Percutaneous coronary intervention (PCI), fibrinolysis and the combination of both methods are current therapeutic options for patients with ST-segment elevation myocardial infarction (STEMI).

Progranulin (PGRN) is an autocrine growth factor with tumorigenic roles in various tumors including cervical cancer. In this study, we investigated mammalian target of rapamycin (mTOR) signaling in response to PGRN induction and the contribution of the PGRN-stimulated PI3K/Akt/mTOR signaling pathway in the transformation and progression of cervical cancer. Here we identified a strong linkage between PGRN and phosphorylated-mTOR in cervical cancer tissues. PGRN promoted the phosphorylation of mTOR and activated mTOR signaling in human cervical mucosa epithelial cells and cervical cancer cells, and TNFR2 was needed for PGRN-stimulated mTOR signaling. Inhibition of mTOR signaling with rapamycin decreased PGRN-stimulated protein synthesis, transformation and proliferation of cervical cells in vitro, and tumor formation and growth in vivo. Thus, our findings update the signal transduction pathways of PGRN by suggesting that mTOR signaling contributes to PGRN-stimulated carcinogenesis of cervical cancer. Inhibition of PGRN/PI3K/Akt/mTOR signaling may be targeted in treatment of cervical cancer.

Hematopoietic stem and progenitor cells have the capacity to self-renew and differentiate into all blood cell lineages, and thus sustain life-long homeostasis of the hematopoietic system. Although intensive studies have focused on the orchestrated genetic network of hematopoietic stem and progenitor cell specification and expansion, relatively little is known on the regulation of hematopoietic stem and progenitor cell survival during embryogenesis. Here, we generated two types of miR-142a-3p genetic mutants in zebrafish and showed that the loss-of-function mutants displayed severe reduction of hematopoietic stem and progenitor cells. Further analysis showed that the diminished proliferation and excessive apoptosis in miR-142a-3p mutants were attributed to the increased p53 signaling. Mechanistically, we demonstrated that miR-142a-3p directly targets p53 during hematopoietic stem and progenitor cell development, and the hematopoietic stem and progenitor cell survival defect in miR-142a-3p mutants could be rescued by loss of p53. Therefore, our work reveals the significance of the miR-142a-3p-p53 pathway in controlling hematopoietic stem and progenitor cell survival, and thus advances our understanding of the role of p53 in vertebrate hematopoiesis.

To investigate the association between single nucleotide polymorphism 12 in estrogen receptor α gene and hypospadias, four databases (PubMed, Web of Science, Embase and Cochrane Library) were electronically searched by 2nd November 2015. Finally, four studies were included for our meta-analysis, involving 1379 cases and 1648 controls. A quality assessment was performed using the Newcastle-Ottawa Scale of case-control study. Meta-analysis and publication bias measuring were all done by Stata 12.0. No significant publication bias (PBegg = 0.296, PEgger = 0.161) was found. Overall, there was statistically significant association for recessive genetic model (AA vs. GA + GG: OR 3.45, 95 % CI [1.89, 6.30], P = 0.038). Moreover, the positive result was confirmed using trial sequential analysis even only three original studies. For allele model, there was also statistically significant association (allele A vs. G: OR 1.43, 95 % CI [1.23, 1.67], P = 0.034). Meanwhile, A allele as a risk factor turned out to be true positive by trial sequential analysis. In a word, this meta-analysis suggested that the single nucleotide polymorphism 12 definitely increase the risk of hypospadias.

The present study aimed to examine the functional role of miR-223 in the regulation of mast cell apoptosis. Overexpressed miR-223 in mast cells transfected by Lipofectamine 2000 was used as a model, and miR-223 was found to promote mast cell apoptosis. To investigate the underlying mechanisms involved, the potential and putative target molecules of miR-223 were detected by bioinformatical analysis using predictive software, and western blotting. Insulin-like growth factor-1 receptor (IGF-1R) was found to be the functional target of miR-223 in the promotion of cell apoptosis. The downstream PI3K/protein kinase B (Akt) signaling pathway was also inhibited, and signaling was mediated by IGF-1R. Furthermore, the relative luciferase activity of the reporter containing the 3'-untranslated region (3'-UTR) of IGF-1R was significantly suppressed, while suppression of miR-223-inhibited IGF-1R protein expression was also observed. In conclusion, the results suggest that IGF-1R is the functional target for miR-223 promotion of cell apoptosis, and its downstream PI3K/Akt signaling pathway was suppressed by miR-223 through targeting of IGF-1R.

CD36, a scavenger receptor, plays an important role in the progression of atherosclerosis through its interaction with oxidized low-density lipoprotein (ox-LDL). Porphyromonas gingivalis (P. gingivalis, Pg) has been shown to promote macrophage-derived foam cell formation by affecting the expression of CD36. However, the regulatory role of CD36 in macrophages infected with Pg remains largely unknown. Therefore, the aim of the present study was to explore the molecular mechanism of Pg induced CD36 expression in macrophages. Our results showed that Pg promoted ox-LDL uptake by macrophages and the formation of foam cells. Pg infection increased CD36 mRNA and protein levels in ox-LDL-untreated macrophages. Moreover, small interferon RNA (siRNA) targeting CD36 significantly reduced foam cell formation induced by Pg. Additionally, Pg stimulated nuclear translocation of p65, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of p65, NF-κB or ERK1/2 blocked Pg-induced CD36 production; whereas, overexpression of NF-κB subunits p65 and p50 upregulated CD36. Furthermore, Ras inhibitors significantly attenuated ERK1/2 activation and CD36 expression. Taken together, the data indicated that stimulation of the ERK/NF-κB pathway by Pg led to transactivation of the CD36 promoters, thereby upregulating CD36 expression in the infected macrophages. These findings may help design new treatment strategies in atherosclerosis.

Patients with treatment-resistant depression (TRD) and those with treatment-response depression (TSD) respond to antidepressants differently and previous studies have commonly reported different brain networks in resistant and nonresistant patients. Using the amplitude of low-frequency fluctuations (ALFF) approach, we explored ALFF values of the brain regions in TRD and TSD patients at resting state to test the hypothesis of the different brain networks in TRD and TSD patients.

Parasitic helminths need to suppress the host immune system to establish chronic infections. Paradoxically, immunosuppression induced by the worm also benefits the host by limiting excessive inflammation and tissue damage, which remains the major cause leading to serious morbidity and mortality. Regulatory T cells (Tregs) are key immune regulators of this mutualism. The successive rise in Tregs during schistosome infection plays a critical role in immunoregulation. We and others previously showed that Schistosoma japonicum (S. japonicum) egg antigens (SEA) induce Tregs both in vitro and in vivo. In addition, we identified that SjHSP60 derived from SEA significantly induces Tregs in vivo and in vitro. However, the contribution of SjHSP60 in SEA to Treg induction and the related mechanisms of the Treg induction have not yet been identified.

In clinical studies, the findings on sulfur mustard (SM) toxicity for CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocyte subsets are contradictory. In animal experiments, the effect of SM on the T cell number and proliferation is incompatible and is even the opposite of the results in human studies. In this study, we observed the dynamic changes of T lymphocytes in the first week in a high-dose SM-induced model.

Members of the microRNA (miR)-30 family have been reported to promote adipogenesis and inhibit osteogenesis, yet their role in the regulation of thermogenesis remains unknown. In this study, we show that miR-30b/c concentrations are greatly increased during adipocyte differentiation and are stimulated by cold exposure or the β-adrenergic receptor activator. Overexpression and knockdown of miR-30b and -30c induced and suppressed, respectively, the expression of thermogenic genes such as UCP1 and Cidea in brown adipocytes. Forced expression of miR-30b/c also significantly increased thermogenic gene expression and mitochondrial respiration in primary adipocytes derived from subcutaneous white adipose tissue, demonstrating a promoting effect of miRNAs on the development of beige fat. In addition, knockdown of miR-30b/c repressed UCP1 expression in brown adipose tissue in vivo. miR-30b/c targets the 3'-untranslated region of the receptor-interacting protein 140 (RIP140), and overexpression of miR-30b/c significantly reduced RIP140 expression. Consistent with RIP140 as a target of miR-30b/c in regulating thermogenic gene expression, overexpression of RIP140 greatly suppressed the promoting effect of miR-30b/c on the expression of UCP1 and Cidea in brown adipocytes. Taken together, the data from our study identify miR-30b/c as a key regulator of thermogenesis and uncover a new mechanism underlying the regulation of brown adipose tissue function and the development of beige fat.

Angiogenesis is spatially and temporally orchestrated by a myriad of signaling pathways, including the Notch signaling pathway. Here, we identified UXT as an evolutionarily conserved and developmentally expressed protein, indispensable for intersegmental vessel (ISV) formation in zebrafish. Deficiency of UXT in zebrafish embryos results in shorter ISVs, loss of tip cell behavior, and impairment of endothelial cell migration and division. Significantly, UXT attenuates the expression of the Notch-responsive genes in vitro and in vivo. Mechanistically, UXT binds to the promoters of the Notch signaling target genes and specifically interacts with the transactivation region domain of the Notch intracellular domain (NICD), impairing the interaction between NICD and the transcription factor RBP-Jκ endogenously. This prevents RBP-Jκ/CSL from activation and thus inhibits the consequent gene inductions. Furthermore, blockade of Notch signaling rescues the angiogenesis defect caused by UXT knockdown both in vitro and in vivo. Taken together, the data presented in this study characterize UXT as a novel repressor of Notch signaling, shedding new light on the molecular regulation of angiogenesis.

Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis. Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system. Netrin-1 exhibits dual activities in angiogenesis: either promoting or inhibiting angiogenesis. The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor. However, how netrin-1 promotes angiogenesis remained unclear. Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1. Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner. Conditional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-1-induced angiogenesis. In zebrafish embryos, downregulating either netrin-1a or CD146 results in vascular defects with striking similarity. Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression. Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development.

Resistance to pathogens is important for the sustainability and profitability of food fish production. In immune-related genes, the lipopolysaccharide-binding protein (LBP) gene is an important mediator of the inflammatory reaction. We analyzed the cDNA and genomic structure of the LBP gene in tilapia. The full-length cDNA (1901 bp) of the gene contained a 1416 bp open reading frame, encoding 471 amino acid residues. Its genomic sequence was 5577 bp, comprising 15 exons and 14 introns. Under normal conditions, the gene was constitutively expressed in all examined tissues. The highest expression was detected in intestine and kidney. We examined the responses of the gene to challenges with two bacterial pathogens Streptcoccus agalactiae and Aeromonas hydrophila. The gene was significantly upregulated in kidney and spleen post-infection with S. agalactiae and A. hydrophila, respectively. However, the expression profiles of the gene after the challenge with the two pathogens were different. Furthermore, we identified three SNPs in the gene. There were significant associations (p < 0.05) of two of the three SNPs with the resistance to A. hydrophila, but not with the resistance to S. agalactiae or growth performance. These results suggest that the LBP gene is involved in the acute-phase immunologic response to the bacterial infections, and the responses to the two bacterial pathogens are different. The two SNPs associated with the resistance to A. hydrophila may be useful in the selection of tilapia resistant to A. hydrophila.

Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.

Radiation-induced pulmonary fibrosis is a common disease and has a poor prognosis owing to the progressive breakdown of gas exchange regions in the lung. Recently, a novel strategy of administering mesenchymal stem cells for pulmonary fibrosis has achieved high therapeutic efficacy. In the present study, we attempted to use human adipose tissue-derived mesenchymal stem cells to prevent disease in Sprague-Dawley rats that received semi-thoracic irradiation (15 Gy). To investigate the specific roles of mesenchymal stem cells in ameliorating radiation-induced pulmonary fibrosis, we treated control groups of irradiated rats with human skin fibroblasts or phosphate-buffered saline. After mesenchymal stem cells were infused, host secretions of hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) were elevated compared with those of the controls. In contrast, tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-β1) levels were decreased after infusion of mesenchymal stem cells. Consequently, the architecture of the irradiated lungs was preserved without marked activation of fibroblasts or collagen deposition within the injured sites. Moreover, mesenchymal stem cells were able to prevent the irradiated type II alveolar epithelial cells from undergoing epithelial-mesenchymal transition. Collectively, these data confirmed that mesenchymal stem cells have the potential to limit pulmonary fibrosis after exposure to ionising irradiation.

To summarize the evidence regarding the treatment effect of adjuvant hormone therapy (AHT) in patients with prostate cancer (PCa). AHT following radiotherapy, chemotherapy, or surgery is widely used in patients with PCa. However, the treatment effect is inconsistent in individual trials.

The plant-specific WRKY transcriptional regulatory factors have been proven to play vital roles in plant growth, development, and responses to biotic and abiotic stresses. However, there are few studies on the WRKY gene family in sugarcane (Saccharum spp.). In the present study, the characterization of a new subgroup, IIc WRKY protein ScWRKY3, from a Saccharum hybrid cultivar is reported. The ScWRKY3 protein was localized in the nucleus of Nicotiana benthamiana leaves and showed no transcriptional activation activity and no toxic effects on the yeast strain Y2HGold. An interaction between ScWRKY3 and a reported sugarcane protein ScWRKY4, was confirmed in the nucleus. The ScWRKY3 gene had the highest expression level in sugarcane stem pith. The transcript of ScWRKY3 was stable in the smut-resistant Saccharum hybrid cultivar Yacheng05-179, while it was down-regulated in the smut-susceptible Saccharum hybrid cultivar ROC22 during inoculation with the smut pathogen (Sporisorium scitamineum) at 0⁻72 h. ScWRKY3 was remarkably up-regulated by sodium chloride (NaCl), polyethylene glycol (PEG), and plant hormone abscisic acid (ABA), but it was down-regulated by salicylic acid (SA) and methyl jasmonate (MeJA). Moreover, transient overexpression of the ScWRKY3 gene in N. benthamiana indicated a negative regulation during challenges with the fungal pathogen Fusarium solani var. coeruleum or the bacterial pathogen Ralstonia solanacearum in N. benthamiana. The findings of the present study should accelerate future research on the identification and functional characterization of the WRKY family in sugarcane.

Seven-spot ladybird beetles, Coccinella septempunctata L., are critical aphidophagous predators in the agricultural environment. Thiamethoxam, a neonicotinoid insecticide, is commonly used for controlling pests but impairs their natural enemies at the same time. To improve effective IPM (integrated pest management) strategies, we evaluated the sublethal and transgenerational effects of thiamethoxam on C. septempunctata. Our results showed that thiamethoxam at doses of 0.1 × LC10 (0.053 mg L-1) and LC10 (0.53 mg L-1) significantly reduced adult emergence, fecundity and fertility of the parental generation. In unexposed progeny (F1) of thiamethoxam-exposed parents, at the two doses 0.1 × LC10 and LC10, the larval stage was prolonged, and total longevity was decreased by 18.76 and 24.46%, respectively. The higher concentrations (0.1 × LC10 and LC10) also decreased the fecundity by 33.74 and 46.56%, respectively, and the oviposition period by 19.67 and 25.01%, respectively. In addition, demographic parameters including the intrinsic rate of increase (r), finite rate of increase (λ), net reproductive rate (R0), and mean generation time (T) were significantly reduced when exposed to LC10. Moreover, the predation activity of the F1 generation was reduced by the transgenerational effects of LC10. These results disclose negative influence of thiamethoxam at sublethal concentrations on this ladybird predator and its subsequent generation.

Adjuvant chemotherapy has become the frequently adopted standard therapeutic approach for non-small cell lung cancer (NSCLC). However, the development of multidrug resistance (MDR) is a major obstacle contributing to the failure of chemotherapy. This study aimed to identify genes associated with MDR development that predict tumor response to chemotherapy in NSCLC. In the present study, a multidrug-resistant NSCLC cell sub-line, A549/MDR, was established from the A549/DDP cell line and characterized. The resistance index (RI) of this subline was calculated according to the IC50 of A549/MDR relative to the parental A549/DDP cells. The gene expression profiles of A549/DDP and A549/MDR were obtained using an oligonucleotide microarray (Agilent SureHyb microarray chip). The microarray results were validated by qRT-PCR and selected genes were analyzed by in vitro loss-of-function experiments. Gene expression profiling identified 921 differentially expressed genes (DEGs) according to the selection criteria, in which 541 genes were upregulated and 380 genes were downregulated in A549/MDR compared with A549/DDP cells. We found that these DEGs are involved in diverse biological processes, including ribonucleoprotein complex, drug metabolism, the Hippo signaling pathway and transcriptional misregulation. NOLC1, as one of the identified DEGs, was confirmed to be overexpressed in A549/MDR cells and its knockdown significantly enhanced the drug sensitivity of A549/MDR cells in response to multidrug treatment. Furthermore, knockdown of NOLC1 downregulated the expression levels of drug resistance-associated molecules (LRP and MDR1) in A549/MDR cells. These findings provide a new and comprehensive expression profile of MDR in NSCLC cells. Identification and validation of NOLC1 might be a promising therapeutic strategy for the management of MDR of NSCLC patients.

Purpose: Adiposity is one of the important determinants of blood pressure. The aim of this study is to evaluate the association between blood pressure and body composition indices throughout the whole lifespan of healthy adults. Patients and Methods: This study was from an ongoing cross-sectional survey of the Chinese health wherein data included basic physiological parameters. Partial Pearson correlation analysis was used to assess the correlation between blood pressure and body composition indices. Multiple linear regression analysis was used to assess the association of body mass index, lean mass percent, and visceral fat rating against blood pressure in each age group. Results: In the whole population stratified by gender, while body mass index had the highest r-value of correlation with systolic blood pressure in both males (r = 0.296, p < 0.001) and females(r = 0.237, p < 0.001), and fat mass percent had the highest r-value of correlation with diastolic blood pressure in males (r = 0.351, p < 0.001) and females(r = 0.277, p < 0.001), the strength of association with blood pressure were similar across most of the body composition indices. In multiple linear regression analysis, both body mass index and visceral fat rating were positively while lean mass percent was negatively associated with blood pressure in all age groups in both genders, whereas all the association was weaker in the elderly compared to the younger. Conclusion: Maintain the total body fat in a favorable range and appropriately increase the body muscle mass is a strategy to reduce the occurrence of cardiovascular event by decreasing the risk of hypertension through the whole adult life.