressed in peroxisome. The present study examined the role of endogenous catalase in early stage of NAFLD. 8-week-old male catalase knock-out (CKO) and age-matched C57BL/6J wild type (WT) mice were fed either a normal diet (ND: 18% of total calories from fat) or a high fat diet (HFD: 60% of total calories from fat) for 2 weeks. CKO mice gained body weight faster than WT mice at early period of HFD feeding. Plasma triglyceride and ALT, fasting plasma insulin, as well as liver lipid accumulation, inflammation (F4/80 staining), and oxidative stress (8-oxo-dG staining and nitrotyrosine level) were significantly increased in CKO but not in WT mice at 2 weeks of HFD feeding. While phosphorylation of Akt (Ser473) and PGC1α mRNA expression were decreased in both CKO and WT mice at HFD feeding, GSK3β phosphorylation and Cox4-il mRNA expression in the liver were decreased only in CKO-HF mice. Taken together, the present data demonstrated that endogenous catalase exerted beneficial effects in protecting liver injury including lipid accumulation and inflammation through maintaining liver redox balance from the early stage of HFD-induced metabolic stress., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

A hollow metal micro/nanomaterial with a porous wall is one of the most attractive structures for catalysts. The synthesis of hollow porous Cu particles remains a challenge due to their air-sensitive characteristics. In this study, we report a facile and scalable method for the preparation of high-quality hollow porous Cu particles in the range of 500 nm-1.5 μm with a well-defined structure from Cu 2 O nanoparticle aggregates (NPAs). The synthetic procedure involves the silica-encapsulation and depth-controlled reduction of Cu 2 O NPAs followed by heat-treatment in air and selective removal of the encapsulating layer. The catalytic performance of the hollow porous Cu particles was evaluated through the catalytic reduction of 4-nitrophenol with NaBH 4 as a model reaction. The hollow porous Cu particles exhibited a high activity factor, K = 186 s -1 g -1 , which is the highest K value obtained among the unsupported Cu catalysts to date. And the K value is better than that of some noble metal catalysts, such as Au, Ag, and Pd. In addition, the catalyst could be easily separated from the reaction system and still possessed high activity as well as stability in recycled reactions.

Patients with chronic pain have significantly higher incidences of depression and anxiety than the average person. However, the mechanism underlying this link has not been elucidated in terms of how chronic pain causes significant mood changes and further develops into severe anxiety or depression. The serotonergic system in the raphe nuclei is an important component in both pain processing and the pathogenesis of depression. Since the lateral habenular nucleus (LHb) controls the raphe nuclei, it may participate in the regulation of pain-associated depression. Thus, the aim of the current study was to investigate the role of the LHb in this pathophysiological process. We used chronic constriction injury (CCI) of the sciatic nerve in rats as a model for neuropathic pain and assessed the changes potentially related to the mood disorders. The forced swim test (FST) and sucrose preference test (SPT) were performed to determine the behavioral changes 28 days after pain surgery. Expression of β calmodulin-dependent protein kinase type II (βCaMKII) in the LHb, cytochrome-c oxidase (COX) activity in the LHb and dorsal raphe nucleus (DRN) and serotonin (5-HT) levels in the DRN were measured. We found an increasing in LHb activity and βCaMKII expression, and a decrease in neuronal activity in the DRN and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the CCI rats. These effects were accompanied by the depression-like behaviors. Lesions in the LHb improved the pain threshold and depression-like behavior in the rats. These results suggest that the LHb may play a role in pain-associated depression by affecting the activity of 5-HT neurons in the DRN. Furthermore, we showed that increases in the LHb-DRN pathway activity were a common neurobiological mechanisms for pain and depression, which may explain the coexistence of pain and depression.

Background: Adipose-derived adipokines have been demonstrated to be associated with the development of experimental heart disease through chronic inflammation and cardiac cell apoptosis. Omentin is to be one of the novel adipokines. The aim of this study is to investigate the relationship between circulating omentin and cardiac dysfunction in patients with chronic heart failure (CHF)., Methods: A total of 189 CHF patients were studied, determining serum omentin and echocardiographic parameters. All participants were divided into two experimental groups: the 111 patients who had a left ventricular ejection fraction (EF) ≥40% (EF-H) and the 78 patients exhibiting EF values <40% (EF-L)., Results: The EF-L group showed significantly higher circulating omentin levels compared to the EF-H group (210.8±67.2 vs. 155.3±45.3, P<0.001; Student's t-test). Overall, the data of the linear regression analysis revealed that serum omentin levels correlated positively with left atrial diameters (r=0.31, P=0.006), left ventricular end-systolic dimensions (r=0.42, P<0.001), and left ventricular end-diastolic dimensions (r=0.38, P=0.002) and negatively with left ventricular EF (r=-0.45, P=0.001; Spearmen's rank correlations coefficients for each). The multiple regression model included all variables at p<0.1 by the univariate analysis. A multiple logistic regression analysis demonstrated that high levels of patients' serum omentin were associated with cardiac dysfunction in patients with CHF (OR=1.22; 95% CI: 0.91-1.58; P=0.009)., Conclusions: These findings suggested that elevated serum omentin levels were only very mildly related to the changes in cardiac volume and function in CHF patients. Further studies are then needed to assess the real clinical value of omentin in this setting.

Macrophages, as a major cellular component in tumor microenvironment, play an important role in tumor progression. However, their roles in modulation of cytotoxic chemotherapy are still not fully understood. Here, we investigated the influence of Lipoplysaccharides (LPS)-stimulated macrophage products (LSMP) on Withaferin A (WA), a natural compound that derived from the medicinal plant Withania somnifera, as an antitumor agent in human breast cancer cells MDA-MB-231 and prostate cancer cells PC-3. Our results revealed that LSMP may enhance WA-induced apoptosis in both cell lines, the underlying mechanisms of which are closely associated with activation of caspase-8, -9 and -3, cleavage of poly ADP-ribose polymerase (PARP), as well as specifically inhibiting the translocation of nuclear factor-κB (NF-κB) and down-regulation of anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and inhibitor of apoptosis protein (cIAP1/2). These findings demonstrate that macrophages in tumor microenvironment can modulate tumor responses to chemotoxic agents, providing an effective strategy that targets macrophages to enhance the antitumor efficacy of cytotoxic chemotherapy., (Copyright © 2016. Published by Elsevier Ltd.)

Cross-correlation between pairs of variables takes multi-time scale characteristic, and it can be totally different on different time scales (changing from positive correlation to negative one), e.g., the associations between mean air temperature and relative humidity over regions to the east of Taihang mountain in China. Therefore, how to correctly unveil these correlations on different time scales is really of great importance since we actually do not know if the correlation varies with scales in advance. Here, we compare two methods, i.e. Detrended Cross-Correlation Analysis (DCCA for short) and Pearson correlation, in quantifying scale-dependent correlations directly to raw observed records and artificially generated sequences with known cross-correlation features. Studies show that 1) DCCA related methods can indeed quantify scale-dependent correlations, but not Pearson method; 2) the correlation features from DCCA related methods are robust to contaminated noises, however, the results from Pearson method are sensitive to noise; 3) the scale-dependent correlation results from DCCA related methods are robust to the amplitude ratio between slow and fast components, while Pearson method may be sensitive to the amplitude ratio. All these features indicate that DCCA related methods take some advantages in correctly quantifying scale-dependent correlations, which results from different physical processes.

The engineered Salmonella typhimurium ΔppGpp (S.t ΔppGpp) has been studied in terms of its ability to carry imaging probes (bacterial luciferase, Lux) for tumor imaging or carry therapeutic molecules (Cytolysin A) to kill cancer cells. To establish a novel cancer therapy, bacterial therapy was combined with radiotherapy using the attenuated strain S.t ΔppGpp/pBAD-ClyA. Radiotherapy (21Gy) contributed to S. typhimurium colonization in a colon tumor (CT26) model of BALB/c mice. The combination of bacterial therapy and radiotherapy treatments reduced tumor growth compared with only bacterial therapy.

Dipeptidyl peptidase-4 (DPP4) is one of the most potent mammalian serine proteases participated in the pathogenesis of subclinical atherosclerosis. Here we investigated whether the plasma soluble form of DPP4 is associated with the prevalence of coronary artery disease (CAD) with and without diabetes mellitus (DM). A cross-sectional study was conducted of 496 aged 26-81 years with (n = 362) and without (n = 134) CAD. Plasma DPP4 activity, high sensitive C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein levels were measured. The coronary atherosclerotic plaques were evaluated by coronary angiography. The CAD patients with (n = 84) and without (n = 278) DM had significantly higher DPP4 levels (11.8 ± 3.1 vs. 6.9 ± 3.5 ng/mL, P<0.01) than the nonCAD subjects. The acute coronary syndrome patients (n = 299) had elevated DPP4 levels than those with stable angina patients (n = 83). CAD patients even without DM had increased plasma DPP4 activities as compared with nonCAD subjects (10.9 ± 4.9 vs. 6.4 ± 3.1, ng/L, P< 0.01). A linear regression analysis revealed that overall, the DPP4 levels were positively associated with LCL-C and hs-CRP levels as well as syntax scores. A multiple logistic regression analysis demonstrated that plasma DPP4 activity was independent predictor of CAD (odds ratio, 1.56; 95% CI, 1.19-1.73; P<0.01). Our study shows that increased DPP4 activity levels are associated with the presence of CAD and that the plasma DPP4 level serves as a novel biomarker for CAD even without DM., Competing Interests: The authors have no relationships that could be considered a conflict of interest.

Background and Purpose: Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associated metabolic disorder. The level of plasma plasminogen activator inhibitor-1 (PAI-1) is increased in obese subjects, and PAI-1 null mice show improved insulin sensitivity when subjected to high-fat and high-sucrose diet-induced metabolic stress, suggesting that a best-in-class PAI-1 inhibitor may become a novel therapeutic agent for obesity-associated metabolic syndrome. TM5441 is a novel orally active PAI-1 inhibitor that does not cause bleeding episodes. Hence, in the present study we examined the preventive effect of TM5441 on high-fat diet (HFD)-induced adipocyte dysfunction., Experimental Approach: Ten-week-old C57BL/6J mice were fed a normal diet (18% of total calories from fat) or HFD (60% of total calories from fat) for 10 weeks, and TM5441 (20 mg·kg(-1) oral gavage) was administered daily with the initiation of HFD., Key Results: TM5441 prevented HFD-induced body weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulated JNK and Akt phosphorylation, suggesting that it prevents the insulin resistance of adipocytes. TM5441 also attenuated the macrophage infiltration and increased expression of pro-inflammatory cytokines, such as inducible nitric oxide synthase, induced by the HFD. In addition, TM5441 prevented the HFD-induced down-regulation of genes involved in mitochondrial biogenesis and function, suggesting that it may prevent adipocyte inflammation and dysregulation by maintaining mitochondrial fitness., Conclusion and Implications: Our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders., (© 2016 The British Pharmacological Society.)

Objective: Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice., Approach and Results: Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation., Conclusions: This is the first report detailing cross-interaction between toll-like receptor 2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation., (© 2016 The Authors.)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) has rapidly increased over the past 30 years prompting the suggestion that an epidemic may be on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients. TriCurin is a composition of three food-derived polyphenols in unique stoichiometric proportions consisting of curcumin from the spice turmeric, resveratrol from red grapes, and epicatechin gallate from green tea. Cell viability, clonogenic survival, and tumorsphere formation were inhibited and significant apoptosis was induced by TriCurin in UMSCC47 and UPCI:SCC090 HPV-positive HNSCC cells. Moreover, TriCurin decreased HPV16E6 and HPV16E7 and increased p53 levels. In a pre-clinical animal model of HPV-positive HNSCC, intra-tumoral injection of TriCurin significantly inhibited tumor growth by 85.5% compared to vehicle group ( P < 0.05, n = 7). Our results demonstrate that TriCurin is a potent anti-tumor agent for HPV-positive HNSCC. Further development of TriCurin as a novel anti-cancer therapeutic to manage the HPV-positive HNSCC population is warranted., Competing Interests: CONFLICTS OF INTEREST No conflicts of interest to disclose.

Background: Smooth muscle cell (SMC) migration from the media to the intima, a process affecting plaque stability in advanced-stage atherosclerosis, is under the control of LR11. To delineate the clinical significance of the circulating soluble form of LR11 (sLR11) in patients with type 2 diabetes (T2D), we analyzed the correlation of sLR11 levels with intima-media thickness (IMT) of carotid arteries., Methods: Plasma sLR11 levels were measured in 165 patients with T2D (mean age 56.2±10.4 y, 58.2% males, and BMI 24.6±3.6) by ELISA. Averaged IMT levels of common carotid arteries were determined by ultrasonography., Results: Circulating sLR11 levels were 9.8±3.5ng/ml, and correlated positively with the classical atherosclerosis risk factors age, sex, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C), fasting plasma-glucose (FPG), and glycosylated hemoglobin. Multivariate linear regression analysis indicated that only FPG was associated with sLR11; sLR11 correlated positively with IMT, together with age and FPG, but less with LDL-C. Among the serum risk factors for IMT, multivariate linear regression analysis uncovered that sLR11 was independently associated with IMT. Subsequent logistic analysis revealed that FPG correlated best with IMT values at a cut-off of 0.80mm and sLR11 at a cut-off of 0.90mm, respectively, while LDL-C showed lower discriminatory power at any IMT cut-off values., Conclusion: Increased sLR11 concentrations are highly associated with increased IMT as well as with FPG in middle-aged, non-obese patients with T2D. Circulating sLR11 may be a novel marker representing the pathophysiology of intimal SMCs in patients with T2D., (Copyright © 2016 Elsevier B.V. All rights reserved.)

During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating-factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respectively. Previously, we observed the following: i) the preeclamptic decidua contains an excess of both macrophages and GM-CSF, ii) the preeclampsia-associated proinflammatory cytokines, IL-1β and tumor necrosis factor-α, markedly enhance GM-CSF and M-CSF expression in cultured leukocyte-free first-trimester decidual cells (FTDCs), iii) FTDC-secreted GM-CSF polarizes macrophages toward an M1 subtype. The microenvironment is a key determinant of macrophage phenotype. Thus, we examined proinflammatory stimulation of FTDC-secreted M-CSF and its role in macrophage development. Immunofluorescence staining demonstrated elevated M-CSF-positive decidual cell numbers in preeclamptic decidua. In FTDCs, IL-1β and tumor necrosis factor-α signal through the NF-κB pathway to induce M-CSF production, which does the following: i) enhances differentiation of and elevates CD163 expression in macrophages, ii) increases macrophage phagocytic capacity, and iii) inhibits signal-regulatory protein α expression by macrophages. These findings suggest that FTDC-secreted M-CSF modulates the decidual immune balance by inducing M2 macrophage polarization and phagocytic capacity in response to proinflammatory stimuli., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We previously reported that the histone lysine methyltransferase SUV39H2, which is overexpressed in various types of human cancer, plays a critical role in the DNA repair after double strand breakage, and possesses oncogenic activity. Although its biological significance in tumorigenesis has been elucidated, the regulatory mechanism of SUV39H2 activity through post-translational modification is not well known. In this study, we demonstrate in vitro and in vivo automethylation of SUV39H2 at lysine 392. Automethylation of SUV39H2 led to impairment of its binding affinity to substrate proteins such as histone H3 and LSD1. Furthermore, we observed that hyper-automethylated SUV39H2 reduced methylation activities to substrates through affecting the binding affinity to substrate proteins. Our finding unveils a novel autoregulatory mechanism of SUV39H2 through lysine automethylation., Competing Interests: Y. Nakamura is a stock holder and a scientific advisor of Oncotherapy Science and also has research grants from Oncotherapy Science. No potential conflicts of interest were disclosed by the other authors.

In this study, relations between winter-time Pacific-Northern America pattern (PNA)/East Pacific wave-train (EPW) and winter-time drought in the west United States over the period of 1951-2010 are analyzed. Considering traditional Pearson's Correlation Coefficient can be influenced by non-stationarity and nonlinearity, a recently proposed method, Detrended Partial-Cross-Correlation Analysis (DPCCA) is applied. With DPCCA, we analyzed the "intrinsic" correlations between PNA/EPW and the winter drought with possible effects of ENSO and PDO removed. We found, i) significant negative correlations between PNA/EPW and drought on time scales of 5-6 years after removing the effects of ENSO, ii) and significant negative correlations between PNA/EPW and drought on time scales of 15-25 years after removing the effects of PDO. By further studying the temporal evolutions of the "intrinsic" correlations, we found on time scales of 5-6 years, the "intrinsic" correlations between PNA/EPW and drought can vary severely with time, but for most time, the correlations are negative. While on interdecadal (15-25 years) time scales, after the effects of PDO removed, unlike the relations between PNA and drought, the "intrinsic" correlations between EPW and drought takes nearly homogeneous-sign over the whole period, indicating a better model can be designed by using EPW.

Macrophages are important components of adipose tissue inflammation, which results in metabolic diseases such as insulin resistance. Notably, obesity induces a proinflammatory phenotypic switch in adipose tissue macrophages, and oxidative stress facilitates this switch. Thus, we examined the role of endogenous catalase, a key regulator of oxidative stress, in the activity of adipose tissue macrophages in obese mice. Catalase knockout (CKO) exacerbated insulin resistance, amplified oxidative stress, and accelerated macrophage infiltration into epididymal white adipose tissue in mice on normal or high-fat diet. Interestingly, catalase deficiency also enhanced classical macrophage activation (M1) and inflammation but suppressed alternative activation (M2) regardless of diet. Similarly, pharmacological inhibition of catalase activity using 3-aminotriazole induced the same phenotypic switch and inflammatory response in RAW264.7 macrophages. Finally, the same phenotypic switch and inflammatory responses were observed in primary bone marrow-derived macrophages from CKO mice. Taken together, the data indicate that endogenous catalase regulates the polarization of adipose tissue macrophages and thereby inhibits inflammation and insulin resistance.

Objective: To investigate factors associated with successful transabdominal sonography-guided dilation and curettage for the treatment of cesarean scar pregnancy (CSP)., Methods: In a retrospective study, data were reviewed from patients who received transabdominal sonography-guided dilation and curettage (TASDC) as the primary treatment for early CSP at The Second Xiangya Hospital, Changsha, China, between 2009 and 2013., Results: Among 232 patients, 185 (79.7%) women with CSP were successfully treated with TASDC. Among them, 81 (43.8%) required insertion of a Foley catheter into the lower uterine segment to stop bleeding. The complication rate was 37.9% (88/232) and the failure rate was 21.3% (47/232). Overall, 28 (12.1%), 5 (2.2%), and 4 (1.7%) patients with massive intraoperative uterine bleeding were treated with wedge resection of the uterus, hysterectomy, and uterine artery embolization as a secondary treatment, respectively. In binary logistic regression analysis, pregnancy of 7 weeks or less and pregnancy without missed abortion were associated with successful TASDC for patients with CSP (P<0.001)., Conclusion: Pregnancy of 7 weeks or less and pregnancy without missed abortion were found to be important factors for successful TASDC among patients with CSP. Wedge resection was the main secondary treatment to preserve the uterus and remove gestational tissue among patients with massive bleeding., (Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti-inflammatory and cardio-protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury., Experimental Approach: Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical- and ferric chloride-induced carotid artery thrombosis were employed to evaluate platelet function., Key Results: FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX-1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury-induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co-administration of FO and aspirin decreased the expression of pro-inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro-resolution lipid mediator-Resolvin E1, was significantly elevated in plasma in FO/aspirin-treated mice., Conclusions and Implications: Co-administration of FO and low-dose aspirin may act synergistically to protect against thrombosis and injury-induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease., (© 2014 The British Pharmacological Society.)

Inner centromere protein (INCENP) is a part of a protein complex known as the chromosomal passenger complex (CPC) that is essential for correcting non-bipolar chromosome attachments and for cytokinesis. We here demonstrate that a protein arginine methyltransferase PRMT1, which are overexpressed in various types of cancer including lung and bladder cancer, methylates arginine 887 in an Aurora Kinase B (AURKB)-binding region of INCENP both in vitro and in vivo. R887-substituted INCENP revealed lower binding-affinity to AURKB than wild-type INCENP in the presence of PRMT1. Knockdown of PRMT1 as well as overexpression of methylation-inactive INCENP attenuated the AURKB activity in cancer cells, and resulted in abnormal chromosomal alignment and segregation. Furthermore, introduction of methylation-inactive INCENP into cancer cells reduced the growth rate, compared with those introduced wild-type INCENP or Mock. Our data unveils a novel mechanism of PRMT1-mediated CPC regulation through methylation of INCENP.

Human first-trimester decidual cells (FTDCs) chemoattract CXCR3-expressing circulating CD56(bright)CD16(-) natural killer (NK) cells, which increase uteroplacental blood flow by remodeling spiral arteries and arterioles. This recruitment reflects elevated FTDC expression of NK cell-recruiting induced protein 10 and interferon (IFN)-inducible T-cell-α chemoattractant produced in response to the synergistic effects of tumor necrosis factor α (TNF-α) and IFN-γ stimulation. Decidual macrophages express TNF-α, whereas the cellular origin of IFN-γ is unclear. Therefore, this study aims to identify the cell source(s) of IFN-γ in human first trimester decidua. Immunostaining of decidual sections revealed that both FTDCs and decidual NK (dNK) cells express IFN-γ. Although individual dNK cells express higher IFN-γ levels, the more numerous FTDCs account for greater proportion of total IFN-γ immunostaining. Freshly isolated FTDCs express greater IFN-γ staining than dNK cells as measured by flow cytometry, whereas incubation of dNK cells with documented NK cell activators significantly increases IFN-γ above FTDC levels. Confluent FTDCs intrinsically produce, but paradoxically respond to, exogenous IFN-γ., (© The Author(s) 2015.)

Background: Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome. However, high-level expression of LETM1 has been correlated with multiple human malignancies, suggesting roles in carcinogenesis and tumor progression. This study is aimed to explore the clinicopathological characteristics and prognostic value of LETM1 overexpression in breast cancer., Methods: Immunohistochemical (IHC) staining, and immunofluorescence (IF) were performed to examine LETM1 expression in breast cancer cell line/tissues compared with adjacent normal tissues. Statistical analysis was applied to evaluate the correlation between LETM1 overexpression and the clinicopathological features of breast cancer. Survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed using the Cox proportional hazard models., Results: LETM1 protein showed cytoplasmic staining pattern in breast cancer. The strongly positive rate of LETM1 protein was 61.6% (98/159) in breast cancer, which was significantly higher than in DCIS (29.7%, 11/37), hyperplasia (16.7%, 3/18) and adjacent normal breast tissues (15.9%, 7/44). High-level expression of LETM1 protein was correlated with lymph node metastasis, poor differentiation, late clinical stage, disease-free survival (DFS) and overall survival (OS) rates in breast cancer. Moreover, multivariate analysis suggested that LETM1 emerged as a significant independent prognostic factor along with clinical stage of patients with breast cancer., Conclusions: LETM1 plays an important role in the progression of breast cancer. High level expression of LETM1 is an independent poor prognostic factor of breast cancer.

Epithelial-restricted with serine box (ESX), a member of the ETS transcription factor family, is elevated and regulates EGFR in head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms that contribute to ESX dysregulation remain to be elucidated. In this study, in silico analysis of the 3'-untranslated region (UTR) of ESX predicted two miR-124-binding sites. Delivery of miR-124 inhibited the 3'UTR ESX-driven reporter activity by 50% (P < 0.05) confirming ESX as a direct target of miR-124. Loss of miR-124 was found to be a frequent event in HNSCC. miR-124 expression was significantly depleted in the primary tumor compared with matched normal tissue in 100% (12/12) of HNSCC patients; relative mean miR-124 expression of 0.01197 and 0.00118 (P < 0.001, n = 12) in matched normal adjacent tissue and primary HNSCC tumor, respectively. Overexpression of miR-124 decreased ESX and EGFR levels in miR-124(low)/ESX(high)/EGFR(high) SCC15 HNSCC cells and reduced cell invasion, migration, proliferation, and colony formation. SCC15 cells with miR-124 restoration were less tumorigenic in vivo than miR-control SCC15 cells (70% inhibition, P < 0.01). Restoration of miR-124 in SCC15 cells enhanced the antiproliferative efficacy of the EGFR/Her2 tyrosine kinase inhibitors. Furthermore, recapitulation of EGFR in miR-124-overexpressing SCC15 cells was sufficient to completely block the antiproliferative effects of lapatinib and afatinib. Taken together, our work provides intriguing evidence that miR-124 is a novel therapeutic approach to reduce ESX/EGFR, and may be a tractable strategy to enhance the response rate of HNSCC patients to current anti-EGFR/Her2 therapies., (©2015 American Association for Cancer Research.)

Background and Purpose: It has been suggested that oxidative stress is one of the pathomechanisms underlying amyotrophic lateral sclerosis (ALS), and thus antioxidants such as uric acid (UA) that could reduce oxidative stress might be beneficial in the prevention or treatment of this disease. The objective of this study was to prospectively investigate serum UA levels in Korean ALS patients and to relate them to disease progression., Methods: ALS patients and healthy controls who were individually well-matched for sex, age, and body mass index (BMI) underwent blood testing for serum UA levels, and analyzed whether UA levels were correlated with the disease status of the patients, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R)., Results: The study included 136 ALS patients and 136 matched controls. The UA level was lower in the ALS patients (4.50±1.17 mg/dL, mean±SD) than in the controls (5.51±1.22 mg/dL; p<0.001). Among the ALS patients, the level of UA acid was inversely correlated with the rate of disease progression (decrease in ALSFRS-R score). Kaplan-Meier analysis revealed that a better survival rate was more strongly correlated with top-tertile levels of serum UA than with bottom-tertile levels (log-rank test: p=0.035)., Conclusions: ALS patients had lower serum UA levels than did healthy individuals. UA levels in ALS were negatively correlated with the rate of disease progression and positively associated with survival, suggesting that UA levels contribute to the progression of ALS. UA levels could be considered a biomarker of disease progression in the early phase in ALS patients.

Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the "lowLVEF" group) and the 90 patients showing LVEF values ≥ 40% (the "highLVEF" group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = -0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84-0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.

We theoretically investigate the collapse (i.e., wetting) transition of the air-water interface on fully submerged superhydrophobic surfaces with micro-sized grooves under the fluctuating water pressure and the diffusion of the trapped air pockets. For the analysis, a nonlinear oscillator equation to describe the dynamics of the two-dimensional air-water interface on a single groove is derived, which is solved for a range of parameters of groove geometry and harmonically fluctuating water pressure. The results show that the pressure fluctuation across the interface encourages the early collapse of a plastron before reaching the critical hydrostatic pressure (i.e., maximum immersion depth) predetermined by the geometry. The dependence of plastron longevity on the surface geometry is found such that the plastron on a narrow groove (≤∼5 μm) (collapses mostly due to gas diffusion) lasts days while the ones on wider grooves (>∼35-45 μm, for example), more susceptible to the oscillating pressure, last a much shorter duration. The interplay between the air compression due to water impalement and the change of the volume of impaled water due to gas diffusion determines the response of plastron to fluctuating water pressure, which is analyzed in detail through the introduction of nondimensional parameters, and the critical groove width (most vulnerable to the external perturbations) is explained further. Finally, as a countermeasure to the fluctuating water pressure, it is suggested that the enhanced advancing contact angle of the groove sidewall (e.g., hierarchical structure) mitigates the negative effects.

LSD1 is a histone lysine demethylase, which is highly expressed in multiple types of human cancer. Although its roles in transcriptional regulation have been well-studied, functional regulation of LSD1 by post-translational modifications still remains unknown. Here, we demonstrate that the histone lysine methyltransferase SUV39H2 trimethylated LSD1 on lysine 322. Knockdown of SUV39H2 resulted in a decrease of LSD1 protein even though the mRNA levels were unchanged. SUV39H2-induced LSD1 methylation suppresses LSD1 polyubiquitination and subsequent degradation. In addition, we also observed indirect effect of SUV39H2 overexpression on LSD1-target genes. Our results reveal the regulatory mechanism of LSD1 protein through its lysine methylation by SUV39H2 in human cancer cells.

Encapsulation of a nanoparticle (NP) followed by tailoring of the core materials is an effective strategy for constructing hollow and yolk-shell NPs. Herein, we report the facile synthesis of Cu@SiO2 yolk-shell NPs by converting the silica-encapsulated Cu2O nanoparticle aggregates (NPAs) via a disproportionation reaction. This method is extremely simple and scalable. In addition, all reactions were conducted in air and water solutions that are easily scalable to a mass production scale.

Diverse titanium dioxide (TiO 2 ) nanostructures have attracted considerable attention owing to their broad applications in photocatalytic and photoelectrochemical fields. Herein, TiO 2 hollow single nanocrystals are reported for the first time by using TiO 2 nanopowders as the raw material and hydrofluoric acid as a capping and etching agent through a simple hydrothermal treatment. The influence of experimental parameters such as the concentration of HF, the amount of TiO 2 nanoparticles, the reaction time, and temperature was investigated systematically. The obtained hollow single nanocrystals exhibited enhanced photoelectrochemical and photocatalytic performances attributed to their good crystallinity, suppressed charge recombination, and increased active sites. The current study will provide new insights into the nanostructured engineering of anatase TiO 2 as well as opportunities for the controllable synthesis of hollow single nanocrystals., (Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Triple negative breast cancer (TNBC) is a heterogeneous disease with higher rates of relapse and decreased overall survival in metastatic tumors. Due to its poor prognosis, it is necessary to identify effective biomarkers that are associated with tumor growth and metastasis. The leucine zipper/EF hand-containing transmembrane-1 (LETM1) protein, which is a mitochondrial inner membrane protein, can reduce mitochondrial biogenesis and ATP production. The expression levels of LETM1 were significantly increased in numerous human malignancies. However, the clinicopathological characteristics and prognostic value of LETM1 overexpression in TNBC remains unclear. LETM1 protein was detected in 107 TNBC, 42 ductal carcinoma in situ (DCIS) and 65 adjacent non-tumor breast tissues using immunohistochemical (IHC) staining. Immunofluorescence (IF) staining was also performed to detect the localization of LETM1 protein in MCF-7 BC cells. The correlations between LETM1 overexpression and clinicopathological features of TNBC were evaluated using Chi-squared test and Fisher's exact tests. The survival rate was calculated using the Kaplan-Meier method. LETM1 protein showed cytoplasmic staining patterns in TNBC. The strongly positive rate of LETM1 in TNBC was 69.2% (74/107), which was significantly higher than in both DCIS 35.7% (15/42) and adjacent non-tumor tissues 12.3% (8/65). High-level expression of LETM1 was positively correlated with late clinical stage, poor differentiation, lymph node metastasis, disease-free survival (DFS) and 10-year overall survival (OS) rates in TNBC. Further analysis showed that high LETM1 expression along with clinical stage emerged as significant independent risk factors in patients with TNBC. In conclusion, LETM1 protein overexpression is associated with TNBC progression, and may be a potential biomarker for poor prognostic evaluation of TNBC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro-MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension.

Objectives: Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest., Design: Laboratory investigation., Setting: University laboratory., Interventions: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-minute KCl-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of Mdivi-1 (0.24 mg/kg), a small molecule dynamin-related protein 1 inhibitor or vehicle (dimethyl sulfoxide)., Measurements and Main Results: Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by dynamin-related protein 1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during cardiopulmonary resuscitation inhibited dynamin-related protein 1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (116 ± 4 vs 143 ± 7 s; p < 0.001) during cardiopulmonary resuscitation and enhanced myocardial performance post-return of spontaneous circulation. These improvements were associated with significant increases in survival (65% vs 33%) and improved neurological scores up to 72 hours post cardiac arrest., Conclusions: Post-cardiac arrest inhibition of dynamin-related protein 1 improves time to return of spontaneous circulation and myocardial hemodynamics, resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.

In this paper, a new method, detrended partial-cross-correlation analysis (DPCCA), is proposed. Based on detrended cross-correlation analysis (DCCA), this method is improved by including partial-correlation technique, which can be applied to quantify the relations of two non-stationary signals (with influences of other signals removed) on different time scales. We illustrate the advantages of this method by performing two numerical tests. Test I shows the advantages of DPCCA in handling non-stationary signals, while Test II reveals the "intrinsic" relations between two considered time series with potential influences of other unconsidered signals removed. To further show the utility of DPCCA in natural complex systems, we provide new evidence on the winter-time Pacific Decadal Oscillation (PDO) and the winter-time Nino3 Sea Surface Temperature Anomaly (Nino3-SSTA) affecting the Summer Rainfall over the middle-lower reaches of the Yangtze River (SRYR). By applying DPCCA, better significant correlations between SRYR and Nino3-SSTA on time scales of 6 ~ 8 years are found over the period 1951 ~ 2012, while significant correlations between SRYR and PDO on time scales of 35 years arise. With these physically explainable results, we have confidence that DPCCA is an useful method in addressing complex systems.

Recently developed flexible mechanosensors based on inorganic silicon, organic semiconductors, carbon nanotubes, graphene platelets, pressure-sensitive rubber and self-powered devices are highly sensitive and can be applied to human skin. However, the development of a multifunctional sensor satisfying the requirements of ultrahigh mechanosensitivity, flexibility and durability remains a challenge. In nature, spiders sense extremely small variations in mechanical stress using crack-shaped slit organs near their leg joints. Here we demonstrate that sensors based on nanoscale crack junctions and inspired by the geometry of a spider's slit organ can attain ultrahigh sensitivity and serve multiple purposes. The sensors are sensitive to strain (with a gauge factor of over 2,000 in the 0-2 per cent strain range) and vibration (with the ability to detect amplitudes of approximately 10 nanometres). The device is reversible, reproducible, durable and mechanically flexible, and can thus be easily mounted on human skin as an electronic multipixel array. The ultrahigh mechanosensitivity is attributed to the disconnection-reconnection process undergone by the zip-like nanoscale crack junctions under strain or vibration. The proposed theoretical model is consistent with experimental data that we report here. We also demonstrate that sensors based on nanoscale crack junctions are applicable to highly selective speech pattern recognition and the detection of physiological signals. The nanoscale crack junction-based sensory system could be useful in diverse applications requiring ultrahigh displacement sensitivity.

The presence of phosphorylated histone H2AX (γ-H2AX) is associated with the local activation of DNA-damage repair pathways. Although γ-H2AX deregulation in cancer has previously been reported, the molecular mechanism involved and its relationship with other histone modifications remain largely unknown. Here we find that the histone methyltransferase SUV39H2 methylates histone H2AX on lysine 134. When H2AX was mutated to abolish K134 methylation, the level of γ-H2AX became significantly reduced. We also found lower γ-H2AX activity following the introduction of double-strand breaks in Suv39h2 knockout cells or on SUV39H2 knockdown. Tissue microarray analyses of clinical lung and bladder tissues also revealed a positive correlation between H2AX K134 methylation and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemosensitivity of cancer cells. Overall, our results suggest that H2AX methylation plays a role in the regulation of γ-H2AX abundance in cancer.