MEG3-Mediated Oral Squamous-Cell-Carcinoma-Derived Exosomal miR-421 Activates Angiogenesis by Targeting HS2ST1 in Vascular Endothelial Cells.

Exosomal microRNAs (miRNAs) from cancer cells play a key role in mediating the oral squamous cell carcinoma (OSCC) microenvironment. The objective of this study was to investigate how the long non-coding RNA (lncRNA) MEG3 affects OSCC angiogenesis through exosomal miR-421. Global miRNA microarray analysis and quantitative real-time PCR (qRT-PCR) were performed to determine the level of miRNAs in OSCC cell-derived exosomes. Cell migration, invasion, tube formation, immunohistochemistry, and hemoglobin concentrations were used to study the effects of exosomal miR-421 in angiogenesis. Western blotting was used to determine the expression level of HS2ST1 and VEGFR2-related downstream proteins. MiRNA array and qRT-PCR identified the upregulation of miR-421 in OSCC cell-derived exosomes. Furthermore, exosomal miR-421 can be taken up by human umbilical vein endothelial cells (HUVECs) and then target HS2ST1 through VEGF-mediated ERK and AKT phosphorylation, thereby promoting HUVEC migration, invasion, and tube formation. Additionally, forced expression of the lncRNA MEG3 in OSCC cells reduced exosomal miR-421 levels and then increased HS2ST1 expression, thereby reducing the VEGF/VEGFR2 pathway in HUVECs. Our results demonstrate a novel mechanism by which lncRNA MEG3 can act as a tumor suppressor and regulate endothelial angiogenesis through the exosomal miR-421/HS2ST1 axis, which provides a potential therapeutic strategy for OSCC angiogenesis.

Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction.

BACKGROUND: Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. METHODS: By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. RESULTS: The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. CONCLUSIONS: Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs.

Generalizable Natural Language Processing Framework for Migraine Reporting from Social Media.

Migraine is a highly prevalent and disabling neurological disorder. However, information about migraine management in real-world settings is limited to traditional health information sources. In this paper, we (i) verify that there is substantial migraine-related chatter available on social media (Twitter and Reddit), self-reported by those with migraine; (ii) develop a platform-independent text classification system for automatically detecting self-reported migraine-related posts, and (iii) conduct analyses of the self-reported posts to assess the utility of social media for studying this problem. We manually annotated 5750 Twitter posts and 302 Reddit posts, and used them for training and evaluating supervised machine learning methods. Our best system achieved an F1 score of 0.90 on Twitter and 0.93 on Reddit. Analysis of information posted by our 'migraine cohort' revealed the presence of a plethora of relevant information about migraine therapies and sentiments associated with them. Our study forms the foundation for conducting an in-depth analysis of migraine-related information using social media data.

Elimination of cancer stem-like "side population" cells in hepatoma cell lines by chinese herbal mixture "tien-hsien liquid".

There are increasing pieces of evidence suggesting that the recurrence of cancer may result from a small subpopulation of cancer stem cells, which are resistant to the conventional chemotherapy and radiotherapy. We investigated the effects of Chinese herbal mixture Tien-Hsien Liquid (THL) on the cancer stem-like side population (SP) cells isolated from human hepatoma cells. After sorting and subsequent culture, the SP cells from Huh7 hepatoma cells appear to have higher clonogenicity and mRNA expressions of stemness genes such as SMO, ABCG2, CD133, ß-catenin, and Oct-4 than those of non-SP cells. At dose of 2 mg/mL, THL reduced the proportion of SP cells in HepG2, Hep3B, and Huh7 cells from 1.33% to 0.49%, 1.55% to 0.43%, and 1.69% to 0.27%, respectively. The viability and colony formation of Huh7 SP cells were effectively suppressed by THL dose-dependently, accompanied with the inhibition of stemness genes, e.g., ABCG2, CD133, and SMO. The tumorigenicity of THL-treated Huh7 SP cells in NOD/SCID mice was also diminished. Moreover, combination with THL could synergize the effect of doxorubicin against Huh7 SP cells. Our data indicate that THL may act as a cancer stem cell targeting therapeutics and be regarded as complementary and integrative medicine in the treatment of hepatoma.

Identification of antrocin from Antrodia camphorata as a selective and novel class of small molecule inhibitor of Akt/mTOR signaling in metastatic breast cancer MDA-MB-231 cells.

The PI3K/Akt/mTOR pathway is considered to be an attractive target for the development of novel anticancer molecules. This paper reports for the first time that a small molecule, antrocin (MW = 234), from Antrodia camphorata was a potent antagonist in various cancer types, being highest in metastatic breast cancer MDA-MB-231 cells (MMCs) with an IC(50) value of 0.6 µM. Antrocin was a superior antiproliferator in MMCs as compared with doxorubicin and cisplatin, prevents colony formation, and was nontoxic to nontumorgenic MCF10A and HS-68 cells. Antrocin induced dose-dependent apoptosis in MMCs and caused cleavage of caspase-3 and poly(ADP-ribose) polymerase. Antrocin also caused a time-dependent decrease in protein expression of anti-apoptotic Bcl-2, Bcl-xL, survivin, and their mRNA, with concomitant increase in pro-apoptotic Bax and cytosolic cytochrome c. In a mechanistic study, antrocin suppressed the phosphorylation of Akt and its downstream effectors mTOR, GSK-3ß, and NF-κB. Furthermore, down-regulation of Akt by small interfering RNA prior to antrocin treatment resulted in enhanced cell growth inhibition and apoptosis. Thus, antrocin as an Akt/mTOR dual inhibitor has broad applicability in the development of a clinical trial candidate for the treatment of metastatic breast cancer.

Effects of exercise training in heart transplant recipients: a meta-analysis.

OBJECTIVES: Muscle wasting and exercise intolerance are common in heart transplant recipients. Most studies on the effects of exercise training have used relatively small sample sizes and are heterogeneous in nature. The purpose of this meta-analysis was to systematically review the relevant studies and investigate the effects of exercise training on exercise capacity and muscle strength in heart transplant recipients. METHODS: A systematic search was adopted from electronic databases and relevant references, using medical subject heading key words related to heart transplantation and exercise. Only randomized controlled trials with exercise intervention versus usual care were included. The data were expressed as the weighted mean differences with 95% confidence intervals (CIs). RESULTS: Altogether 6 studies were included. Peak oxygen consumption (VO(2)) was reported in 4 trials (117 patients), and muscle strength was reported in 3 trials (67 patients). Peak VO(2) was significantly increased by 2.34 ml/kg/min (95% CI 0.63-4.05). One-repetition maxima of the chest press (23.28 kg, 95% CI 0.64-45.91) and leg press (28.84 kg, 95% CI 5.70-51.98) were significantly improved by exercise training. CONCLUSION: Exercise training is recommended for heart transplant recipients to improve peak VO(2) and muscle strength despite the small number of trials included in this meta-analysis.

Effect of diallyl trisulfide-rich garlic oil on blood coagulation and plasma activity of anticoagulation factors in rats.

Diallyl trisulfide (DAT)-rich garlic oil was fed to Sprague-Dawley rats and the effects of this DAT-rich garlic oil on bleeding time, clotting time and anticoagulation factors were examined. Garlic oil supplement at 5 or 50mg garlic oil/kg bodyweight significantly prolonged bleeding time and thrombin time, and enhanced anticoagulation factor activity, such as antithrombin III and protein C (P<0.05). These results suggested that the anticoagulant action of DAT-rich garlic oil was due to inhibition and/or inactivation of thrombin. In addition, DAT-rich garlic oil benefits blood anticoagulation factors, which might further prevent the development of thrombus formation. However, the intake of garlic oil at high dose significantly increased plasma fibrinogen concentration (P<0.05), and affected the levels of several hematological parameters such as erythrocyte count, hemoglobin and platelets (P<0.05). The adverse effect of high doses of garlic oil might further influence the hemostatic balance. Therefore, the concentration of DAT-rich garlic oil should be carefully considered in its application. Supplementation of garlic oil at 5mg/kg bodyweight has anticoagulation effect in this animal study.

Corrigendum to "Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/ß-Catenin Signaling and Apoptosis Induction".

[This corrects the article DOI: 10.1155/2013/146136.].

Blood monocyte chemotactic protein-1 (MCP-1) and adapted disease activity Score28-MCP-1: favorable indicators for rheumatoid arthritis activity.

OBJECTIVE: We assessed blood pentraxin 3 (PTX3) and macrophage chemotactic factor-1 (MCP-1) levels as indicators of disease activity in rheumatoid arthritis (RA) patients, because data on disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) and DAS28-C-reactive protein (CRP) are still imperfect. METHODS: In 111 patients with RA, we examined longitudinal and cross-sectional correlations of blood PTX3, MCP-1, CRP, and ESR levels with measures of clinical arthritic activity, namely, swollen joint count (SJC), tender joint count (TJC), visual analog scale for general health (GH), DAS28, and adapted DAS28-MCP-1. RESULTS: Blood MCP-1, but not PTX3, was significantly correlated with SJC, TJC, DAS28, and DAS28-CRP. DAS28-MCP-1 was strongly correlated with DAS28 (r  = 0.984, P<0.001) and DAS28-CRP (r  = 0.971, P<0.001), and modestly correlated with CRP (r  = 0.350, P<0.001), and ESR (r  = 0.386, P<0.001). Similarly, the duration of arthritic symptoms, but not sex, was significantly correlated with variables of arthritic activity. In particular, DAS28-MCP-1 significantly correlated with DAS28 during a 6-month period (r  = 0.944, P<0.001; r  = 0.951, P<0.001; r  = 0.862, P<0.001; and r  = 0.865, P<0.001 for month 0, 1, 3, and 6, respectively). CONCLUSION: Blood MCP-1 and adapted DAS28-MCP-1, but not blood PTX3, may be useful in monitoring RA activity.

Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/ ß -Catenin Signaling and Apoptosis Induction.

Honokiol, an active compound of Magnolia officinalis, exerted many anticancer effects on various types of cancer cells. We explored its effects on the elimination of cancer stem-like side population (SP) cells in human oral squamous cell carcinoma SAS cells. The sorted SP cells possessed much higher expression of stemness genes, such as ABCG2, ABCC5, EpCAM, OCT-4, CD133, CD44, and ß -catenin, and more clonogenicity as compared with the Non-SP cells. After 48 h of treatment, honokiol dose dependently reduced the proportion of SP from 2.53% to 0.09%. Apoptosis of honokiol-treated SP cells was evidenced by increased annexin V staining and cleaved caspase-3 as well as decreased Survivin and Bcl-2. Mechanistically, honokiol inhibited the CD44 and Wnt/ ß -catenin signaling of SP cells. The Wnt signaling transducers such as ß -catenin and TCF-4 were decreased in honokiol-treated SP cells, while the ß -catenin degradation promoting kinase GSK-3 α / ß was increased. Consistently, the protein levels of ß -catenin downstream targets such as c-Myc and Cyclin D1 were also downregulated. Furthermore, the ß -catenin-related EMT markers such as Slug and Snail were markedly suppressed by honokiol. Our findings indicate honokiol may be able to eliminate oral cancer stem cells through apoptosis induction, suppression of Wnt/ ß -catenin signaling, and inhibition of EMT.

Changing cytokine patterns in systemic lupus: a prospective longitudinal study.

BACKGROUND/PURPOSE: We have previously reported that lupus monocytes display distinctively differing patterns of C-reactive protein (CRP)-inducing cytokine interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha secretion when stimulated with either immune complexes (ICs) or lipopolysaccharide (LPS). In this study, we investigated whether the cytokine patterns of peripheral blood mononuclear cells (PBMCs) isolated from lupus patients acquired an IC or LPS pattern, either over time, or following corticosteroid or hydroxychloroquine use. METHODS: PBMCs from lupus patients were obtained at 0, 1, 3, and 6 months post diagnosis and stimulated with ICs or LPS. Cells were obtained for polymerase chain reaction to determine the IL-6, IL-1beta, and TNF-alpha mRNA expression, and were assigned as having acquired either an IC or an LPS pattern. RESULTS: Upon stimulation, the mRNA expression levels of the IL-6 and IL-1beta were significantly higher in IC-pattern PBMCs than in LPS-pattern PBMCs (p= 0.021 and 0.028, respectively). Consistent with this, serum CRP levels in the IC-pattern group were significantly higher than those in the LPS-pattern groups (p = 0.027). Total serum CRP levels were positively correlated with serum C3c and C4 concentrations, and inversely correlated with serum anti-double stranded DNA (anti-dsDNA) levels. Conversely, circulating ICs were positively correlated with serum anti-dsDNA levels and inversely correlated with serum C4 concentrations. CONCLUSION: Within the same individual, the CRP-inducing cytokine patterns can be changed, either naturally or after medication. Pre-existing serum circulating ICs are not predisposed to either IC or LPS cytokine patterns. Finally, CRP levels were correlated with anti-dsDNA consumption.