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Chronic low-grade inflammation is regarded to an important signature of atherosclerosis (AS). Macrophage (Mψ) and related polarization have been demonstrated to play a crucial role in the occurrence and development of AS inflammation. Butyrate, a bioactive molecule produced by the intestinal flora, has been increasingly demonstrated to exhibit a vital role for regulating the inflammation in chronic metabolic diseases. However, the effectiveness and multiple anti-inflammation mechanisms of butyrate on AS still need to be further understood. ApoE-/- mice fed with high-fat diet as AS model were administered with sodium butyrate (NaB) for 14 weeks of treatment. Our results showed that the atherosclerotic lesion in the AS group was dramatically reduced after NaB intervention. Moreover, deteriorated routine parameters of AS including body weights (BWs), low-density lipoprotein (LDL-C), triglyceride (TG), total cholesterol (TC) were significantly reversed by NaB administration. Abnormal elevated plasma and aorta pro-inflammatory indicators including interleukin (IL)-1β, IL-6, IL-17A, tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS), as well as reduced anti-inflammatory IL-10 in plasma were respectively rectified after NaB administration. Consistently, accumulated Mψ and associated imbalance of polarization in the arota were attenuated with NaB treatment. Importantly, we demonstrated that the suppression of Mψ and associated polarization of NaB was dependent on binding G-protein coupled receptor (GPR) and inhibiting histone deacetylase HDAC3. Moreover, we found that intestinal butyrate-producing bacteria, anti-inflammatory bacteria and intestinal tight junction protein zonula occludens-1 (ZO)-1 may contribute to this effectiveness. Intriguingly, according to transcriptome sequencing of atherosclerotic aorta, 29 elevated and 24 reduced miRNAs were found after NaB treatment, especially miR-7a-5p, suggesting that non-coding RNA may possess a potential role in the protection of NaB against AS. Correlation analysis showed that there were close complicated interactions among gut microbiota, inflammation and differential miRNAs. Collectively, this study revealed that dietary NaB may ameliorate atherosclerotic inflammation by regulating Mψ polarization via GPR43/HDAC-miRNAs axis in ApoE-/- mice.

There are currently no preventive or disease-modifying therapies for Parkinson's Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSC) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSC derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the α-synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiated and aged neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-α-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.

BackgroundPatients with coronary heart disease (CHD) often experience anxiety, but the current studies on anxiety mostly focused on a certain point in time. Therefore, this study aimed to investigate the dynamic changes of peri-procedure anxiety, status of post-procedure quality of life, and cardiovascular readmission rates in patients with CHD who undergoing elective percutaneous coronary intervention (PCI), and to analyze the influence of peri-procedure anxiety on quality of life and readmission rate after PCI.MethodsThis prospective study was conducted at Changshu NO.1 People's Hospital. A total of 220 patients with CHD undergoing elective PCI were selected as study subjects. The general information, clinical data, anxiety, quality of life and readmission of patients were collected. Multivariate linear regression was used to examine the effect of peri-procedure anxiety on quality of life, and multivariate logistic regression was used to analyze the influence of peri-procedure anxiety on readmission rate.ResultsThis study showed the anxiety scores at hospitalization appointment(T1), 3 days before procedure(T2), 1 day before procedure(T3), 1 day after procedure(T4) were 57(55,61),64(61,68),54(51.58), and 54(50,60), respectively. And, at 3 months and 6 months after PCI, the scores of Seattle Angina Questionnaire (SAQ) were 346.61(319.06,366.52) and 353.34(334.18,372.84) respectively. During 6 months follow-up, 54 cases were readmitted, with a readmission rate of 25.5%. Statistical analysis showed that T1 with anxiety (P = 0.002) and T2 with anxiety (P = 0.024) were independent risk factors for treatment satisfaction at 3 months after PCI. Anxiety in T4 (P = 0.005) was an independent risk factor on the angina frequency at 6 months after PCI. T2 with anxiety (B = 1.445, P = 0.010, 95%CI:1.409-12.773) and T4 without anxiety (B = -1.587, P = 0.042, 95%CI:-0.044-0.941) were risk factors affecting readmission for cardiovascular reasons within 6 months.ConclusionPatient anxiety at T1 and T2 affects the treatment satisfaction dimension of the SAQ at 3 months after PCI, and anxiety at T4 affects the angina frequency dimension of the SAQ at 6 months after PCI. Anxiety at T2 and no anxiety at T4 increase short-term readmission rates. In the future, interventions should be strengthened at various time points in the peri-procedure period to improve post-procedure rehabilitation effect.

BackgroundAs a malignant tumor with poor prognosis, accurate and effective prediction of the prognosis of pancreatic cancer (PC) is crucial.MethodsA total of 12,909 patients diagnosed with pancreatic cancer were selected from the Surveillance, Epidemiology, and End Results program between 2004 and 2016. The sex, age, ethnicity, marital status, metastasis status, radiotherapy, chemotherapy, tumor size, regional nodes examined, regional nodes positive of each patient were recorded. Univariate and multivariate Cox regression analyses were used to identify prognostic factors with a threshold of PResultsAge, year of diagnosis, sex, grade, histologic, marital, TNM stage, surgery of the primary site, tumor size, regional nodes positive and regional nodes examined ratio (LNR), lymph node dissection, radiotherapy, and chemotherapy were identified as prognostic factors for the construction of the nomogram. The nomogram exhibited a clinical predictive ability of 0.675(95% CI, 0.669~0.681) in the internal verification. The predicted calibration curve was similar to the standard curve. Decision curve analysis showed that the nomogram had value in terms of clinical application. Besides, the nomogram was able to divide the patients into different groups according to total points.ConclusionsHence, our nomogram was highly effective in predicting overall survival in patients with PC, which may provide a reference tool for clinicians to guide individualized treatment and follow-ups for patients with PC, accurately determine the 1-,3- and 5-year overall survival of patients.

OBJECTIVE:PTH1-34 (parathyroid hormone 1-34) is the only clinical drug to promote osteogenesis. MSCs (mesenchymal stem cells) have multidirectional differentiation potential and are closely related to fracture healing. This study was to explore the effects of PTH1-34 on proliferation and differentiation of endothelial cells and MSCs in vitro, and on angiogenesis, and MSCs migration during fracture healing in vivo. METHODS:Mice with stabilized fracture were assigned to 4 groups: CON, PTH (PTH1-34 40 μg/kg/day), MSC (transplanted with 105 MSCs), PTH+MSCs. Mice were sacrificed 14 days after fracture, and callus tissues were harvested for microCT scan and immunohistochemistry analysis. The effects of PTH1-34 on angiogenesis, and MSCs differentiation and migration were assessed by wound healing, tube formation and immunofluorescence staining. RESULTS:Treatment with either PTH1-34, or MSCs promoted bone healing and vascular formation in fracture callus. The callus bone mass, bone volume, and bone mineral density were all greater in PTH and/or MSC groups than they were in CON (p50μm). Expression of CD31 within calluses and trabecular bones were significantly higher in PTH1-34 treated group than that of not (p

Cathepsin K (CTSK) is a member of cysteine proteinase family, and is predominantly expressed in osteoclastsfor degradationof bone matrix proteins. Given the similarity in physical properties of bone and dental mineralized tissues, including enamel, dentin and cementum, CTSK is likely to take part in mineralization process during odontogenesis. On the other hand, patients with pycnodysostosis caused by mutations of the CTSK gene displayedmultipledental abnormalities, such as hypoplasia of the enamel, obliterated pulp chambers, hypercementosis and periodontal disease. Thereforeitis necessary to study the metabolic role of CTSK in tooth matrix proteins. In this study, BALB/c mice at embryonic day 18 (E18), post-natal day 1 (P1), P5, P10 and P20 were used (5 mice at each time point)for systematic analyses of CTSK expression in the late stage of tooth germ development. We found that CTSK was abundantly expressed in the ameloblasts during secretory and maturation stages (P5 and P10) by immunohistochemistry stainings.During dentinogenesis, the staining was also intense in the mineralization stage (P5 and P10),but not detectable in the early stage of dentin formation (P1) and after tooth eruption (P20).Furthermore, through zymography and digestion test in vitro, CTSK was proved to be capable of hydrolyzing Emdogain and also cleaving Amelogenininto multiple products. Our resultsshed lights on revealing new functions of CTSK and pathogenesis of pycnodysostosis in oral tissues.

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model.

In this study, a systematic evaluation was conducted to estimate the efficacy and safety of ticagrelor for treating acute coronary syndrome (ACS) in general ACS patients and a diabetes mellitus (DM) group.A search of PubMed, Cochrane Central Register of Controlled Trials, Web of Science, CNKI databases was conducted to analyze relevant randomized controlled trails (RCTs) of ticagrelor treating ACS during 2007 to 2015. Article screening, quality accessing and data extracting was independently undertaken by two reviewers. A meta-analysis was performed to clarify the efficacy and safety of ticagrelor in general ACS patients, and a meta-regression analysis was taken to demonstrate the efficacy and safety of ticagrelor in DM patients compared with general ACS patients.Twenty-two studies with 35004 participants were included. The meta-analysis result implicated that ticagrelor could: 1) reduce the incidence of the composite endpoint [OR = 0.83, 95%CI (0.77, 0.90), P

Exploring the interplay between information spreading and epidemic spreading is a topic that has been receiving increasing attention. As an efficient means of depicting the spreading of information, which manifests as a cascade phenomenon, awareness cascading is utilized to investigate this coupled transmission. Because in reality, different individuals facing the same epidemic will exhibit distinct behaviors according to their own experiences and attributes, it is important for us to consider the heterogeneity of individuals. Consequently, we propose a heterogeneous spreading model. To describe the heterogeneity, two of the most important but radically different methods for this purpose, the degree and k-core measures, are studied in this paper through three models based on different assumptions. Adopting a Markov chain approach, we succeed in predicting the epidemic threshold trend. Furthermore, we find that when the k-core measure is used to classify individuals, the spreading process is robust to these models, meaning that regardless of the model used, the spreading process is nearly identical at the macroscopic level. In addition, the k-core measure leads to a much larger final epidemic size than the degree measure. These results are cross-checked through numerous simulations, not only of a synthetic network but also of a real multiplex network. The presented findings provide a better understanding of k-core individuals and reveal the importance of considering network structure when investigating various dynamic processes.

BACKGROUND:The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations. METHODS:hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 10(6) differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice. RESULTS:The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo. CONCLUSIONS:IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation.

Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (β-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF.

AIMS: Interindividual variability in telomere length is highly heritable. Leukocyte telomere length (LTL) shortening has been shown to be associated with the process of atherosclerosis. But whether the inheritance of LTL is related to stroke is still unclear. The aim of this study was to test if telomere shortening was associated with stroke and whether this association was mainly due to inheritance or acquired cardiovascular risk factors. METHODS: Our study was focused on stroke in patients and their siblings. 450 subjects were recruited into this study: 150 patients with ischemic stroke as case group, 150 siblings of patients free of stroke (sibling group) and 150 healthy people as normal control. LTL was measured by real-time Polymerase Chain Reactions. The association between LTL and the cardiovascular risk factors was also determined. RESULTS: A significant decrease of LTL was found in case group when comparing with sibling (0.92±0.77 vs 1.68±1.24, p

Nitric oxide (NO) plays essential roles in many biotic and abiotic stresses in plant development procedures, including pollen tube growth. Here, effects of NO on cold stress inhibited pollen germination and tube growth in Camellia sinensis were investigated in vitro. The NO production, NO synthase (NOS)-like activity, cGMP content and proline (Pro) accumulation upon treatment with NO scavenger cPTIO, NOS inhibitor L-NNA, NO donor DEA NONOate, guanylate cyclase (GC) inhibitor ODQ or phosphodiesterase (PDE) inhibitor Viagra at 25°C (control) or 4°C were analyzed. Exposure to 4°C for 2 h reduced pollen germination and tube growth along with increase of NOS-like activity, NO production and cGMP content in pollen tubes. DEA NONOate treatment inhibited pollen germination and tube growth in a dose-dependent manner under control and reinforced the inhibition under cold stress, during which NO production and cGMP content promoted in pollen tubes. L-NNA and cPTIO markedly reduced the generation of NO induced by cold or NO donor along with partly reverse of cold- or NO donor-inhibited pollen germination and tube growth. Furthermore, ODQ reduced the cGMP content under cold stress and NO donor treatment in pollen tubes. Meanwhile, ODQ disrupted the reinforcement of NO donor on the inhibition of pollen germination and tube growth under cold condition. Additionally, Pro accumulation of pollen tubes was reduced by ODQ compared with that receiving NO donor under cold or control condition. Effects of cPTIO and L-NNA in improving cold-treated pollen germination and pollen tube growth could be lowered by Viagra. Moreover, the inhibitory effects of cPTIO and L-NNA on Pro accumulation were partly reversed by Viagra. These data suggest that NO production from NOS-like enzyme reaction decreased the cold-responsive pollen germination, inhibited tube growth and reduced Pro accumulation, partly via cGMP signaling pathway in C. sinensis.

P2X purinoceptor 7 (P2X7R), an ATP-gated ion channel, plays an important role during the innate immune response in mammals. However, relatively little is known about the role of P2X7R in the fish immune system. Here, we cloned a cDNA sequence encoding ayu (Plecoglossus altivelis) P2X7R (aP2X7R). The predicted protein was composed of 574 amino acid residues with a P2X family signature, two transmembrane domains, and a long C-terminal. aP2X7R transcripts were mainly distributed in ayu immune tissues and significantly increased in all tested tissues and in macrophages after Listonella anguillarum infection. The aP2X7R protein was upregulated significantly in macrophages upon bacterial challenge. An antibody against the ectodomain of aP2X7R (aEPAb) and an antagonist (oATP) were used to block aP2X7R. aP2X7R siRNA was also used to knockdown the receptor expression in ayu macrophages. Cell death induced by ATP was significantly inhibited in ayu macrophages after aEPAb, oATP, or siRNA treatment. Moreover, aP2X7R ablation also resulted in suppression of phagocytic activity and ATP-induced bacterial killing in ayu macrophages. Our results indicated that aP2X7R was upregulated after infection and mediated cell death, phagocytosis, and bacterial killing of ayu macrophages. [ABSTRACT FROM AUTHOR]

Background and Objectives: Studies investigating the association between glutathione S-transferase M1 (GSTM1) gene polymorphism and laryngeal cancer risk have reported conflicting results. The aim of the present study was to conduct a meta-analysis assessing the possible associations of GSTM1 gene polymorphism with laryngeal cancer risk. Methods: The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge and Chinese National Knowledge Infrastructure until May 2011 and selected on the basis of the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize association of GSTM1 polymorphism with laryngeal cancer susceptibility. Results: Seventeen studies were included instudies showed that GSTM1 null genotype was associated with increased laryngeal cancer risk (OR= 1.17, 95% CI = 1.04~1.31). When stratifying for race, GSTM1 null genotype exhibited increased laryngeal cancer risk in Caucasians (OR=1.15, 95% CI = 1.01~1.31), while no significant association was detected in Asians (OR=1.25, 95% CI = 0.80~1.96). In the subgroup analysis based on source of controls, significant associations were observed in the population-based studies (OR=1.15, 95% CI = 1.01~1.31) yet not in the hospital-based studies (OR = 1.25, 95% CI = 0.93~1.67). Furthermore, in the subgroup analysis based on sample size, significant associations were also found in studies with at least 50 cases and 50 controls (OR = 1.15, 95% CI = 1.02~1.30) but not in studies with fewer than 50 cases or 50 controls (OR = 1.46, 95% CI = 0.87~2.46). Conclusions: This meta-analysis supported that the GSTM1 gene polymorphism was associated with laryngeal cancer, particularly in Caucasians, and these associations varied in different subgroup, which indicated that population-based study with larger sample size was more appropriate in design of future study. [ABSTRACT FROM AUTHOR]

P2X purinoceptor 7 (P2X7R), an ATP-gated ion channel, plays an important role during the innate immune response in mammals. However, relatively little is known about the role of P2X7R in the fish immune system. Here, we cloned a cDNA sequence encoding ayu (Plecoglossus altivelis) P2X7R (aP2X7R). The predicted protein was composed of 574 amino acid residues with a P2X family signature, two transmembrane domains, and a long C-terminal. aP2X7R transcripts were mainly distributed in ayu immune tissues and significantly increased in all tested tissues and in macrophages after Listonella anguillarum infection. The aP2X7R protein was upregulated significantly in macrophages upon bacterial challenge. An antibody against the ectodomain of aP2X7R (aEPAb) and an antagonist (oATP) were used to block aP2X7R. aP2X7R siRNA was also used to knockdown the receptor expression in ayu macrophages. Cell death induced by ATP was significantly inhibited in ayu macrophages after aEPAb, oATP, or siRNA treatment. Moreover, aP2X7R ablation also resulted in suppression of phagocytic activity and ATP-induced bacterial killing in ayu macrophages. Our results indicated that aP2X7R was upregulated after infection and mediated cell death, phagocytosis, and bacterial killing of ayu macrophages. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses and is important in controlling a variety of processes in monocytes and macrophages. However, very little information is available about the functions of HIF-1α in fish monocytes/macrophages (MO/MФ). In this study, the cDNA sequence of the mudskipper (Boleophthalmus pectinirostris) HIF-1α gene (BpHIF-1α) was determined. Sequence comparison and phylogenetic tree analysis showed that BpHIF-1α is clustered in the fish HIF-1α tree. Constitutive expression of BpHIF-1α mRNA was detected by real-time quantitative PCR in all tested tissues, and the expression was found to be dramatically increased in the skin, liver, spleen, and kidney after Edwardsiella tarda infection. In addition, hypoxia and infection induced the expression of the BpHIF-1α transcript and protein in MO/MФ, respectively. Hypoxia caused an increase in phagocytic and bactericidal capacity of mudskipper MO/MФ in a BpHIF-1α-dependent manner. BpHIF-1α induced an anti-inflammatory status in MO/MФ upon E. tarda infection and hypoxia. Therefore, BpHIF-1α may play a predominant role in the modulation of mudskipper MO/MФ function in the innate immune system.

OBJECTIVE:To evaluate the usefulness of skin ultrasound and acoustic radiation force impulse (ARFI) quantification in diffuse cutaneous systemic sclerosis (dcSSc). PATIENTS AND METHODS:28 patients with dcSSc, and 15 age gender matched normal controls were recruited. Skin echogenicity, thickness, and ARFI quantification were measured by ultrasound at 17 sites corresponding to the modified Rodnan skin score (mRSS) in each participant. Compared with controls, skin echogenicity of dcSSc patients was classified into isoechoic, hypoechoic, and hyperechoic. The skin thickness, ARFI quantification and mRSS were compared between isoechoic, hypoechoic, hyperechoic and controls. RESULTS:In patients with dcSSc, the skin thickness increased as the echogenicity changed on the order of isoechoic, hypoechoic and hyperechoic. ARFI quantification was significantly higher in hyperechoic than isoechoic (p

Prostaglandin E2 (PGE2) plays an important role in a broad spectrum of physiological and pathological processes by interacting with E-type prostanoid receptors (EPs). EP4 is one of four EP subtypes known to mediate the immune response in mammalian monocytes/macrophages. However, the precise function and characteristics of EP4 in fish remain unclear. In this study, we characterized a novel EP4-like (PaEP4L) gene from ayu, Plecoglossus altivelis. The cDNA sequence of PaEP4L is 2781 nucleotides (nts) in length, encoding a polypeptide of 459 amino acid residues with a calculated molecular weight of 51.17 kDa. Sequence comparison and phylogenetic tree analysis showed that PaEP4L shared 76% amino acid identity with that of the Atlantic salmon (Salmo salar). PaEP4L mRNA was detected by real-time quantitative PCR (QPCR) in all tested tissues and head kidney-derived monocytes/macrophages (MO/MФ). It varied greatly in liver, spleen and MO/MФ upon Vibrio anguillarum infection. Western blot analysis revealed a significant increase of PaEP4L in cell homogenates from ayu MO/MФ upon V. anguillarum infection. Moreover, anti-PaEP4L IgG reversed the down-regulation of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) mRNA expression as well as phagocytosis in ayu MO/MФ caused by PGE2. There were no significant differences in the respiratory burst response between PGE2 treated and untreated cells. We further found that cAMP mediated PGE2/PaEP4L signal in ayu MO/MФ. In conclusion, our results indicate that PaEP4L mediates PGE2 effects on ayu MO/MФ function, revealing that EP4 also plays a role in the modulation of cells of the fish's innate immune system.

UNLABELLED:Host-pathogen interactions can induce epigenetic changes in the host directly, as well as indirectly through secreted factors. Previously, uropathogenic Escherichia coli (UPEC) was shown to increase DNA methyltransferase activity and expression, which was associated with methylation-dependent alterations in the urothelial expression of CDKN2A. Here, we showed that paracrine factors from infected cells alter expression of another epigenetic writer, EZH2, coordinate with proliferation. Urothelial cells were inoculated with UPEC, UPEC derivatives, or vehicle (mock infection) at low moi, washed, then maintained in media with Gentamycin. Urothelial conditioned media (CM) and extracellular vesicles (EV) were isolated after the inoculations and used to treat naïve urothelial cells. EZH2 increased with UPEC infection, inoculation-induced CM, and inoculation-induced EV vs. parallel stimulation derived from mock-inoculated urothelial cells. We found that infection also increased proliferation at one day post-infection, which was blocked by the EZH2 inhibitor UNC1999. Inhibition of demethylation at H3K27me3 had the opposite effect and augmented proliferation. CONCLUSION:Uropathogen-induced paracrine factors act epigenetically by altering expression of EZH2, which plays a key role in early host cell proliferative responses to infection.

This study aimed to confirm whether strain ratio should be added after evaluation of lesions with 5-point elasticity scoring for differentiating benign and malignant breast lesions on ultrasonographic elastography(UE).From June 2010 to March 2012, 1080 consecutive female patients with breast lesions were recruited into a multicenter retrospective study, which involved 8 centers across China. Each institutional ethic review board approved the study, and all the patients gave written informed consent. All the patients underwent the UE procedure and the strain ratios were calculated and the final diagnosis was made by histological findings. The sensitivity, specificity, accuracy, PPV and NPV were calculated for each of the two evaluation systems and the areas under the ROC curve were compared.The strain ratios of benign lesions (mean, 2.6±2.0) and malignant lesions (mean,7.9±5.8) were significantly different (p 0.05). The strain ratio method shows better a diagnosis performance of the lesions with elasticity score 3 and 4.Although the two UE methods have similar diagnostic performance, separate calculation of the strain ratios seems compulsory, especially for the large solid breast lesions and the lesions with elasticity score 3 and 4.

The aim of this study was to examine the influence of various time intervals on the composition of the supragingival plaque microbiome, especially the dynamic core microbiome, and to find a suitable observation interval for further studies on oral microbiota.Eight qualified volunteers whose respective age ranges from 25 to 28 years participated in the present study. The supragingival plaque was collected from the buccogingival surface of the maxillary first molar at eight time slots with different intervals (day 0, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, and 3 months). Bioinformatic analyses was performed based on 16S rDNA pyrosequencing (454 sequencing platform) targeting at the hypervariable V4-V5 region, in order to assess the diversity and variation of the supragingival plaque microbiome.A total of 359,565 qualified reads for 64 samples were generated for subsequent analyses, which represents 8,452 operational taxonomic units identified at 3% dissimilarity. The dynamic core microbiome detected in the current study included five phyla, 12 genera and 13 species. At the genus level, the relative abundance of bacterial communities under the "1 day," "1 month," and "3 months" intervals was clustered into sub-category. At the species level, the number of overlapping species remained stable between the "1 month" and "3 months" intervals, whereas the number of dynamic core species became stable within only 1 week.This study emphasized the impact of different time intervals (days, weeks and months) on the composition, commonality and diversity of the supragingival microbiome. The analyses found that for various types of studies, the time interval of a month is more suitable for observing the general composition of the supragingival microbiome, and that a week is better for observing the dynamic core microbiome.

Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC.

Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model.Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively.Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups.Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis.

BACKGROUND: Both coronary artery disease (CAD) and diabetes mellitus (DM) are associated with inflammation. However, whether and which leukocytes can predict the presence and extent of CAD in patients with DM has not been investigated. The aim of the present study was to examine the association of leukocyte and its subsets counts with the severity of CAD in patients with DM. METHODS AND FINDINGS: Three hundred and seventy-three diabetic patients who were scheduled for coronary angiography due to typical stable angina pectoris were enrolled in this study. They were classified into the three groups according to tertiles of Gensini score (GS, low group 28, n=121). The relationship between the leukocyte and its subsets counts with the severity of CAD were evaluated. The data indicated that there were significant correlations between leukocyte and neutrophil counts with GS (r=0.154 and 0.156, respectively, all P28 points) was 5.0 × 10(9) cells/L in diabetic patients.

BACKGROUND: Glycated hemoglobin (HbA1c) predicts clinical cardiovascular disease or cardiovascular mortality. However, the relationship between HbA1c and myocardial injury following elective percutaneous coronary intervention (PCI) in patients with type 2 diabetes mellitus (DM) has not been investigated. OBJECTIVES: The study sought to assess the relationship between HbA1c and myocardial injury following elective PCI in patients with type 2 DM. METHODS: We studied a cohort of consecutive 994 diabetic patients with coronary artery disease (CAD) undergoing elective PCI. Periprocedural myocardial injury was evaluated by analysis of troponin I (cTnI). The association between preprocedural HbA1c levels and the peak values of cTnI within 24 hours after PCI was evaluated. RESULTS: Peak postprocedural cTnI > 1×upper limit of normal (ULN), >3×ULN and >5×ULN were detected in 543 (54.6%), 337 (33.9%) and 245 (24.6%) respectively. In the multivariate model, higher HbA1c levels were associated with less risk of postprocedural cTnI >1×ULN (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76-0.95; P = 0.005). There was a trend that higher HbA1c levels were associated with less risk of postprocedural cTnI >3×ULN (OR, 0.90; 95% CI, 0.81-1.02; P = 0.088). HbA1c was not associated with the risk of postprocedural cTnI elevation above 5×ULN (OR, 0.95; 95% CI, 0.84-1.08; P = 0.411). CONCLUSIONS: The present study provided the first line of evidence that higher preprocedural HbA1c levels were associated with less risk of myocardial injury following elective PCI in diabetic patients.