A significant increase in mortality was observed during cold winters in many temperate regions. However, there is a lack of evidence from tropical and subtropical regions, and the influence of ambient temperatures on seasonal variation of mortality was not well documented.
This study included 213,737 registered deaths from January 2003 to December 2011 in Guangzhou, a subtropical city in Southern China. Excess winter mortality was calculated by the excess percentage of monthly mortality in winters over that of non-winter months. A generalized linear model with a quasi-Poisson distribution was applied to analyze the association between monthly mean temperature and mortality, after controlling for other meteorological measures and air pollution.
The mortality rate in the winter was 26% higher than the average rate in other seasons. On average, there were 1,848 excess winter deaths annually, with around half (52%) from cardiovascular diseases and a quarter (24%) from respiratory diseases. Excess winter mortality was higher in the elderly, females and those with low education level than the young, males and those with high education level, respectively. A much larger winter increase was observed in out-of-hospital mortality compared to in-hospital mortality (45% vs. 17%). We found a significant negative correlation of annual excess winter mortality with average winter temperature (rs=-0.738, P=0.037), but not with air pollution levels. A 1 °C decrease in monthly mean temperature was associated with an increase of 1.38% (95%CI:0.34%-2.40%) and 0.88% (95%CI:0.11%-1.64%) in monthly mortality at lags of 0-1 month, respectively.
Similar to temperate regions, a subtropical city Guangzhou showed a clear seasonal pattern in mortality, with a sharper spike in winter. Our results highlight the role of cold temperature on the winter mortality even in warm climate. Precautionary measures should be strengthened to mitigate cold-related mortality for people living in warm climate.
Magnetic resonance imaging; coronary artery disease
Adenosine triphosphate (ATP) is known to be released from the erythrocyte in an oxygen (O2) dependent manner. Since ATP is a potent vasodilator, it is proposed to be a key regulator in the pathway that mediates micro-vascular response to varying tissue O2 demand. We propose that ATP signaling mainly originates in the capillaries due to the relatively long erythrocyte transit times in the capillary and the short ATP diffusion distance to the electrically coupled endothelium. We have developed a computational model to investigate the effect of delivering or removing O2 to limited areas at the surface of a tissue with an idealized parallel capillary array on total ATP concentration. Simulations were conducted when exposing full surface to perturbations in tissue O2 tension (PO2) or locally using a circular micro-outlet (~100 μm in diameter), a square micro-slit (200 × 200 μm), or a rectangular micro-slit (1000 μm wide × 200 μm long). Results indicated the rectangular micro-slit has the optimal dimensions for altering hemoglobin saturations (SO2) in sufficient number capillaries to generate effective changes in total [ATP]. This suggests a threshold for the minimum number of capillaries that need to be stimulated in vivo by imposed tissue hypoxia to induce a conducted micro-vascular response. SO2 and corresponding [ATP] changes were also modeled in a terminal arteriole (9 μm in diameter) that replaces 4 surface capillaries in the idealized network geometry. Based on the results, the contribution of terminal arterioles to the net change in [ATP] in the micro-vascular network is minimal although they would participate as O2 sources thus influencing the O2 distribution. The modeling data presented here provide important insights into designing a novel micro-delivery device for studying micro-vascular O2 regulation in the capillaries in vivo.
adenosine triphosphate (ATP); microcirculation; capillaries; computational model; simulation; local PO2 perturbation; O2 regulation; micro-delivery device
IL-27 promotes the differentiation of monocytes to HIV-resistant macrophages by down-regulating host factor SPTBN1.
The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin β nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1–mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27–treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
Seizure susceptibility to neurological insults, including chemical convulsants, is age-dependent and most likely reflective of overall differences in brain excitability. The molecular and cellular mechanisms underlying development-dependent seizure susceptibility remain to be fully understood. Because the mTOR pathway regulates neurite outgrowth, synaptic plasticity and cell survival, thereby influencing brain development, we tested if exposure of the immature brain to the mTOR inhibitor rapamycin changes seizure susceptibility to neurological insults. We found that inhibition of mTOR by rapamycin in immature rats (3 to 4 weeks old) increases the severity of seizures induced by pilocarpine, including lengthening the total seizure duration and reducing the latency to the onset of seizures. Rapamycin also reduces the minimal dose of pentylenetetrazol (PTZ) necessary to induce clonic seizures. However, in mature rats, rapamycin does not significantly change the seizure sensitivity to pilocarpine and PTZ. Likewise, kainate sensitivity was not significantly affected by rapamycin treatment in either mature or immature rats. Additionally, rapamycin treatment down-regulates the expression of potassium-chloride cotransporter 2 (KCC2) in the thalamus and to a lesser degree in the hippocampus. Pharmacological inhibition of thalamic mTOR or KCC2 increases susceptibility to pilocarpine-induced seizure in immature rats. Thus, our study suggests a role for the mTOR pathway in age-dependent seizure susceptibility.
mTOR; epilepsy; development; rapamycin; seizure; KCC2
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis despite intensive retreatment, due to intrinsic drug resistance1-2. The biological pathways that mediate resistance are unknown. Here we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten pediatric B lymphoblastic leukemia patients using RNA-sequencing. Transcriptome sequencing identified 20 newly acquired novel non-synonymous mutations not present at initial diagnosis, of which two patients harbored relapse specific mutations in the same gene, NT5C2, a 5′-nucleotidase. Full exon sequencing of NT5C2 was completed in 61 additional relapse specimens, identifying five additional cases. Enzymatic analysis of mutant proteins revealed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analogue therapies. Clinically, all patients who harbored NT5C2 mutations relapsed early, or within 36 months of initial diagnosis (p=0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug resistant clones in ALL.
Calcineurin inhibitors (CNIs) may promote post-transplantation cancer through altered expression of cytokines and chemokines in tumor cells. We found that there is a potential cross-talk among CNI-induced signaling molecules and mTOR. Here, we utilized a murine model of post-transplantation cancer to examine the effect of a combination therapy (CNI + mTOR-inhibitor rapamycin) on allograft survival and renal cancer progression. The therapy prolonged allograft survival; and significantly attenuated CNI-induced post-transplantation cancer progression, with down-regulation of mTOR and S6-kinase phosphorylation. Also, rapamycin inhibited CNI-induced over-expression of the angiogenic cytokine VEGF, and the chemokine receptor CXCR3 and its ligands in post-transplantation tumor tissues.
Renal cancer; Angiogenesis; VEGF; Chemokine; Transplantation
Elevated lipoprotein(a) [Lp(a)] levels predict cardiovascular events incidence in patients with coronary artery disease (CAD). Genetic variants in the rs3798220, rs10455872 and rs6415084 single-nucleotide polymorphisms (SNPs) in the Lp(a) gene (LPA) correlate with elevated Lp(a) levels, but whether these SNPs have prognostic value for CAD patients is unknown. The present study evaluated the association of LPA SNPs with incidence of subsequent cardiovascular events in CAD patients after percutaneous coronary intervention (PCI).
TaqMan SNP genotyping assays were performed to detect the rs6415084, rs3798220 and rs10455872 genotypes in 517 Chinese Han patients with CAD after PCI. We later assessed whether there was an association of these SNPs with incidence of major adverse cardiovascular events (MACE: cardiac death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization). Serum lipid profiles were also determined using biochemical methods.
Only the rs6415084 variant allele was associated with higher Lp(a) levels [41.3 (20.8, 74.6) vs. 18.6 (10.3, 40.9) mg/dl, p < 0.001]. During a 2-year follow-up period, 102 patients suffered MACE, and Cox regression analysis demonstrated that elevated Lp(a) (≥30 mg/dl) levels correlated with increased MACE (adjusted HR, 1.69; 95% CI 1.13-2.53), but there was no association between LPA genetic variants (rs6415084 and rs3798220) and MACE incidence (p > 0.05).
Our data did not support a relationship between genetic LPA variants (rs6415084 and rs3798220) and subsequent cardiovascular events after PCI in Chinese Han CAD patients.
Coronary artery disease; Lipoprotein(a); Major adverse cardiovascular events; Percutaneous coronary intervention; Single-nucleotide polymorphism
Camellia, comprising more than 200 species, is a valuable economic commodity due to its enormously popular commercial products: tea leaves, flowers, and high-quality edible oils. It is the largest and most important genus in the family Theaceae. However, phylogenetic resolution of the species has proven to be difficult. Consequently, the interspecies relationships of the genus Camellia are still hotly debated. Phylogenomics is an attractive avenue that can be used to reconstruct the tree of life, especially at low taxonomic levels.
Seven complete chloroplast (cp) genomes were sequenced from six species representing different subdivisions of the genus Camellia using Illumina sequencing technology. Four junctions between the single-copy segments and the inverted repeats were confirmed and genome assemblies were validated by PCR-based product sequencing using 123 pairs of primers covering preliminary cp genome assemblies. The length of the Camellia cp genome was found to be about 157kb, which contained 123 unique genes and 23 were duplicated in the IR regions. We determined that the complete Camellia cp genome was relatively well conserved, but contained enough genetic differences to provide useful phylogenetic information. Phylogenetic relationships were analyzed using seven complete cp genomes of six Camellia species. We also identified rapidly evolving regions of the cp genome that have the potential to be used for further species identification and phylogenetic resolution.
In this study, we wanted to determine if analyzing completely sequenced cp genomes could help settle these controversies of interspecies relationships in Camellia. The results demonstrate that cp genome data are beneficial in resolving species definition because they indicate that organelle-based “barcodes”, can be established for a species and then used to unmask interspecies phylogenetic relationships. It reveals that phylogenomics based on cp genomes is an effective approach for achieving phylogenetic resolution between Camellia species.
AIM: To compare outcome of stapled hemorrhoidopexy (SH) vs LigaSure hemorrhoidectomy (LH) by a meta-analysis of available randomized controlled trials (RCTs).
METHODS: Databases, including PubMed, EMBASE, the Cochrane Library, and the Science Citation Index updated to December 2012, were searched. The main outcomes measured were operating time, early postoperative pain, postoperative urinary retention and bleeding, wound problems, gas or fecal incontinence, anal stenosis, length of hospital stay, residual skin tags, prolapse, and recurrence. The meta-analysis was performed using the free software Review Manager. Differences observed between the two groups were expressed as the odds ratio (OR) with 95%CI. A fixed-effects model was used to pool data when statistical heterogeneity was not present. If statistical heterogeneity was present (P < 0.05), a random-effects model was used.
RESULTS: The initial search identified 10 publications. After screening, five RCTs published as full articles were included in this meta-analysis. Among the five studies, all described a comparison of the patient baseline characteristics and showed that there was no statistically significant difference between the two groups. Although most of the analyzed outcomes were similar between the two operative techniques, the operating time for SH was significantly longer than for LH (P < 0.00001; OR= -6.39, 95%CI: -7.68 - -5.10). The incidence of residual skin tags and prolapse was significantly lower in the LH group than in the SH group [2/111 (1.8%) vs 16/105 (15.2%); P = 0.0004; OR= 0.17, 95%CI: 0.06-0.45). The incidence of recurrence after the procedures was significantly lower in the LH group than in the SH group [2/173 (1.2%) vs 13/174 (7.5%); P = 0.003; OR= 0.21, 95%CI: 0.07-0.59].
CONCLUSION: Both SH and LH are probably equally valuable techniques in modern hemorrhoid surgery. However, LigaSure might have slightly favorable immediate postoperative results and technical advantages.
Stapled hemorrhoidopexy; Ligasure hemorrhoidectomy; Hemorrhoids; Meta-analysis
Yeast 25S rRNA was reported to contain a single cytosine methylation (m5C). In the present study using a combination of RP-HPLC, mung bean nuclease assay and rRNA mutagenesis, we discovered that instead of one, yeast contains two m5C residues at position 2278 and 2870. Furthermore, we identified and characterized two putative methyltransferases, Rcm1 and Nop2 to be responsible for these two cytosine methylations, respectively. Both proteins are highly conserved, which correlates with the presence of two m5C residues at identical positions in higher eukaryotes, including humans. The human homolog of yeast Nop2, p120 has been discovered to be upregulated in various cancer tissues, whereas the human homolog of Rcm1, NSUN5 is completely deleted in the William's-Beuren Syndrome. The substrates and function of both human homologs remained unknown. In the present study, we also provide insights into the significance of these two m5C residues. The loss of m5C2278 results in anisomycin hypersensitivity, whereas the loss of m5C2870 affects ribosome synthesis and processing. Establishing the locations and enzymes in yeast will not only help identifying the function of their homologs in higher organisms, but will also enable understanding the role of these modifications in ribosome function and architecture.
The aim of this study was to investigate the clinical value of serum cytokeratin 19 fragment (CYFRA21-1) and carcinoembryonic antigen (CEA) in the prediction of chemotherapy response and prognosis in patients with advanced non-small cell lung cancer (NSCLC). Serum CYFRA21-1 and CEA levels of 98 patients with advanced NSCLC were measured using immunoradiometric kits prior to and after 2 cycles of chemotherapy. After 2 cycles of chemotherapy, 45 patients achieved a radiological objective response (OR), 30 patients achieved stable disease (SD) and 23 patients had progressive disease (PD). Serum CYFRA21-1 and CEA were significantly decreased compared to baseline levels (P<0.001). By ROC curve analysis, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were the optimal cut-off levels with best sensitivity and specificity for the diagnosis of radiologic OR. The median survival of all patients was 10.2 months (range 2.6–26.3). Univariate survival analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, radiologic OR, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were significant prognostic factors for better overall survival. The median overall survival time in patients with a ≥60% reduction in CYFRA21-1 was significantly longer than in those with a <60% reduction (P<0.001). Similarly, the median overall survival time in patients with a ≥25% reduction in CEA was also significantly longer than in those with a <25% reduction (P<0.001). Multivariate analysis showed that ECOG PS score, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA were independent prognostic factors of survival, while radiologic OR was not. In conclusion, a ≥60% reduction in CYFRA21-1 and a ≥25% reduction in CEA may be reliable surrogate markers for the prediction of chemothrapy response and prognosis, especially for the diagnosis of radiologic OR.
cytokeratin 19 fragment; carcinoembryonic antigen; non-small cell lung cancer; chemotherapy response; prognosis
Marfan syndrome is a systemic connective tissue disease that could affect the cardiovascular system and eventually lead to heart enlargement and heart failure with high mortality, mainly due to progressive heart failure and/or sudden cardiac death caused by malignant arrhythmia. Here we report that a patient received a cardiac resynchronization therapy-defibrillator (CRT-D) with a pre-monitor function for heart failure and experienced obvious improvements in his cardiac function. Postoperative follow-up showed that the patient had reduced morbidity and hospitalization for heart failure, and also experienced improved quality of life.
Acetamiprid (ACE) and imidacloprid (IMI) are two major members in the family of neonicotinoid pesticides, which are synthesized with a higher selectivity to insects. The present study determined and compared in vitro effects of ACE, IMI and nicotine on mammalian reproduction by using an integrated testing strategy for reproductive toxicology, which covered sperm quality, sperm penetration into oocytes and preimplantation embryonic development. Direct chemical exposure (500 µM or 5 mM) on spermatozoa during capacitation was performed, and in vitro fertilization (IVF) process, zygotes and 2-cell embryos were respectively incubated with chemical-supplemented medium until blastocyst formation to evaluate the reproductive toxicity of these chemicals and monitor the stages mainly affected. Generally, treatment of 500 µM or 5 mM chemicals for 30 min did not change sperm motility and DNA integrity significantly but the fertilization ability in in vitro fertilization (IVF) process, indicating that IVF process could detect and distinguish subtle effect of spermatozoa exposed to different chemicals. Culture experiment in the presence of chemicals in medium showed that fertilization process and zygotes are adversely affected by direct exposure of chemicals (P<0.05), in an order of nicotine>IMI>ACE, whereas developmental progression of 2-cell stage embryos was similar to controls (P>0.05). These findings unveiled the hazardous effects of neonicotinoid pesticides exposure on mammalian sperm fertilization ability as well as embryonic development, raising the concerns that neonicotinoid pesticides may pose reproductive risks on human reproductive health, especially in professional populations.
bioorthogonal reactions; cycloaddition; fluorogenic tags; imaging agents; phospholipids
Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces Type-I IFN production. We found that transfection of different types of DNA into various untreated cells induces Type-III IFN (IFN-lambda1) rather than Type-I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that PRDI and ISRE sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-lambda1 induction is associated with the activation of IRF-1 and IRF-7. Thus we show for the first time that Ku70 mediates type III IFN induction by DNA.
Cystic fibrosis (CF) is associated with abnormal lipid metabolism, intense respiratory tract (RT) infection, and inflammation, eventually resulting in lung tissue destruction and respiratory failure. The CF RT inflammatory milieu, as reflected by airway secretions, include a complex array of inflammatory mediators, bacterial products, and host secretions. It is dominated by neutrophils and their proteolytic and oxidative products and includes a wide spectrum of bioactive lipids produced by both host and presumably microbial metabolic pathways. The fairly recent advent of “omics” technologies has greatly increased capabilities of further interrogating this easily obtainable RT compartment that represents the apical culture media of the underlying RT epithelial cells. The current paper discusses issues related to the study of CF omics with a focus on the profiling of CF RT oxylipins. Challenges in their identification/quantitation in RT fluids, their pathways of origin, and their potential utility for understanding CF RT inflammatory and oxidative processes are highlighted. Finally, the utility of oxylipin metabolic profiling in directing optimal therapeutic approaches and determining the efficacy of various interventions is discussed.
cystic fibrosis; inflammation; omics; oxylipins; respiratory tract secretions
Retained respiratory tract (RT) secretions, infection and exuberant inflammatory responses are core abnormalities in cystic fibrosis (CF) lung disease. Factors contributing to the destructive CF airway inflammatory processes remain incompletely characterized. The pro-oxidative inflammatory CF RT milieu is known to contain enzymatically and non-enzymatically produced regulatory lipid mediators, a panel of structurally defined oxidized metabolites of polyunsaturated fatty acids known to play a role in pathology related to inflammation. Using an extraction protocol that maximizes recoveries of sputum-spiked deuterated standards, coupled with an LC/MS/MS detection system, the present study presents a metabolomic method to assess a broad spectrum of regulatory lipid mediators in freshly obtained sputum from CF patients. A broad range of both pro-inflammatory and anti-inflammatory lipid mediators were detected including PGE2, PGD2, TXB2, LTB4, 6-trans-LTB4, 20-OH-LTB4, 20-COOH-LTB4, 20-HETE, 15-HETE, 11-HETE, 12-HETE, 8-HETE, 9-HETE, 5-HETE, EETs, diols, Resolvin E1, 15-deoxy-PGJ2 and LXA4. The vast majority of these oxylipins have not been reported previously in CF RT secretions. Whereas direct associations of individual proinflammatory lipid mediators with compromised lung function (FEV1) were observed, the relationships were not robust. However, multiple statistical analyses revealed that the regulatory lipid mediators profile taken in aggregate proved to have a stronger association with lung function in relatively stable outpatient adult CF patients. Our data reveal a relative paucity of the anti-inflammatory lipid mediator lipoxin A4 (LXA4) in CF sputum. Patients displaying detectable levels of the anti-inflammatory lipid mediator Resolvin E1 demonstrated a better lung function compared to those patients with undetectable levels. Our data suggest that comprehensive metabolomic profiling of regulatory lipid mediators in CF sputum should contribute to a better understanding of the molecular mechanisms underlying CF RT inflammatory pathobiology. Further studies are required to determine the extent to which nutritional or pharmacological interventions alter the regulatory lipid mediators profile of the CF RT and the impact of potential modulations of RT regulatory lipid mediators on the clinical progression of CF lung disease.
Metabolomics; Regulatory Lipid Mediators; Cystic Fibrosis; Sputum; LC/MS/MS
DNA damaging agents typically induce an apoptotic cascade in which p53 plays a central role. However, absence of a p53-mediated response does not necessarily abrogate programmed cell death, due to the existence of p53-independent apoptotic pathways, such as those mediated by the pro-apoptotic molecule ceramide. We compared ceramide levels before and after DNA damage in human osteosarcoma (U2OS) and colon cancer (HCT116) cells that were either expressing or deficient in p53. When treated with mitomycin C, p53-deficient cells, but not p53-expressing cells, showed a marked increase in ceramide levels. Microarray analysis of genes involved in ceramide metabolism identified acid ceramidase (ASAH1, up-regulated), ceramide glucosyltransferase (UGCG, down-regulated), and galactosylceramidase (GALC, up-regulated) as the three genes most affected. Experiments employing pharmacological and siRNA agents revealed that inhibition of UGCG is sufficient to increase ceramide levels and induce cell death. When inhibition of UGCG and treatment with mitomycin C were combined, p53-deficient, but not p53-expressing cells, showed a significant increase in cell death, suggesting that the regulation of sphingolipid metabolism could be used to sensitize cells to chemotherapeutic drugs.
Ceramide; Apoptosis; Ceramide glucosyltransferase; p53; HPV16 E6
Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. There is evidence that dihydrocapsaicin (DHC) can exert multiple pharmacological and physiological effects. Here, we explored the effect of DHC in atherosclerotic plaque progression in apoE−/− mice fed a high-fat/high-cholesterol diet.
Methods and Results
apoE−/− mice were randomly divided into two groups and fed a high-fat/high-cholesterol diet with or without DHC for 12 weeks. We demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased following treatment with DHC in THP-1 macrophage-derived foam cells. We also observed that plasma levels of TG, LDL-C, VLDL-C, IL-1β, IL-6, TNF-α and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and consistent with this, atherosclerotic lesion development was significantly inhibited by DHC treatment of apoE−/− mice fed a high-fat/high-cholesterol diet. Moreover, treatment with both LXRα siRNA and PPARγ siRNA made the up-regulation of DHC on ABCA1, ABCG1, ABCG5, SR-B1, NPC1, CD36, LDLR, HMGCR, apoA1 and apoE expression notably abolished while made the down-regulation of DHC on SRA1 expression markedly compensated. And treatment with PPARγ siRNA made the DHC-induced up-regulation of LXRα expression notably abolished while treatment with LXRα siRNA had no effect on DHC-induced PPARγ expression.
These observations provide direct evidence that DHC can significantly decrease atherosclerotic plaque formation involving in a PPARγ/LXRα pathway and thus DHC may represent a promising candidate for a therapeutic agent for the treatment or prevention of atherosclerosis.
MicroRNA-21 (miR-21) is overexpressed in most inflammatory diseases, but its physiological role in gut inflammation and tissue injury is poorly understood. The goal of this work is to understand the role of miR-21 in colitis and damage progression of intestine in a genetically modified murine model.
Experimental colitis was induced in miR-21 KO and wild-type (WT) mice by 3.5% dextran sulphate sodium (DSS) administration for 7 days. Disease activity index(DAI), blood parameters, intestinal permeability, histopathologic injury, cytokine and chemokine production, and epithelial cells apoptosis were examined in colons of miR-21 KO and WT mice.
miR-21 was overexpressed in intestine of inflammatory bowel diseases (IBD) and acute intestinal obstruction (AIO) patients when compared with normal intestinal tissues. Likewise, miR-21 was up-regulated in colon of IL-10 KO mice when compared with control mice. WT mice rapidly lost weight and were moribund 5 days after treatment with 3.5% DSS, while miR-21 KO mice survived for at least 6 days. Elevated leukocytes and more severe histopathology were observed in WT mice when compared with miR-21 KO mice. Elevated levels of TNF-α and macrophage inflammatory protein-2(MIP-2) in colon culture supernatants from WT mice exhibited significant higher than miR-21 KO mice. Furthermore, CD3 and CD68 positive cells, intestinal permeability and apoptosis of epithelial cells were significantly increased in WT mice when compared with miR-21 KO mice. Finally, we found that miR-21 regulated the intestinal barrier function through modulating the expression of RhoB and CDC42.
Our results suggest that miR-21 is overexpressed in intestinal inflammation and tissue injury, while knockout of miR-21 in mice improve the survival rate in DSS-induced fatal colitis through protecting against inflammation and tissue injury. Therefore, attenuated expression of miR-21 in gut may prevent the onset or progression of inflammatory bowel disease in patients.
In recent years, epidemiologic studies have reported controversial results relating cigarette smoking to myelodysplastic syndromes (MDS) risk. A meta-analysis was performed to assess such potential relationship between cigarette smoking and incidence of MDS.
A search of literature published before October 2012 for observational studies evaluating the association between cigarette smoking and MDS, returned 123 articles and of these, 14 were selected for this study. The outcomes from these studies were calculated and reported as odds ratios (OR). Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the I2 index and source of heterogeneity was detected by sensitivity analyses. Finally, publication bias was assessed through visual inspection of funnel plots and Egger’s test.
The pooled OR of developing MDS in ever-smokers was 1.45 (95% CI, 1.25 to 1.68) versus non-smokers. Current and former smokers had increased risks of MDS, with ORs of 1.81 (95% CI, 1.24 to 2.66) and 1.67 (95% CI, 1.42 to 1.96), respectively. In subset analyses, ever-smokers had increased risks of developing MDS if they were living in the United States, or in Europe, female in gender, had refractory anemia (RA)/RA with ringed sideroblasts (RARS) or RA with excess blasts (RAEB)/RAEB in transformation (RAEBt), respectively. Our results demonstrated that the association was stronger in individuals who smoked ≥20 cigarettes/day (OR, 1.62; 95% CI, 1.03 to 2.55) versus those who smoked <20 cigarettes/day (OR, 1.36; 95% CI, 1.13 to 1.64). Moreover, individuals who smoked more than 20 pack-years had increased MDS risk (OR, 1.94; 95% CI, 1.29 to 2.92).
Our outcomes show that smoking increases the risk of developing MDS in ever-smokers who are current or former smokers. We also demonstrate here that positive association between cigarette smoking and risk of MDS exists, and occurs in a dose-dependent manner.
Myeloperoxidase (MPO) is an endogenous oxidant enzyme that produces reactive oxygen species (ROS) and may be involved in lung carcinogenesis. The MPO−463G>A polymorphism influences MPO transcription and has been associated with lung cancer susceptibility. However, the association between the MPO−463G>A polymorphism and lung cancer risk remains controversial.
To investigate the effect of this polymorphism on lung cancer susceptibility, we performed a meta-analysis based on 22 published case–control studies including 7,520 patients with lung cancer and 8,600 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
Overall, there was no evidence for significant association between MPO−463G>A polymorphism and lung cancer susceptibility (for AA versus GG: OR = 0.91, 95%CI = 0.67–1.24; for GA versus GG: OR = 0.87, 95% CI = 0.78–0.98; for AA/GA versus GG: OR = 0.90, 95% CI = 0.80–1.01; for AA versus GA/GG: OR = 0.96, 95% CI = 0.72–1.28). In the stratified analyses by ethnicity, source of controls and smoking status, we also did not find any significant association between them.
In summary, this meta-analysis suggests MPO−463G>A polymorphism may not be a risk factor for developing lung cancer. However, further prospective well-designed population-based studies with larger sample size are expected to validate the results.
Left atrial (LA) function plays an important role in the maintenance of cardiac output, however, in patients with constrictive pericarditis (CP), whether pericardial restriction and adhesion can lead to LA dysfunction, and the characteristics of LA function remain unclear. The aim of the study is to compare the left atrial (LA) function of patients with CP to that of healthy study participants using speckle tracking echocardiography (STE) and conventional echocardiography.
Methods and Results
Thirty patients with CP and 30 healthy volunteers (controls) were enrolled in the study. The underlying cause of CP was viral pericarditis in 24 (80%) patients and unknown in 6 (20%) patients. The LA maximum volume (Vmax), LA minimal volume (Vmin), and LA volume before atrial contraction (Vpre-a) were measured using biplane modified Simpson’s method. The LA expansion index (LA reservoir function) was determined as follows: ([LAVmax - LAVmin]/LAVmin) ×100. The passive emptying index (LA conduit function) was calculated as follows: ([LAVmax - LAVpre-a]/LAVmax) ×100, and the active emptying index (booster pump function) was calculated as follows: ([LAVpre-a - LAVmin]/LAVpre-a) ×100. All the patients underwent two-dimensional STE. The LA global systolic strain (S), systolic strain rate (SrS), early diastolic strain rate (SrE) and late diastolic strain rate (SrA) were measured. The LA expansion index, passive emptying index, the active emptying index and the LA global S, SrS, SrE, SrA were found to be significantly lower in patients with CP than in the control participants (P <0.001). LA function was correlated with the early diastolic velocity of the lateral mitral annulus (P <0.05).
Although left ventricular systolic function was preserved in patients with CP, the LA reservoir, conduit, and booster functions were impaired. Pericardial restriction and impairment of the LA myocardium may play an important role in the reduction of LA function in patients with CP.