According to the partial smoke-free legislation implemented on 1 September 2010 in Guangzhou, China, smoke-free did not cover all indoor areas. Some places have a full smoking ban (100 % smoke-free), other places have a partial smoking ban, and homes have no ban. This study aimed to compare the smoking behaviors before and after implementation of a smoke-free legislation.
A repeated cross-sectional survey was conducted on smoking-related behaviors with a total of 4,900 respondents before, and 5,135 respondents after the legislation was instituted. For each wave of the survey, a three-stage stratified sampling process was used to obtain a representative sample. Pearson’s Chi-square test was used to determine differences of smoking prevalence and quit ratio between the two samples. Logistic regression models were used to examine the associations of a smoke-free legislation with smoking behaviors.
The overall daily smoking rate declined significantly from 20.8 % to 18.2 % (p < 0.05), especially among those aged 15–24 years. The quit ratios increased significantly (from 14.5 % to 17.9 %), but remained low among 15–44 year olds. The overall self-reported smoking behaviors in locations with a full smoking ban decreased significantly from 36.4 % to 24.3 % with the greater drops occurring in cultural venues, public transport vehicles, and government offices. Smoking in places with partial smoking bans remained high (89.6 % vs. 90.4 %), although a slight decrease was observed in some of these areas. The implementation of a smoke-free legislation did not lead to more smoking in homes (91.0 % vs 89.4 %), but smoking in homes remained high.
These findings highlight the urgent need for a comprehensive smoke-free legislation covering all public places in Guangzhou, simultaneously educational interventions and campaigns promoting voluntary changes in home smoking need to occur.
Smoke-free; Tobacco control; Smoking
7-O-ethylfangchinoline (YH-200) is a bisbenzylisoquinoline derivative. The aim of this study was to investigate the antidepressant-like action and underlying mechanisms of YH-200 in mice.
Mice were treated with YH-200 (15, 30, and 60 mg/kg, ig) or tetrandrine (30 and 60 mg/kg, ig) before conducting forced swimming test (FST), tail suspension test (TST), or open field test (OFT).
YH-200 (60 mg/kg) significantly decreased the immobility time in both FST and TST, and prolonged the latency to immobility in FST. YH-200 (60 mg/kg) was more potent than the natural bisbenzylisoquinoline alkaloid tetrandrine (60 mg/kg) in FST. Pretreatment with α1-adrenoceptor antagonist prazosin (1 mg/kg), β-adrenoceptor antagonist propranolol (2 mg/kg), dopamine D1/D5 receptor antagonist SCH23390 (0.05 mg/kg), dopamine D2/D3 receptor antagonist haloperidol (0.2 mg/kg) or AMPA receptor antagonist NBQX (10 mg/kg) prevented the antidepressant-like action of YH-200 (60 mg/kg) in FST. In contrast, pretreatment with α2 adrenoceptor antagonist yohimbine (1 mg/kg) augmented the antidepressant-like action of YH-200 (30 mg/kg) in FST. Chronic administration of YH-200 (30 and 60 mg/kg for 14 d) did not produce drug tolerance; instead its antidepressant-like action was strengthened. Chronic administration of YH-200 did not affect the body weight of mice compared to control mice.
YH-200 exerts its antidepressant-like action in mice via acting at multi-targets, including α1, α2 and β-adrenoceptors, D1/D5 and D2 /D3 receptors, as well as AMPA receptors.
depression; antidepressant; 7-O-ethylfangchinoline; tetrandrine; adrenoceptor; dopamine receptor; AMPA receptor; forced swimming test; tail suspension test
Myocardial infarction (MI) has likely contributed to the increased prevalence of heart failure (HF). As a result of reduced cardiac function, splanchnic blood flow decreases, causing ischemia in villi and damage to the intestinal barrier. The induction of heme oxygenase-1 (HO-1) could prevent, or lessen the effects of stress and inflammation. Thus, the effect and mechanism thereof of HO-1 on the intestines of rats with HF was investigated.
Male Wistar rats with heart failure through ligation of the left coronary artery were identified with an left ventricular ejection fraction of < 45% through echocardiography and then divided into various experimental groups based on the type of peritoneal injection they received [MI: saline; MI + Cobalt protoporphyrin (CoPP): CoPP solution; and MI + Tin mesoporphyrin IX dichloride (SnMP): SnMP solution]. The control group was comprised of rats without coronary ligation. Echocardiography was performed before ligation for a baseline and eight weeks after ligation in order to evaluate the cardiac function of the rats. The bacterial translocation (BT) incidence, mesenteric microcirculation, amount of endotoxins in the vein serum, ileum levels of HO-1, carbon oxide (CO), nitric oxide (NO), interleukin (IL)-10, tumour necrosis factor-α (TNF-α), and the ileum morphology were determined eight weeks after the operation.
The rats receiving MI + CoPP injections exhibited a recovery in cardiac function, an amelioration of mesenteric microcirculation and change in morphology, a lower BT incidence, a reduction in serum and ileac NO and TNF-α levels, and an elevation in ileac HO-1, CO, and interleukin-10 (IL-10) levels compared to the MI group (P < 0.05). The rats that received the MI + SnMP injections exhibited results inverse to the MI (P < 0.05) group.
HO-1 exerted a protective effect on the intestines of rats with HF by inhibiting the inflammation and amelioration of microcirculation through the CO pathway. This protective effect could be independent from the recovery of cardiac function.
Carbon monoxide; Heart failure; Heme oxygenase-1; Intestine
Tapiscia sinensis Oliv (Tapisciaceae) is an endangered species native to China famous for its androdioecious breeding system. However, there is a lack of genomic and transcriptome data on this species. In this study, the Tapiscia sinensis transcriptomes from two types of sex flower buds were sequenced. A total of 97,431,176 clean reads were assembled into 52,169 unigenes with an average length of 1116 bp. Through similarity comparison with known protein databases, 36,662 unigenes (70.27%) were annotated. A total of 10,002 (19.17%) unigenes were assigned to 124 pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Additionally, 10,371 simple sequence repeats (SSRs) were identified in 8608 unigenes, with 16,317 pairs of primers designed for applications. 150 pairs of primers were chosen for further validation, and the 68 pairs (45.5%) were able to produce clear polymorphic bands. Six polymorphic SSR markers were used to Bayesian clustering analysis of 51 T. sinensis individuals. This is the first report to provide transcriptome information and to develop large-scale SSR molecular markers for T. sinensis. This study provides a valuable resource for conservation genetics and functional genomics research on T. sinensis for future work.
Tapiscia sinensis; transcriptome; Illumina sequencing; EST-SSRs (Expressed sequence tag simple sequence repeats)
Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.
We aimed to evaluate the therapeutic effect and safety of transcatheter arterial embolization with various volume ratios of lipiodol and ethanol in a rabbit VX2 tumor model to identify the optimal volume ratio.
Eighteen adult male New Zealand white rabbits implanted with VX2 tumors in their left liver lobes were randomly divided into six groups based on volume ratios of lipiodol to ethanol: group A, 3:1; group B, 2:1; group C, 1:1; group D, 1:2; group E, 1:3; and group F, 1:4. Pre- and post-treatment unenhanced magnetic resonance imaging was used to detect tumor formation and evaluate tumor growth rates. Liver samples were harvested one week after the procedure, and apoptosis index of tumor tissues was evaluated by pathologic examination and TUNEL assay.
Tumor size decreased in groups B, C, and D, but increased in groups A, E, and F. Tumor growth rates in groups A–F were 0.40±0.03, −0.11±0.21, −0.08±0.09, −0.12±0.07, 0.06±0.12, and 0.05±0.09, respectively. The change in tumor size was significantly different in group A compared with the rest of the groups, but no significant difference was observed among groups B–F. Apoptosis indexes of the six groups were 4.7±2.1%, 6.7±2.1%, 11.7±3.1%, 11.0±2.0%, 10.7±3.2%, and 12±3%, respectively. Apoptosis index was significantly lower in group A compared with groups C–F (P < 0.05). Apoptosis index of group B was significantly lower than groups C and F. There was no significant difference among the other groups.
The volume ratios of lipiodol to ethanol ranging from 2:1 to 1:4 were equally effective, the ratios 2:1 and 1:3 had equal safety, and the ratios 1:1 and 1:2 indicated better long-term therapeutic effect. Increasing ethanol in the mixture caused more severe liver injury. Optimal efficacy and safety was achieved with a lipiodol to ethanol volume ratio of 1:1.
Talin-1 is a cytoskeletal protein that plays an important role in tumourgenesis, migration and metastasis in several malignant tumors. The aim of this study was to evaluate the expression and prognostic value of Talin-1 in nasopharyngeal carcinoma (NPC).
Talin-1 mRNA and protein expression were examined in NPC cell lines and clinical nasopharyngeal tissues by quantitative RT-PCR, agarose gel electrophoresis and western blotting. The expression of Talin-1 was analyzed by immunohistochemical staining in 233 paraffin-embedded NPC specimens with clinical follow-up data and cox regression analysis was used to identify independent prognostic factors. The functional role of Talin-1 in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by the wound healing and transwell invasion assays.
The expression of Talin-1 was significantly upregulated in most NPC cell lines and clinical tissues at both the mRNA and protein levels. High expression of Talin-1 was significantly associated with distant metastasis (P = 0.001) and patient death (P = 0.001). In addition, high expression of Talin-1 was associated with significantly poorer overall survival (OS: HR, 2.15; 95% CI, 1.28-3.63; P = 0.003) and poorer distant metastasis-free survival (DMFS: HR, 2.39; 95% CI, 1.38-4.15; P = 0.001). Cox regression analysis indicated that high expression of Talin-1 and TNM stage were independent prognostic indicators (both P < 0.05). Stratified analysis demonstrated that high expression of Talin-1 was associated with significantly poorer survival in patients with advanced stage disease (stage III-IV, HR, 1.91; 95% CI, 1.09-3.35; P = 0.02 for OS and HR, 2.22; 95% CI, 1.24-3.99; P = 0.006 for DMFS). Furthermore, the depletion of Talin-1 suppressed the migratory and invasive ability of NPC cells in vitro.
Our data demonstrate that high expression of Talin-1 is associated with significantly poorer OS and poorer DMFS in NPC and depletion of Talin-1 expression inhibited NPC cell migration and invasion. Talin-1 may serve as novel prognostic biomarker in NPC.
Talin-1; Nasopharyngeal carcinoma; Prognosis; Biomarker
Gαq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to alleviate pathological cardiomyocyte hypertrophy induced by various factors. Pathological cardiac hypertrophy increases the morbidity and mortality of cardiovascular diseases while it compensates for poor heart function. This study was designed to investigate the effects of GCIP-27 on heart function in rats with heart failure induced by doxorubicin.
Methods and Results
Forty-eight rats were randomly divided into the following six groups receiving vehicle (control), doxorubicin (Dox), losartan (6 mg/kg, i.g.) and three doses of GCIP-27 (10, 30, 90 μg/kg; i.p., bid), respectively. Heart failure was induced by Dox, which was administered at a 20 mg/kg cumulative dose. After 10 weeks of treatment, we observed that GCIP-27 (30, 90 μg/kg) significantly increased ejection fraction, fraction shortening, stroke volume and sarcoplasmic reticulum Ca2+ ATPase activity of Dox-treated hearts. Additionally, GCIP-27 decreased myocardial injury, heart weight index and left ventricular weight index, fibrosis and serum cardiac troponin-I concentration in Dox-treated mice. Immunohistochemistry, western blotting and real-time PCR experiments indicated that GCIP-27 (10–90 μg/kg) could markedly upregulate the protein expression of myocardial α-myosin heavy chain (MHC), Bcl-2, protein kinase C (PKC) ε and phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 as well as the mRNA expression of α-MHC, but downregulated the expression of β-MHC, Bax and PKC βII, and the mRNA expression levels of β-MHC in Dox-treated mice. It was also found that GCIP-27 (30, 90 μg/L) decreased cell size and protein content of cardiomyocytes significantly in vitro by comparison of Dox group.
GCIP-27 could effectively ameliorate heart failure development induced by Dox. PKC–ERK1/2 signaling might represent the underlying mechanism of the beneficial effects of GCIP-27.
Based on our recent microarray analysis, we found that miR-145 was obviously downregulated in nasopharyngeal carcinoma (NPC) tissues. However, little is known about its function and mechanism involving in NPC development and progression.
Quantitative RT-PCR was used to detect miR-145 expression in NPC cell lines and clinical samples. Wound healing, Transwell migration and invasion, three-dimension spheroid invasion assays, and lung metastasis model were performed to test the migratory, invasive, and metastatic ability of NPC cells. Luciferase reporter assay, quantitative RT-PCR, and Western blotting were used to verify the target of miR-145.
MiR-145 was obviously decreased in NPC cell lines and clinical samples (P<0.01). Ectopic overexpression of miR-145 significantly inhibited the migratory and invasive ability of SUNE-1 and CNE-2 cells. In addition, stably overexpressing of miR-145 in SUNE-1 cells could remarkably restrain the formation of metastatic nodes in the lungs of mice. Furthermore, fascin actin-bundling protein 1 (FSCN1) was verified as a target of miR-145, and silencing FSCN1 with small RNA interfering RNA could suppress NPC cell migration and invasion.
Our findings demonstrated that miR-145 function as a tumor suppressor in NPC development and progression via targeting FSCN1, which could sever as a potential novel therapeutic target for patients with NPC.
Stress induced constant increase of cortisol level may lead to sleep disorder, but the mechanism remains unclear. Here we described a novel model to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). After 7 days treatment of CORT, rats showed significant sleep disturbance, meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO), the remarkable elevation of norepinephrine in LC, VLPO and hypothalamus, as well as increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO after CORT treatment. Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC may play a key role in stress-related sleep disorders and support the hypothesis that repeated CORT treatment may decrease GR levels and induce the activation of noradrenergic neurons in LC, consequently inhibit GABAergic neurons in VLPO and result in sleep disorders. Our findings provide novel insights into the effect of stress-inducing agent CORT on sleep and GRs' role in sleep regulation.
We demonstrate a newly-developed magneto-fluorescent carbon nanotube (CNT) mediated siRNA (CNT-siRNA) delivery system, which significantly silences our target of interest, gastrin-releasing peptide receptor (GRP-R), in neuroblastoma. CNT-siGRP-R resulted in a 50% silencing efficiency and a sustained efficacy of 9 days for one-time siRNA treatment in vitro, whereas siRNA delivered by the commercial transfection reagent couldn’t knockdown GRP-R expression. We further show that CNT-siRNA efficiently inhibits the growth of subcutaneous xenograft tumors in vivo. This system allows us to track the CNT-siRNA distribution via both near-infrared fluorescence and magnetic resonance imaging. Moreover, our delivery system can be used to knockdown GRP-R expression in other cancer cell types, such as human breast cancer cells. The high efficiency and sustained efficacy may indicate that the natural stacking interactions between CNTs and siRNAs can protect siRNAs from degradation and enhance their stability during the delivery process.
CNT; siRNA; Fluorescence; MRI; Neuroblastoma; GRP-R
Regular use of aspirin after diagnosis is associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. In this study, we showed that clinically achievable concentrations of aspirin and ABT-737 in combination could induce a synergistic growth arrest in several human PIK3CA wild-type cancer cells. In addition, our results also demonstrated that long-term combination treatment with aspirin and ABT-737 could synergistically induce apoptosis both in A549 and H1299 cells. In the meanwhile, short-term aspirin plus ABT-737 combination treatment induced a greater autophagic response than did either drug alone and the combination-induced autophagy switched from a cytoprotective signal to a death-promoting signal. Furthermore, we showed that p38 acted as a switch between two different types of cell death (autophagy and apoptosis) induced by aspirin plus ABT-737. Moreover, the increased anti-cancer efficacy of aspirin combined with ABT-737 was further validated in a human lung cancer A549 xenograft model. We hope that this synergy may contribute to failure of aspirin cancer therapy and ultimately lead to efficacious regimens for cancer therapy.
aspirin; ABT-737; combination; p38
A new epitetrathiodioxopiperizine, secoemestrin D (1), five sesterterpenoids bearing a new carbon skeleton, emericellenes A–E (2–6), together with previously known fungal metabolites, sterigmatocystin (7), arugosin C (8), and epiisoshamixanthone (9), were obtained from the endophytic fungal strain Emericella sp. AST0036 isolated from a healthy leaf tissue of Astragalus lentiginosus. The planar structures and relative configurations of the new metabolites 1–6 were elucidated using MS, 1D and 2D NMR spectroscopic data. All compounds were evaluated for their potential anticancer activity using a panel of six tumor cell lines and normal human fibroblast cells. Only metabolites 1 and 7 showed cytotoxic activity. More importantly, secoemestrin D (1) exhibited significant cytotoxicity with IC50s ranging from 0.06–0.24 µM and moderate selectivity to human glioma (SF-268) and metastatic breast adenocarcinoma (MDA-MB-231) cell lines.
Mitochondria and the ER form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein PTPIP51 to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to ALS and FTD perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.
AIM: To investigate the effects of Glytan on splanchnic hemodynamics and its reduction of portal pressure in portal hypertensive rats.
METHODS: Glytan (Ganluotong in Chinese), is composed of salvianolic acid B and diammonium glycyrrhizinate. Portal hypertension (PHT) was induced in the rats by common bile duct ligation (BDL). Hemodynamic studies were performed using the colored microsphere method. Radioimmunoassay (RIA) was used to determine endothelin (ET)-1 levels in the mesenteric circulation. Western blotting methods were used to investigate the effect of Glytan on ET A receptor (ETAR), ET B receptor (ETBR), endothelial NO synthase (eNOS), G-protein-coupled receptor kinase (GRK)2, and β-arrestin 2 expression in the mesentery. The mRNA of ETAR and ETBR was determined using real-time polymerase chain reaction.
RESULTS: Treatment with Glytan reduced portal pressure (PP) and portal territory blood flow (PTBF) and increased both mean arterial pressure (MAP) and splanchnic vascular resistance (SVR). Especially at 4 wk, PP decreased by about 40%, while MAP increased by 13%, SVR increased by 12%, and PTBF decreased by about 21%. The effect of blood flow reduction was greatest in the mesentery (about 33%) at 4 wk. The mesenteric circulation ET-1 levels of BDL rats were lower and negatively correlated with PP at 4 wk. Glytan can increase mesenteric ET-1 content and inhibit ETBR, eNOS, GRK2, and β-arrestin 2 expression in the mesentery. Moreover, Glytan showed no effect on the expression of ETAR protein and mRNA.
CONCLUSION: The decreased PP and PTBF observed after Glytan treatment were related to increased mesenteric vasoconstriction and increased receptor sensitivity to vasoconstrictor.
Glytan; Portal hypertension; Hemodynamics; Mesentery; Endothelin-1; Receptor; Sensitivity
Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007–0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2–16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma.
non-small cell lung cancer; gefitinib; targeted therapy
AIM: To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism.
METHODS: Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 μg/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1β, interferon-γ, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 μmol/L) before treatment with LPS.
RESULTS: In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.
CONCLUSION: FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages.
Farnesoid X receptor; Nonalcoholic fatty liver disease; GW4064; Nonalcoholic fatty liver disease activity score; Lipopolysaccharide-induced hepatic inflammation; Macrophage activation
Trans-activating response region (TAR) DNA-binding protein of 43 kDa (TDP-43) is an RNA-binding protein that is mutated in familial amyotrophic lateral sclerosis (ALS). Disease-linked mutations in TDP-43 increase the tendency of TDP-43 to aggregate, leading to a corresponding increase in formation of stress granules, cytoplasmic protein/RNA complexes that form in response to stress. Although the field has focused on stress granules, TDP-43 also forms other types of RNA granules. For example, TDP-43 is associated with RNA granules that are prevalent throughout the dendritic arbor in neurons. Because aggregation of TDP-43 is also important for the formation of these neuronal RNA granules, we hypothesized that disease-linked mutations might alter granule formation even in the absence of stress. We now report that ALS-linked mutations in TDP-43 (A315T and Q343R) increase the size of neuronal TDP-43 granules in the dendritic arbor of rat hippocampal neurons. The mutations correspondingly reduce the granule density, movement, and mobility of TDP-43 granules. Depolarization of rat hippocampal neurons with KCl stimulates TDP-43 granule migration into dendrites, but A315T and Q343R TDP-43 granules migrate shorter distances and into fewer dendrites than wild-type TDP-43. These findings highlight novel elements of TDP-43 biology that are affected by disease-linked mutations and suggest a neuronally selective mechanism through which TDP-43 mutations might elicit neuronal dysfunction.
G3BP; induced pluripotent stem cells; stress granule; TIA-1; trafficking; translation
The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1336-5) contains supplementary material, which is available to authorized users.
Amyotrophic lateral sclerosis; C9ORF72; Expanded repeat; Frontotemporal dementia; Repeat-associated non-ATG translation; Poly(GA) proteins; Proteasome activity; ER stress
Studies conducted in the past mostly rely on models of functional health literacy in adult populations. However, such models do not satisfy the need for health intervention in adolescents. The identification of key factors influencing adolescents' health literacy is essential in developing effective prevention and intervention measures. This study aimed to test a theoretical model of predictors on health skills and health behaviors in adolescents.
A cross-sectional survey was conducted in Guangdong using a multi-stage stratified cluster sample design. A representative random sample of 3821 students aged 13–25 years was selected using multi-stage stratified cluster sampling. The path analysis was used to test a hypothesized model of health literacy.
The path analysis showed that knowledge of infectious disease (β = 0.26), health skills (β = 0.22), health concept (β = 0.20), general health knowledge (β = 0.15), gender (β = 0.12), and school performance (β = 0.06) had positive direct effect on health behaviors in adolescents. The explanatory variables accounted for 43% of the variance in explaining health behaviors. Knowledge of infectious disease (β = 0.30), health concept (β = 0.17), general health knowledge (β = 0.13), and school performance (β = 0.05) had positive indirect effect on health behaviors through the impacts on health skills.
This study identified several direct and indirect factors influencing health skills and health behaviors in adolescents. These findings will assist health professionals designing effective health interventions that aim to improve health skills and health behaviors in adolescents.
Examining deaths caused by anaphylaxis may help identify factors that may decrease the risk of these unfortunate events. However, information on fatal anaphylaxis is limited. The objectives of our study were to examine all cases of fatal anaphylaxis in Ontario to determine cause of death, associated features, co factors and trends in mortality. The identification of these factors is important for developing effective strategies to overcome gaps in monitoring and treatment of patients with food allergies and risk for anaphylaxis.
This was a retrospective case-series analysis of all causes of anaphylaxis-related deaths using data from the Ontario Coroner’s database between 1986 and 2011. Quantitative data (e.g. demographic) were analyzed using descriptive statistics and frequency analysis using SPSS. Qualitative data were analyzed using content analysis of grounded theory methodology.
We found 92 deaths in the last 26 years related to anaphylaxis. Causes of death, in order of decreasing frequency, included food (40 cases), insect venom (30 cases), iatrogenic (16 cases), and idiopathic (6 cases). Overall, there appears to be a decline in the frequency of food related deaths, but an increase in iatrogenic causes of fatalities. We found factors associated with fatal anaphylaxis included: delayed epinephrine administration, asthma, allergy to peanut, food ingestion outside the home, and teenagers with food allergies.
Our findings indicate the need to improve epinephrine auto-injector use in acute reactions, particularly for teens and asthmatics with food allergies. In addition, education can be improved among food service workers and food industry in order to help food allergic patients avoid potentially fatal allergens. The increasing trend in iatrogenic related anaphylaxis is concerning, and requires monitoring and more investigation.
Anaphylaxis; Severe allergic reaction; Anaphylaxis mortality; Food allergy; Medication allergy; Adverse drug reaction; Venom allergy; Insect sting allergy; Iatrogenic anaphylaxis
The transition from liver fibrosis to hepatocellular carcinoma (HCC) has been suggested to be a continuous and developmental pathological process. MicroRNAs (miRNAs) are recently discovered molecules that regulate the expression of genes involved in liver disease. Many reports demonstrate that miR-483-5p and miR-483-3p, which originate from miR-483, are up-regulated in HCC, and their oncogenic targets have been identified. However, recent studies have suggested that miR-483-5p/3p is partially down-regulated in HCC samples and is down-regulated in rat liver fibrosis. Therefore, the aberrant expression and function of miR-483 in liver fibrosis remains elusive. In this study, we demonstrate that overexpression of miR-483 in vivo inhibits mouse liver fibrosis induced by CCl4. We demonstrate that miR-483-5p/3p acts together to target two pro-fibrosis factors, platelet-derived growth factor-β and tissue inhibitor of metalloproteinase 2, which suppress the activation of hepatic stellate cells (HSC) LX-2. Our work identifies the pathway that regulates liver fibrosis by inhibiting the activation of HSCs.
liver fibrosis; microRNA; HSCs; transgenic mice
The authors investigated the utility of an intravascular magnetic resonance (MR) contrast agent, poly-L-lysine-gadolinium diethylenetriaminepentaacetic acid (DTPA), for differentiating acutely ischemic from normally perfused myocardium with first-pass MR imaging. Hypoperfused regions, identified with microspheres, on the first-pass images displayed significantly decreased signal intensities compared with normally perfused myocardium (P < .0007). Estimates of regional myocardial blood content, obtained by measuring the ratio of areas under the signal intensity-versus-time curves in tissue regions and the left ventricular chamber, averaged 0.12 mL/g ± 0.04 (n = 35), compared with a value of 0.11 mL/g ± 0.05 measured with radiolabeled albumin in the same tissue regions. To obtain MR estimates of regional myocardial blood flow, in situ calibration curves were used to transform first-pass intensity-time curves into content-time curves for analysis with a multiple-pathway, axially distributed model. Flow estimates, obtained by automated parameter optimization, averaged 1.2 mL/min/g ± 0.5 [n = 29), compared with 1.3 mL/min/g ± 0.3 obtained with tracer microspheres in the same tissue specimens at the same time. The results represent a combination of T1-weighted first-pass imaging, intravascular relaxation agents, and a spatially distributed perfusion model to obtain absolute regional myocardial blood flow and volume.
Contrast agent, blood pool; Contrast enhancement; Coronary vessels, diseases, 54.76; Heart, flow dynamics; Heart, MR, 51.12143; Model, mathematical; Myocardium, blood supply, 511.12143; Myocardium, MR, 511.12143; Perfusion studies
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that acts as a prognostic marker for several human malignancies. In this study, we investigated the clinical significance of CIP2A and its function in nasopharyngeal carcinoma (NPC).
Quantitative RT-PCR, western blot, and immunohistochemistry analyses were used to quantify CIP2A expression in NPC cell lines and clinical samples. Kaplan-Meier curves were used to estimate the association between CIP2A expression and patient survival. The functional role of CIP2A in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and xenograft growth.
CIP2A levels were upregulated in NPC cell lines and clinical samples at both the mRNA and protein levels (P < 0.01). Patients with high CIP2A expression had poorer overall survival (HR, 1.98; 95% CI, 1.16-3.34; P = 0.01) and poorer disease-free survival (HR, 1.68; 95% CI, 1.07-2.62; P = 0.02) rates than patients with low CIP2A expression. In addition, CIP2A expression status was an independent prognostic indicator for NPC patients. The depletion of CIP2A expression inhibited c-Myc protein expression in NPC cell lines, suppressed cell viability, colony formation, and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo.
Our data demonstrate that high CIP2A expression in patients was associated with poor survival in NPC, and depletion of CIP2A expression inhibited NPC cell proliferation and tumor growth. Thus, these results warrant further investigation of CIP2A as a novel therapeutic target for the treatment of NPC.
Nasopharyngeal carcinoma; CIP2A; Proliferation; Cell growth; Survival
We present a successful combined endovascular repair of a rare huge spontaneous pseudoaneurysm in a patient troubled solely with fever of unknown origin.
A 79-year-old Chinese man complained of repeated episodes of fever for 10 days. His medical history, physical examination and laboratory tests were not significant. Routine antibiotics were given for suspected sepsis lasting 4 weeks without clinical improvement. Finally, an 81.9×61.6mm iliac pseudoaneurysm was found. The pseudoaneurysm originated from his left iliac arteries and covered the bifurcation of the left common iliac artery and proximal ends of both internal and external iliac arteries. A combination of endovascular repair with coil embolization and stent graft implantation was successfully performed. He underwent an uneventful recovery.
Spontaneous pseudoaneurysm with fever of unknown origin should not be ignored, especially for patients with a high risk for atherosclerosis. Combined transcatheter managements might be an alternative approach to deal with complex pseudoaneurysms, effectively and safely.